Monthly Archives: March 2022

Testosterone Injections: Are They Right for You?

Posted: March 25, 2022 at 2:21 am

Testosterone

Testosterone is a male steroid hormone that does a lot more for men than just promote a healthy sex drive. The hormone affects several other factors in your health, including body fat, muscle mass, bone density, red blood cell count, and mood.

Normal testosterone levels are between 300 and 1,000 ng/dL. If a blood test shows that your levels are far below the norm, your doctor may suggest testosterone injections. These are a form treatment called testosterone replacement therapy.

Testosterone injections are most often given by your doctor. The injection site is typically in the gluteal muscles in the buttocks. However, your doctor may allow you to self-administer the injections. In that case, the injection site would be in your thigh muscles.

Men naturally start losing some of their testosterone when they hit their 30s or 40s. A more rapid decline in testosterone levels may indicate a problem called low testosterone (low T). Common symptoms of low T include:

Some men may also have changes in the size of their penis and testicles. Others may have breast swelling.

Some men may want to diagnose themselves with low T. The problem with self-diagnosis is that many of the symptoms of low T are normal parts of aging, so using them for diagnosis isnt reliable. A doctor-ordered testosterone level test is the only way to find out if your testosterone levels are too low.

When you see your doctor, they will take a thorough health history and do a physical exam. In addition to a blood test to measure your testosterone levels, youll also likely have a test that measures your red blood cell count. Testosterone injections can increase your red blood cell count, so this test is done to make sure you arent at risk of a dangerous increase in these cells.

If your exam and tests reveal that you have low T, your doctor may suggest testosterone injections.

The purpose of testosterone injections is to help regulate male hormone levels to help address problems related to low T. For men with low T, the benefits of these injections can include:

Men generally have less body fat than women. This is partly related to testosterone, which regulates fat distribution and muscle maintenance in your body. With low T, youll likely notice an increase in body fat, especially around your midsection.

Your hormones also help regulate muscle growth. So, with low T, you may feel like youre losing muscle size or strength. However, this only occurs if your low T is prolonged and severe.

Testosterone shots can help regulate fat distribution, but you shouldnt expect significant weight changes from hormone therapy alone. As for muscle maintenance, testosterone therapy has been found to help increase muscle mass, but not strength.

Low sperm count is a common side effect of low T. This problem can make it difficult if you and your partner are trying to get pregnant. However, if low T is to blame for problems with conception, dont count on testosterone injections to help. Testosterone therapy can itself lead to reduced sperm counts, especially at high doses.

According to GoodRx.com, the cost of 1 mL (200 mg/mL) of Depo-Testosterone is about $30. The same amount of testosterone cypionate, the generic version of that drug, runs about $12$26. The Depo-Testosterone label states that shots should be given every two to four weeks. Considering that dosage varies by patient, the cost could run anywhere from less than $24 per month to more than $120 per month.

These estimates only cover the drug itself, and not all possible costs of treatment. For instance, if you receive the injections from your doctor, theres a cost for the office visits. This is in addition to the cost of office visits for monitoring, as your doctor will likely monitor your condition carefully to check for side effects and to make sure the injections are working properly. If you give yourself the injections, you may also need to buy needles and syringes.

Testosterone therapy doesnt cure the cause of low T, it just raises testosterone levels up to a normal range. Therefore, injections could be a lifelong treatment if you continue to need them.

Some insurance companies cover portions of the costs, but youll want to check your coverage in advance. If you have questions about the costs, talk to your doctor.

Testosterone shots can help many men with low T. Still, this doesnt mean that these powerful injections are safe for all men. Be sure to tell your doctor about all health conditions you have before starting testosterone therapy.

You will likely need extra monitoring from your doctor if you have heart disease, sleep apnea, or a high red blood cell count. And you should not use testosterone injections at all if you have breast cancer or prostate cancer.

Testosterone shots may also increase your risk of certain health problems, such as:

Testosterone injections can be helpful, but only if you actually have low T. If youre wondering if these injections might be right for you, talk to your doctor. They can test you for low T. If they diagnose you, you can discuss whether these injections would be a good choice for you.

If you dont end up having low T but still feel like your hormone levels might be off, keep in mind that good nutrition, regular exercise, and avoiding smoking could help you feel better. If those dont help, be sure to talk to your doctor.

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Testosterone Therapy After Prostate Cancer Treatment: A …

Posted: March 25, 2022 at 2:21 am

Introduction: Although testosterone therapy (TTh) is the standard practice in otherwise healthy hypogonadal men, this therapy has historically been contraindicated in men with a history of prostate cancer. Recent evidence suggests that there is minimal or no prostate cancer growth in the setting of TTh administration in men definitively treated for non-metastatic prostate cancer.

Objective: To review the evidence supporting the safety and efficacy of TTh in patients previously treated for localized prostate cancer.

Methods: A literature review of the PubMed database was performed to identify studies evaluating the safety and efficacy of TTh in patients with a history of prostate cancer. Search terms included Testosterone Therapy, Testosterone Replacement Therapy and Radical Prostatectomy, Radiotherapy, External Beam Radiation Therapy, EBRT, Brachytherapy; Prostate Cancer and Hypogonadism, Low Testosterone; Bipolar Androgen Therapy.

Results: Available literature provides evidence for the safe application of TTh in patients previously treated for prostate cancer with either radical prostatectomy or radiotherapy. Furthermore, there exists evidence that severely hypogonadal levels of testosterone may lead to worse oncological outcomes. More recent research has begun to elucidate the effectiveness of bipolar androgen deprivation therapy in the treatment of prostate cancer. This mechanism of action increases the level of evidence indicating that the traditional management of maintaining testosterone levels at low levels may no longer be standard of care. TTh likely has a role in improved erectile function and other quality-of-life concerns in patients developing testosterone deficiency after being treated for prostate cancer.

Conclusions: TTh should be offered to select hypogonadal patients who have a history of definitively treated prostate cancer. Adequately designed randomized controlled trials are necessary to confirm the safety and efficacy of TTh in this population. Natale C, Carlos C, Hong J, et al. Testosterone Replacement Therapy After Prostate Cancer Treatment: A Review of Literature. Sex Med Rev 2021;9:393-405.

Keywords: Androgen Deprivation Therapy; Hypogonadism; Prostate Cancer; Radical Prostatectomy; Radiotherapy; Testosterone Therapy.

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Erectile Dysfunction (ED) Drugs Market: 4.76% YOY Growth Rate in 2022 | By Product (oral drugs, topical drugs, and others) and Geography | Growth,…

Posted: March 25, 2022 at 2:21 am

Erectile Dysfunction (ED) Drugs Market 2022-2026: Segmentation

The erectile dysfunction (ED) drugs market share growth by the oral drugssegment will be significant during the forecast period.Oral drugs have the advantage of high patient compliance due to easy route of administration and high bioavailability.These drugs have been dominating the market for a long time due to the ease of administration or self-administration. Moreover, the OTC availability of these drugs is a major factor that contributes to their large market share.The oral drugs segment is expected to exhibit decelerating growth during the forecast period. Most of the leading drugs used for the treatment of ED belong to this segment. The patent expiration of these drugs is paving the way for genericization, which is responsible for the declining growth of this segment.

39% of the market's growth will originate from North America during the forecast period. The USand Canada are the key markets forerectile dysfunction (ED) drugsin North America. Market growth in this region will be slower than the growth of the market in the European and Asian regions.

The increasing prevalence of chronic diseaseswill facilitate theerectile dysfunction (ED) drugs market growth in North America over the forecast period.

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Increasing Prevalence of Chronic Diseases to Boost the Market Growth

Sexual dysfunction disorders are more common in women than in men and involve loss of desire, orgasm problems, and pain during sex. The onset of sexual dysfunction disorders in women is attributed to hormonal factors, menstrual irregularities, amenorrhea, lack of vaginal lubrication, and failure to conceive.Female sexual dysfunction can be caused due to various chronic diseases such as diabetes. Globally, diabetes is one of the most common chronic diseases. Patients with diabetes may have several clinical conditions, including overweight, hypertension, obesity, metabolic syndrome, cigarette smoking, and atherogenic dyslipidemia, which are risk factors for sexual dysfunction. The rising prevalence of these conditions across the globe is expected to increase the patient pool with a large number of men and women having sexual dysfunctions, which, in turn, will drive the growth of the global ED drugs market during the forecast period.

Patent Expiry of Blockbuster Drugs to Hamper the Market Growth

The blockbuster drugs dominating the global ED drugs market have already faced or are on the verge of facing patent expiration. The key drugs in the market include VIAGRA (Pfizer), CIALIS (Eli Lilly), and LEVITRA and STAXYN (Bayer). For instance, the patents for VIAGRA expired in December 2017 in the US. To recover the losses due to patent expiration, Pfizer has entered into a patent litigation settlement with Teva Pharmaceuticals and has launched the generic version of VIAGRA in the US in December 2017. For manufacturing the generic version of a drug, there are limited legal procedures, and the production expenses are also low. Hence, the market emergence of a wide range of generic versions, which are priced lower than the branded versions, is a major challenge faced by the market.

Download Free sample Report for insights on the Drivers, Trends, and Challenges that will help companies evaluate and develop growth strategies for 2022-2026

Our Erectile Dysfunction (ED) Drugs Market Report Covers the Following Areas:

Erectile Dysfunction (ED) Drugs Market 2022-2026: Vendor Analysis

The erectile dysfunction (ED) drugs market report offers information on several market vendors, including Aurobindo Pharma Ltd., Bayer AG, Cadila Healthcare Ltd., Cipla Ltd., Dr. Reddys Laboratories Ltd., Eli Lilly and Co., Endo International Plc, Futura Medical plc, GlaxoSmithKline Plc, Innovcare Lifesciences Pvt. Ltd., Lupin Ltd., Pfizer Inc., SK Chemicals Co. Ltd., Teva Pharmaceutical Industries Ltd., TTK Healthcare Ltd., Viatris Inc., VIVUS Inc., and Sanzyme (P) Ltd. among others.

Moreover, the market is fragmented and the vendors are deploying growth strategies such asforming strategic alliances to increase their product offerings and geographical reachto compete in the market.

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Erectile Dysfunction (ED) Drugs Market 2022-2026: Key Highlights

Related Reports:

Testosterone Replacement Therapy Market by Product and Geography - Forecast and Analysis: The testosterone replacement therapy market size has the potential to grow by USD113.54 million and the market's growth momentum will decelerateduring the forecast period. To get more exclusive research insights: Download Our FREE Sample Report

Sexual Enhancement Supplements Market by Product and Geography - Forecast and Analysis: The sexual enhancement supplements market size has the potential to grow by USD407.16 million and the market's growth momentum will accelerateduring the forecast period. To get more exclusive research insights: Download Our FREE Sample Report

Erectile Dysfunction (ED) Drugs Market Scope

Report Coverage

Details

Page number

120

Base year

2021

Forecast period

2022-2026

Growth momentum & CAGR

Accelerate at a CAGR of 6.1%

Market growth 2022-2026

$ 1.20 billion

Market structure

Fragmented

YoY growth (%)

4.76

Regional analysis

North America, Europe, Asia, and Rest of World (ROW)

Performing market contribution

North America at 39%

Key consumer countries

US, Canada, Germany, UK, and China

Competitive landscape

Leading companies, competitive strategies, consumer engagement scope

Companies profiled

Aurobindo Pharma Ltd., Bayer AG, Cadila Healthcare Ltd., Cipla Ltd., Dr. Reddys Laboratories Ltd., Eli Lilly and Co., Endo International Plc, Futura Medical plc, GlaxoSmithKline Plc, Innovcare Lifesciences Pvt. Ltd., Lupin Ltd., Pfizer Inc., SK Chemicals Co. Ltd., Teva Pharmaceutical Industries Ltd., TTK Healthcare Ltd., Viatris Inc., VIVUS Inc., and Sanzyme (P) Ltd.

Market Dynamics

Parent market analysis, Market growth inducers and obstacles, Fast-growing and slow-growing segment analysis, COVID-19 impact and future consumer dynamics, market condition analysis for the forecast period,

Customization preview

If our report has not included the data that you are looking for, you can reach out to our analysts and get segments customized.

Table of Contents:

1 Executive Summary

2 Market Landscape

3 Market Sizing

4 Five Forces Analysis

5 Market Segmentation by Product

6 Customer Landscape

7 Geographic Landscape

8 Drivers, Challenges, and Trends

9 Vendor Landscape

10 Vendor Analysis

11 Appendix

About Us

Technavio is a leading global technology research and advisory company. Their research and analysis focus on emerging market trends and provides actionable insights to help businesses identify market opportunities and develop effective strategies to optimize their market positions. With over 500 specialized analysts, Technavio's report library consists of more than 17,000 reports and counting, covering 800 technologies, spanning across 50 countries. Their client base consists of enterprises of all sizes, including more than 100 Fortune 500 companies. This growing client base relies on Technavio's comprehensive coverage, extensive research, and actionable market insights to identify opportunities in existing and potential markets and assess their competitive positions within changing market scenarios.

Contact

Technavio ResearchJesse MaidaMedia & Marketing ExecutiveUS: +1 844 364 1100UK: +44 203 893 3200Email: [emailprotected]Website: http://www.technavio.com/

SOURCE Technavio

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Intersectionality and its effects on women’s rights – Northern Iowan

Posted: March 25, 2022 at 2:21 am

What some people may imagine when they think of feminism are the womens marches that were predominantly white, and occured during Trumps inauguration. Feminism is much more complex than that. As Womens History Month draws to a close, the world around us continually reminds us how important intersectionality is, and how it affects all women.

The term intersectional feminism was first introduced in 1989 by Kimberl Crenshaw, a law professor at UCLA School of Law and Columbia Law. Intersectional feminism is defined as the interconnected nature of social categorizations such as race, class, and gender as they apply to a given individual or group, regarded as creating overlapping and interdependent systems of discrimination or disadvantage, or, as Crenshaw describes it, how not all inequality is created equally. Womens rights and womens rights activists didnt start at intersectionality. One of the first and largest womens rights movements in America started with the womens suffrage movement. But, the suffrage movement catered to white women specifically, and many of the larger suffrage groups discriminated against women of color. In turn, when the 19th amendment was ratified in 1920, women were granted the right to vote. But, due to the movements discrimination, Black, Latina and Asain women were disenfranchised in many states. This led to many women of color not being able to cast votes until the 1960s. This is just one of many examples of how when feminism isnt intersectional, it is actively working against women that arent white, cis or straight.

Today, people who identify as feminists are much more likely to practice intersectionality, and work to uplift women who are different than themselves. But, there are still people who discriminate against women in their community. Headlines have swirled recently about Lia Thomas, who is a competitive swimmer for the University of Pennsylvania womens swim team, and who also happens to be transgender. Thomas competed at the NCAA championship, and swam a season best in the 500 free at 4:33:24. She placed first in the event, making her the first transgender woman to take home an NCAA championship title. But, this win was also followed with heavy criticism and controversy. Thomas has undergone two and a half years of hormone replacement treatment which works to block the hormone testosterone, and works to replace that with estrogen, which promotes female characteristics in the body. Even though she has been using hormone replacement therapy for two and a half years, she is still facing ridicule. One of her harshest critics being fellow competitor Reka Gyorgy, a Hungarian swimmer who competes for Virginia Tech. Gyorgy blames her failure to qualify for finals on Thomas and the NCAA for letting her compete. In her open letter to NCAA, Gyorgy states, One spot was taken away from the girl who got 9th in the 500 free and didnt make it back to the A final preventing her from being an All-American. Every event that transgender athletes competed in was one spot taken away from biological females throughout the meet. Considering that Thomas is hormonally female, Gyorgy technically has no one else to blame but herself. Scapegoating Thomas for being faster doesnt take away from the fact that Gyorgy could have swam faster. There wasnt a word from Gyorgy when she didnt make it to the semifinals at the Olympics. Blaming transgender athletes for her lack of accomplishments doesnt make Gyorgy look better or more worthy, it makes her look like shes making transphobic excuses. Thomas wasnt shattering records, as the New York Post reported. In fact, her time at the NCAA Championships is nine seconds slower than Katie Ledekys world record.

This is just a current example of how feminism can be discriminatory when it isnt intersectional, and paints a picture of just how important it is to be intersectional. While Gyorgy believed that she was fighting for her counterparts within the NCAA, she shrinks the room made for women that are transgender. It has taken decades for the NCAA to even recognize transgender athletes, and Gyorgys discriminatory letter illustrates why it was so hard in the first place.

This focus on Thomas and her accomplishments also takes away from actual issues that press collegiate athletes, such as funding discrepancies between male and female teams, and sexual harrassment. Fellow swimmer Erica Sullivan, who did make it to the final for the 500 freestyle, echoes this in her comments on the controversy. Womens sports are stronger when all women including trans women are protected from discrimination, and free to be their true selves, Sullivan said.

Intersectional feminism doesnt just stop with welcoming and accomodating trans people, but rather starts with it. Intersectional feminism is meant to welcome and fight for women of all different backgrounds, women of color, disabled women, women in the LGBTQ+ community and women who come from impoverished areas. Intersectional feminism reminds women that we are stronger together than we are apart. It reminds us that every woman deserves equal opportunity, not just a select few, and that its up to women ourselves to make that happen.

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I Wish I Medically Transitioned Before Giving Birth – www.autostraddle.com

Posted: March 25, 2022 at 2:21 am

This Trans Day of Visibility, were publishing a series of essays from trans writers who pose questions about what being visible has meant for us. Who is seeing us? How do we want to be seen? And at what cost? You can read all essays from the series here.

The moment I realized I wanted to have a baby, I was also coming to terms with the fact that I am transgender. I had just changed my name and started using gender-neutral pronouns, and the possibilities of who I could become were overwhelming. I couldnt stop thinking about starting Hormone Replacement Therapy (HRT). Everything was new to me: the language around being nonbinary, how testosterone actually changed a body, the thought of living past my twenties.

I called a local clinic and quietly asked if they had any doctors accepting new patients. When they asked me why I needed to schedule an appointment, my throat became an empty churchmy sins exposed. I thought, going into that appointment, that I was certain about starting testosterone. But, when my doctor recommended I also find a back up birth control method like an IUD, I realized how much I had been holding onto the desire to have a baby.

Existing as a person who wants to have a baby in a world where the representation of pregnancy is mostly for cis women is exhausting. My community then was rock climbers and yoga teachers. Not the most trans-inclusive (or aware) groups of people. I didnt know who to turn to for support with my unique experience of both wanting to transition and have a baby.

Artist: A. Andrews.

I decided to wait to medically transition. Sometimes I think I waited out of fear of what the people in my life would think of me. For years, I preached self-love and acceptance, exactly the way you were. I didnt realize how much I needed to physically change before I could love myself.

A year into my decision to wait, the pandemic reached the United States. Days later, I got a positive pregnancy result. I remember watching myself pee on the stick, astral projecting into the tiny studio apartment bathroom where the clawfoot tub took up most of the space. I saw the range of emotions play on my face: fear, excitement, the idea that this meant I could have a baby and then transition.

Having a baby was by far one of the most badass and amazing things Ive done in my life, but I did it all with a body that didnt feel like mine. Pregnancy was rough. My body was changing at a rate most people would be uncomfortable with. I would stand in front of the full-length mirror in my bedroom and stare from every angle. At my chest that wouldnt flatten anymore. At my stomach that I secretly hoped people saw as a beer belly. At my hips widening, possibly forever.

My mom used to complain that having four kids ruined her bodyher reason for getting a breast augmentation. My entire pregnancy I thought about the possibility that having a baby would completely deflate my chest. I hoped.

When it was time to give birth, I once again watched from the outside. I stood by the hospital bed, watching this other person push for three hours, incapable of opening their eyes. I whispered promises to this rented body: the sooner they are out, the sooner you can begin your own life.

My baby was born on January 6th, 2021. My partner and I stared at the freshness of this new living, breathing being. Hours after delivery, my doctor came in to check on us. Well, she sighed, Democracy has failed us today. We turned on our phones for the first time, abruptly losing the moment wed waited nine months for, to see the white supremacist insurrection at the Capitol. Being a parent has been an overwhelming amount of feeling guilty. My therapist asks what Im feeling guilty about and I recite: for letting my kid watch TV sometimes, for feeding them french fries, for bringing them into a world that is full of violence and climate catastrophe.

Following my doctor was the lactation consultant. She asked how I was feeling about breastfeeding, how the baby was latching. There had been no issues so far, and it was nice to feel like my chest had a job. But I knew I didnt want this to be long term. I wanted to chestfeed for three to six months, but the lactation consultant pushed for a full year, and I didnt want to deprive my baby of something that seemed so urgently necessary for their health.

As the months went on, I found myself dreading feeding sessions. I knew that weaning was a possibility, there was always formula, but everyone kept telling me how great I was doing, feeding them only my milk. I once again bought into the rhetoric of there being just one good way to have a baby. Around six months in, the depression and thoughts of self-harm were taking over my every breath. I knew my medical transition couldnt be paused for much longer.

Finally, I would begin the process of weaning my baby off so that I could begin my own growth. It happened when they were 10 months old. I began testosterone on my 27th birthday, almost a year after giving birth. I wish it had been sooner. I wish I had started transitioning before I even got pregnant, so that I could have gone through pregnancy more comfortable in my weird body. I wish it was me giving birth that day.

Having a baby was by far one of the most badass and amazing things Ive done in my life, but I did it all with a body that didnt feel like mine.

Since starting testosterone, everything has changed. The cloud of dysphoria is beginning to clear. Despite the new challenges that come with a second puberty in my late twenties, getting up in the morning is no longer an act of resilience. Ive been exploring my sexuality in a completely new waywhere I used to avoid touch, I now lean into comfortably. I am starting to understand my body. Communicating my needs and desires to my partner has been a revelation, and the possibilities we can now discover together have invigorated a relationship where Ive mostly felt absent. In the mirror, I recognize myself looking back. When I move, touch, breathe, I feel it happening in my body and my mind. Im no longer watching myself exist, but coming into an existence of my own.

I dont regret my choices around medically transitioning, but knowing now what I didnt know then, I never would have waited. Transitioning has allowed me to prioritize my own mental health, something that pregnancy and parenting often kicks to the side. Ive found empowerment through putting myself first, so that I can have the confidence to show up as a parent and a partner.

My therapist asks what Im proud of, and I say, Im proud that my kid can see someone every day who isnt afraid of being the truest version of themselves.

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50 Top Women in STEM – TheBestSchools.org

Posted: March 25, 2022 at 2:19 am

From left-to-right: Carol Greider, Jane Luu, May-Britt Moser, Radia Perlman, Barbara Askins, Uma Chowdhry, Susan Solomon, andMaureenRaymo.

They say that success is the best revenge.

For every woman who has ever felt exasperated by the various speculations regarding the existence or non-existence of innate differences between the sexes with respect to mathematical ability, what better rebuttal could there be than a list like this one?

The very fact that these fifty women have achieved what they have shows the superficiality of the whole debate. It ought to be clear by now that the mature expression of sophisticated human capacities depends upon a complex interaction between biological endowment and cultural and educational opportunity (that is, nature and nurture).

And if someone were to object that these fifty women are not typical well, the men who could be accounted the peers of these women would constitute a tiny minority of their sex, as well! Very high achievement, by its very nature, is something out of the ordinary.

Even readers who may have no interest at all in the nature-nurture problem and its echo in our present culture wars ought to take notice of this list. Why is that?

Consider this. Practically everyone allows that the fields of science, technology, engineering, and math (STEM) hold the key to the economic future of our country. Moreover, today well over half of all college graduates are female. In fact, women have been increasing their numbers in other academic fields by leaps and bounds in recent years; in STEM fields, not so much.

Therefore, we submit that the entrance of women into STEM fields in greater numbers is of vital importance to our national interest.

Also note that in order to compile this list, we had no recourse at all to affirmative action. There was simply no need for it. If anyone finds our list empowering, we are happy for them, but that is not really the main point.

We simply looked for the best women in their respective fields women who have gotten where they are by simply plowing through whatever obstacles may have stood in their path. Women with a lot of innate talent, certainly, but who have also put in a great deal of extremely hard work.

In other words, what our list shows to todays young women and whoever else may be interested is that it can be done. If a young woman has a taste and a talent for math and science and a capacity to stick with it to accomplish her goals that is really all she needs. At the end of the day, everything else is sound and fury signifying very little.

In short, the highly accomplished women on this list provide the best sort of role models for mathematically and scientifically inclined younger women. They say it loud and clear, for all the world to hear:

Just get out of my way, and let me get on with the work!

Note: We have tried to balance our list which is alphabetical among the various STEM fields, and within the exact sciences, among the main disciplines, such as physics, chemistry, biology, astronomy, and geology. To be selected for inclusion on this list, the woman had of course to be still living as of the date of publication, and also be born after 1937 (and thus be under the age of eighty). We reluctantly decided to institute an age requirement in order ensure a list with more younger scholars still engaged in active research. We hope to revisit the path-breaking achievements of older women scientists on another occasion.

Askins (ne Scott) was born in Belfast, Tennessee. After first working as a teacher and raising a family, she went back to school and took her bachelors and masters of science degrees from the University of Alabama in Huntsville. She was then employed as a physical chemist by NASAs Marshall Space Flight Center in Huntsville.

Askins is best known for inventing the autoradiograph, a method of greatly enhancing the density and contrast of photographic images by exposing the silver in the emulsion of a photographic negative to radiation, and then creating a second image by exposing a second emulsion to the radiation from the first one. Askinss process was initially applied with great success in astronomy, to images taken through light telescopes. Subsequently, it found wide application in medical technology, in the enhancement of X-ray images. In 1978, Askins was named Inventor of the Year by the Association for the Advancement of Inventions and Innovations the first woman to receive the honor.

Bertozzi was born in Boston, Massachusetts. She received her AB summa cum laude in chemistry from Harvard University. She received her Ph.D. in chemistry in 1993 from University of CaliforniaBerkeley, where she worked with Mark Bednarsky on the synthesis of oligosaccharide analogs. She joined the Berkeley faculty in 1996. Today, she is Anne T. and Robert M. Bass Professor in the School of Humanities and Sciences at Stanford University, as well as Director of the Bertozzi Research Lab in the Department of Chemistry at Stanford. In addition, since 2000 she has been a Howard Hughes Medical Institute investigator.

Bertozzis research focuses on the role of glycans (polysaccharides) in cell surface receptors, especially the connection between cell-signaling disruption and diseases like cancer and arthritis. Her lab is perhaps best known for developing powerful new research tools for cell biology, notably so-called bioorthogonal chemical reporters, which are man-made chemical handles that can be altered by means of externally controlled but non-perturbing reactions within the living system basically a new way of designing macromolecules to order. Bertozzis new method has been essential, among other things, to the development of modern forms of fluorescent labeling of macromolecules for purposes of advanced imaging. Bertozzi has won numerous prizes and awards, and is involved in several start-ups and other commercial ventures connected to her pioneering work.

Blackburn was born in Hobart, Tasmania, in Australia. When she was sixteen, her family relocated to Melbourne, where she attended high school, and obtained her bachelors and masters of science degrees from the University of Melbourne. Next, she traveled to the United Kingdom, where she enrolled in Darwin College, Cambridge, obtaining her Ph.D. in 1974 for work on bacteriophage viruses. After graduating, she taught at University of CaliforniaSan Francisco, where her ground-breaking work on telomeres was done. She is currently President of the Salk Institute for Biological Studies in La Jolla, California.

In 2009, Blackburn was awarded the Nobel Prize for Physiology or Medicine, along with Carol W. Greider (see below on this list) and Jack W. Szostak, for her discovery of telomerase, a member of the reverse transcriptase family of enzymes. Telomeres are non-coding buffer regions at the ends of chromosomes which become shortened during chromosome replication. Telomerase controls the bonding of new nucleotide units to the shortened telomere regions after completion of cell replication, a function that is vital to the longevity of the cell. in 2002, Blackburn was appointed to the Presidents Council on Bioethics by President George W. Bush. She supported the use of human embryonic stem cells in biomedical research, which put her at odds with the majority of the Council. In 2004, she was removed from her position on the Council by President Bush amid heated public controversy.

Blau was born in London, but earned her bachelors degree from the University of York in the United Kingdom. She obtained her MA and Ph.D. degrees from Harvard University, where she worked under Fotis C. Kafatos. After a postdoc as University of CaliforniaSan Francisco, she joined Stanford University in 1978, where she received an endowed chair in the Department of Microbiology and Immunobiology in 1999. In 2002, she was appointed as the founding Director of the Baxter Laboratory for Stem Cell Biology at Stanford.

Blau is best known for her experiments with heterokaryons (fusions of differentiated cells from two different species), work which proved that even mature, differentiated cells retain the latent capacity for the expression of different cell types, and that mature cell type could in fact be reversed something that had previously been assumed to be impossible. Her work also showed that the maintenance of the differentiated cell state is the result of a continuing, active process which points to a new, more dynamic vision of all living processes. Blaus work is considered to be fundamental to the young but burgeoning fields of stem cell biology and regenerative medicine. Her work also has profound implications for our eventual understanding of the physiological basis of cancer.

Breazeal was born in Albuquerque, New Mexico. She received her bachelor of science degree in electrical and computer engineering from University of CaliforniaSanta Barbara in 1989, and her doctor of science degree in electrical engineering and computer science from Massachusetts Institute of Technology in 2000. At MIT, Breazeal worked in the Artificial Intelligence Laboratory under Rodney A. Brooks, fabled pioneer of the actionist approach to robotics. For her doctoral dissertation, she developed Kismet (see video clip, below), a highly expressive humanoid robot capable of unscripted, emotionally intuitive, and hence lifelike interaction with human beings.

Following the breakthrough with Kismet, Breazeal helped develop a number of more sophisticated robots utilizing similar principles, including Cog, Leonardo, and Nexi. The general term now in use for these more-advanced descendants of Kismet is MDS (mobile, dexterous, social) robots. Several commercial spin-offs have been derived from her work, as well, including the personal trainer, Autom, the interactive robot companion, Huggable, and the enhanced video-conferencing system, MeBot. Breazeal is currently Director of the Personal Robots Group under the aegis of MITs famed Media Lab.

Buck was born in Seattle, Washington. She received her bachelor of science degree in psychology and microbiology from the University of Washington at Seattle in 1975, and her Ph.D. in immunology from the University of Texas Southwestern Medical Center in Dallas in 1980. At the latter institution, she worked under Ellen S. Vitetta, co-discoverer of the cytokine Interleukin-4, which plays an essential role in the formation of T cells. After a couple of years of postdoctoral research at Columbia University, Buck joined Richard Axels lab at Columbias Institute of Cancer Research.

Inspired by the pioneering work of Solomon H. Snyder during the 1970s on the opioid receptor in the brain (as well as the receptors for many other major neurotransmitters), Buck and Axel decided to try to map an entire sensory system at the molecular level. They chose the olfactory system in rats for its relative simplicity. Beginning in 1991, they began publishing work that eventually identified genes and gene families responsible for coding for more than 1,000 different neural receptors (sensors) in the olfactory receptor cells at the back of the nose at the base of the brain. For this ground-breaking work, Buck and Axel received the 2004 Nobel Prize for Physiology or Medicine. In 1991, Buck joined the Neurobiology Department of Harvard Medical School, where she soon became head of her own lab. There, she traced the molecular basis of olfaction still further, showing how information from the various receptor cells are integrated in the olfactory bulb before being passed on to higher-level structures in the brain for interpretation. Buck is currently a Full Member of the Basic Sciences Division at Fred Hutchinson Cancer Research Center in Seattle.

Burnell (ne Bell) was born in Lurgan, Northern Ireland, in the United Kingdom. She became interested in astronomy at an early age. She took her bachelors degree in physics in 1965 from the University of Glasgow, and received her Ph.D. in 1969 from the University of Cambridge. While at Cambridge and still known as Jocelyn Bell she was enlisted by her doctoral advisor, Antony Hewish, to work with Martin Ryle and others on the construction and testing of a new radio telescope designed to study the then-recently discovered radio sources known as quasi-stellar objects, or quasars. In 1967, while poring over data from the new telescope, Bell discovered a never-before-observed type of signal being emitted with great regularity at the rate of about one and one-third pulses per second. She immediately showed the strange signal to her advisor, and the two worked closely together to try to understand what she had found.

Initially given the facetious name of LGM-1 (for little green men) by Bell and Hewish, their discovery was soon conjectured by Thomas Gold to be caused by a highly magnetized, rapidly rotating neutron star. This conjecture proved to be correct, and the phenomenon then became officially known as a pulsating star, or pulsar. In 1968, Bell married Martin Burnell and, after taking her degree the following year, at first worked only part-time. Eventually, the couple divorced and Burnell resumed a full-time academic career, initially as Professor of Physics at the Open University (1991 2001). After occupying a visiting professorship at Princeton University, she next served as Dean of Science at the University of Bath (2001 2004). During this time, she also served as President of the Royal Astronomical Society (2002 2004), and later as President of the Institute of Physics (2008 2010). She is currently Visiting Professor of Astrophysics at the University of Oxford. Though passed over for the Nobel Prize for Physics awarded to Hewish and Ryle in 1974, Burnell was elected a Fellow of the Royal Society (FRS) in 2003 and was made a Dame Commander of the Order of the British Empire (DBE) in 2007, among many other honors too numerous to mention.

Burns was born in Torrington, Wyoming (a small town of less than 7,000 souls). She earned her bachelors degree from Florida International University in Miami, and a Ph.D. in organic chemistry from Iowa State University. She then did post-doctoral work at the University of Montpellier, France. In 1983, she joined the French division of the American company, Dow Corning, as a researcher specializing in organosilicon chemistry (the chemistry of organometallic compounds containing carbon silicon bonds). While still working for the company as a research scientist, Burns invented several new types of heat-resistant synthetic rubber made from silicone (a polymer consisting of long silicon oxygen chains, as well as carbon atoms). She holds three patents for these inventions.

Burns soon made the transition at Dow Corning from the laboratory bench to the corporate suite. In 1997, she moved to Brussels, where she oversaw important aspects of the companys European operations. In 2000, she returned to the United States in order to assume the role of Executive Vice President of the company, and to serve on its board of directors. In 2003, she was named President and Chief Operating Officer of Dow Corning, and in 2004 she added CEO to her titles, serving in that capacity until her retirement in 2011. She was also Chairman of the company from 2006 until her retirement. Under Burnss leadership, Dow Corning began developing new uses for organosilicon compounds in cutting-edge areas like solar energy and biotechnology.

Caraiani was born in Bucharest, Romania. She earned her bachelors degree summa cum laude from Princeton University in 2007. At Princeton, she wrote her senior thesis on Galois representations under the supervision of Andrew Wiles, widely known for having completed a proof in 1995 of Fermats Last Theorem. Caraiani did her doctoral work at Harvard under the supervision of Wiless former student, Richard Taylor. Her doctoral dissertation concerned local-global compatibility in the Langlands correspondence. After graduating in 2012, she first taught briefly at the University of Chicago, before returning to Princeton University from 2013 to 2016. While at Princeton, she also served as a Veblen Research Instructor in Mathematics at the Institute for Advanced Study (IAS). Since 2016, Caraiani has been a Bonn Junior Fellow at the Hausdorff Center for Mathematics (HCM), a highly prestigious mathematics research institute located in Bonn, Germany. She has also been invited for shorter visits to the Mathematical Sciences Research Institute at University of CaliforniaBerkeley and the cole Normale Suprieure in Paris.

So far, Caraiani has worked primarily on problems at the interface of the Langlands correspondence with arithmetic algebraic geometry. (The local Langlands correspondences are a part of the overarching Langlands program, which explores conjectured deep connections among diverse areas of mathematics, such as number theory, algebra, and analysis.) Regarding the direction of her future research, Caraiani has said that she hopes to extend the results, in work done jointly with Peter Scholze, about torsion in the cohomology of compact unitary Shimura varieties to the non-compact case. In the spring of 2018, Caraiani is due to take up a position as a von Neumann Fellow at the IAS.

Charlesworth (ne Maltby) was born in the United Kingdom. She received her Ph.D. in genetics in 1968 from Cambridge University. Married to the geneticist Brian Charlesworth in 1967, for many years she followed in the wake of his career, holding only temporary positions at a number of institutions, including Cambridge University, the University of Chicago, Liverpool University, the University of Sussex, and the University of North Carolina, before finally received a full-time appointment as Assistant Professor at the University of Chicago in 1988. In 1997, she moved to the University of Edinburgh, where she is currently a Professorial Research Fellow.

Charlesworth has made signal contributions to our understanding of population genetics and evolution, especially in relation to genetic recombination, sex chromosomes, and mating systems in both plants and animals. More particularly, her work on linkage disequilibrium in the genome region containing the self-incompatibility alleles of the plant Arabidopsis lyrata has been widely recognized as highly original and important. Charlesworth has published more than 300 research papers, which have been cited more than 10,000 times. In 2005, she was named a Fellow of the Royal Society.

Chowdhry was born in Mumbai (then Bombay), India. She received her bachelors degree from the Indian Institute of Science in Mumbai in 1968. In 1970, she received a masters degree in engineering from the California Institute of Technology (Caltech), in Pasadena, California. After working for two years with the Ford Motor Company, she returned to graduate school, taking her Ph.D. in materials science from Massachusetts Institute of Technology in 1976. The following year, Chowdhry joined the DuPont company as a research scientist at the DuPont Experimental Facility in Wilmington, Delaware.

While still at the laboratory bench, Chowdhry worked primarily on developing new ceramic materials for the field of high-temperature superconductivity. This work generated over fifty research papers and twenty patents. In addition to her work on ceramics and superconductors, she has also worked in the areas of catalysis, proton conductors, microelectronics, and nanotechnology. In 2002, she was named DuPonts Vice President of Global, Central Research & Development. In 2006, she became Senior Vice President of the company, as well as Chief Science and Technology Officer, positions she continued to hold until her retirement in 2010. In 2003, Chowdhry was elected to the American Academy of Arts and Sciences.

Cummings was born in a small town in Tennessee. Cummings received her bachelors degree in mathematics from the United States Naval Academy in 1988. She received her masters degree in space systems engineering from the Naval Postgraduate School in 1994, and her Ph.D. in Systems Engineering from the University of Virginia in 2004. From 1988 until 1999, Cummings was a naval officer and military pilot. In 1989, she was one of the first women to land a supersonic jet fighter a Boeing F/A-18 Hornet on the deck of an aircraft carrier.

Cummings began her academic career while still in the Navy, at Pennsylvania State University, afterwards also teaching at Virginia Tech. In 2010, MIT appointed her an Associate Professor in its Department of Aeronautics and Astronautics, where she was Director of the Humans and Automation Lab in the Engineering Systems Division. She is currently Associate Professor in the Department of Mechanical Engineering and Materials Science at Duke University, where once again she is Director of the Humans and Autonomy Lab (the new incarnation of the lab she previously headed up at MIT). She also holds joint appointments with Dukes Institute of Brain Sciences and Electrical and Computer Engineering Department. Cummingss research extends across several fields, including human interaction with autonomous vehicle systems, modeling human interaction with complex systems, and decision support design for time-pressured, uncertain systems. In addition, she has a strong interest in the ethics of technology, including the impact of technology on society.

Curry took her bachelors degree in geography from Northern Illinois University in 1974, and her Ph.D. in geophysical sciences from the University of Chicago in 1982. In 2017, under intense pressure and amid public controversy, she resigned her long-time position as Professor in the School of Atmospheric Sciences at Georgia Tech University, where she had served as Chair of the School from 2002 until 2013. Prior to coming to Georgia Tech, Curry had been Professor of Atmospheric and Oceanic Sciences at the University of Colorado-Boulder, and before that had taught at a number of other prestigious universities, including Penn State, Purdue, and the University of Wisconsin-Madison. She has published nearly 200 peer-reviewed papers, and is co-author or -editor of three important textbooks: with Vitaly I. Khvorostyanov, Thermodynamics, Kinetics, and Microphysics of Clouds (Cambridge University Press, 2014); with James R. Holton and John Pyle, Encyclopedia of Atmospheric Sciences (Academic Press, 2003); and with Peter J. Webster, Thermodynamics of Atmospheres and Oceans (Academic Press, 1998). Curry has served on NASAs Advisory Council Earth Science Subcommittee, on the Climate Working Group of the National Ocean and Atmospheric Administration (NOAA), and on the National Academies Space Studies Board and Climate Research Group. In 2004, she was elected a Fellow of the American Geophysical Union, and in 2007, a Fellow of the American Association for the Advancement of Science.

In spite of these solid credentials and achievements and despite her entrenched position within the institutions of mainstream American academic climatology Curry came under vitriolic attack for publicly censuring what she perceives as the growing politicization of climate science, which she feels has resulted in claims that are not adequately supported scientifically, in the stifling of needed further research, and in intimidation, fear, and conformity throughout the discipline. It was this courageous public stance including an op-ed piece in the Wall Street Journal in 2014 and culminating in congressional testimony in 2015 and again in 2017 that eventually led to her resignation from her tenured position at Georgia Tech earlier this year.

Donald (ne Griffith) was born in London. She was educated at the Camden School for Girls and Girton College, University of Cambridge. She took her bachelors degree in theoretical physics from the latter institution, where she went on to take her Ph.D. in 1977 for work on electron microscopy. After postdoctoral work at Cornell University in the US, where she switched the focus of her research from metals to polymers, she returned to Cambridge in 1981, and two years later became a member of the world-renowned Cavendish Laboratory there, forever associated with the name of Ernest Rutherford. Since 1998, she has been Professor of Experimental Physics at the University of Cambridge, where she is also Master of Churchill College.

Donald works within the Soft Matter and Biological Physics group at the Cavendish Laboratory. Over the years, she has moved from the study of nonliving polymer and colloidal systems to research on the soft-matter properties of living systems, especially protein aggregation. Of the many techniques at the disposal of the soft-matter physicist, she is particularly noted for her work using the environmental scanning electron microscope (ESEM), a device which allows for the study of untreated or wet specimens, and hence is of particular value for studying the physics of biological systems (macromolecules, organelles, and cells). Donalds work has placed her at the forefront of efforts to develop and institutionalize the burgeoning new field of biological physics. In 1999, she was elected a Fellow of the Royal Society (FRS), and in 2010, she was appointed a Dame Commander of the Order of the British Empire (DBE).

Doudna was born in Washington, DC, but spent most of her childhood in Hilo, Hawaii. She earned her bachelors degree in chemistry in 1985 from Pomona College and her Ph.D. in biological chemistry and molecular pharmacology in 1989 from Harvard Medical School. At Harvard, she worked on ribozymes under Jack W. Szostak. She did post-doctoral work on the same topic at the University of Colorado-Boulder under Thomas R. Cech, who had just won the 1989 Nobel Prize in Chemistry for his co-discovery of the catalytic properties of RNA. After several years at Yale, Doudna moved to the University of California-Berkeley in 2002 in order to be near the synchrotron at the Lawrence Berkeley National Laboratory. She is currently Professor of Chemistry and of Molecular and Cell Biology in the Department of Chemistry and Chemical Engineering at University of CaliforniaBerkeley. She has published nearly 200 research papers and is co-author of a popular molecular biology textbook. However, Doudna is undoubtedly best-known for her recent involvement in the development of a powerful new method of gene editing that in a few short years has already revolutionized genetic engineering, and whose future contributions to medicine therapy as well as basic research are incalculable.

The method is called CRISPR/Cas9. CRISPR stands for clustered, regularly spaced, short palindromic repeats, and is basically a region of the bacterial chromosome that acts as a spacer between different coding regions, or genes. Cas9 is an enzyme produced by certain bacteria that acts like scissors, cutting a chromosome at the CRISPR region. The discovery of this pair of structures and how they operate together has made it possible for the first time for scientists to contemplate editing genes virtually at will. Teaming up with Emmanuelle Charpentier, now of Ume University in Sweden, Doudna published a seminal paper on the CRISP/Cas9 technique in 2012. Since then, however, other labs have claimed to have made similar discoveries independently, and there has been a considerable amount of legal wrangling over priority, the outcome of which has many important implications not just for the Nobel Prize and other forms of recognition but potentially for biotech ventures that may someday be worth billions of dollars.

As the daughter of physicist Sidney Drell, Persis Drell grew up on the campus of Stanford University, where today she is Provost. She earned her bachelors degree in mathematics and physics in 1977 from Wellesley College, and her Ph.D. in atomic physics in 1983 from University of CaliforniaBerkeley. She did post-doctoral work at the Lawrence Berkeley National Laboratory, and in 1988, she took a position as Assistant Professor at Cornell, where she was appointed a full Professor 1998. In 2002, she moved to Stanford University as Professor and Associate Director of Research at the Stanford Linear Accelerator Center (SLAC). In 2007, she was named Director of SLAC, a position she held until 2012.

During her tenure as Director, Drell oversaw the so-called BaBar experiment conducted at SLAC by an international consortium of over 500 scientists, which was designed to study the relationship between matter and anti-matter by investigating the phenomenon of charge parity violation. The name of this important experiment (inspired by Babar the Elephant) comes from the symbols B and B (B-bar), standing for the B meson and its antiparticle, respectively. In 2014, Drell was named Dean of Stanfords School of Engineering, with joint appoints as James and Anna Marie Spilker Professor, Professor of Materials Science and Engineering, and Professor of Physics. In 2017, she became Provost of Stanford University.

Faber was born in Boston, Massachusetts. She took her bachelors degree from Swarthmore College in 1966, with a major in physics and minors in mathematics and astronomy. She received her Ph.D. from Harvard University in 1972, with a dissertation on optical observational astronomy. In 1972, she became the first woman to join the staff of the Lick Observatory at University of CaliforniaSanta Cruz. In 1976, working with one of her graduate students, Robert Jackson, Faber observed a correlation now known as the Faber-Jackson relation between the brightness and spectra of galaxies and the orbital speeds and motions of the stars within them. In the early 1980s, now collaborating with Martin Reese and others, she published an influential series of articles on cold dark matter, proving that dark matter could not be composed of fast-moving neutrinos, and thus that the hot dark matter hypothesis must be wrong.

Next, Faber became closely involved with the development of the two Keck telescopes atop Mauna Kea, the tallest volcano on earth, on the Big Island of Hawaii. Then as now, the Kecks are the worlds most powerful optical instruments. Their highly innovative design includes a ten-meter primary mirror consisting of thirty-six hexagonal segments. Faber was crucial in selling the concept behind the original Keck instrument to governments and private funding agencies around the world, changing forever the face of optical astronomy. She remained closely involved with the development of the second-generation Keck II telescope, as well as with plans for the wide-field planetary camera for the Hubble Space Telescope. When a flaw was discovered in the Hubbles main optical system, Faber was charged with putting together a team, which diagnosed the cause as spherical aberration, thus permitting a technical fix to salvage the mission. The Hubble went on to a long and fruitful career producing many outstanding images of the far reaches of the universe. Faber is currently University Professor of Astronomy and Astrophysics at University of CaliforniaSanta Cruz.

Freedman was born in Toronto, where she received her bachelors degree in astronomy from the University of Toronto in 1979. She remained there for her graduate work, as well, taking her Ph.D. in astronomy and astrophysics from the same university in 1984. Upon graduation, she joined the staff of the Carnegie Observatories, which operate the telescopes at Las Campanas, high in the Andes mountains of northern Chile, but whose headquarters are in Pasadena, California. She worked there first as a post-doc, then three years later as a regular faculty member, becoming the first woman on the permanent staff. While at the Carnegie, where in 2003 she became the Crawford H. Greenewalt Chair and Director of Observatories, Freedman worked on refining estimates of the size and age of the universe based on improved observations of Cepheid variable stars. The known relation between the periodicity of the rotation and the brightness of these stars has long been one of the main tools astronomers use to calculate intergalactic distances.

After the Hubble Space Telescope became operational in the mid-1990s, Freedman was selected to be co-leader of the Intergalactic Distance Scale project, an international team tasked with using the Hubbles greatly increased observational power to refine the value of the Hubble constant, a key value upon which depends the rate of the cosmic expansion, and thus our knowledge of the size and age of the universe. For the past fifteen years or so, Freedman has been involved with another international team planning and building the next generation of earth-based, optical telescopes, the Giant Magellan Telescope (GMT). With seven segments collectively equivalent to an 80-ft. primary mirror, the GMT is being built at the Las Campanas site in the Andes under the auspices of the Carnegie Observatories. When fully operational around 2025, the GMT will be the worlds largest optical instrument, with a resolving power an order of magnitude greater than the Hubbles. In 2014, Freedman moved to the University of Chicago, where she the John & Marion Sullivan University Professor of Astronomy and Astrophysics.

Freese was born in Freiburg, Germany (West Germany, at the time). Brought to the US at the age of nine, she received her bachelors degree in physics in 1977 from Princeton University (the second woman there to major in the subject), her masters degree in physics in 1981 from Columbia, and her Ph.D. in physics in 1984 from the University of Chicago, where David Schramm directed her dissertation. After post-docs at the Harvard-Smithsonian Center for Astrophysics, at the Kavli Institute for Theoretical Physics at University of CaliforniaSanta Barbara, and at University of CaliforniaBerkeley, she was hired as an Assistant Professor at MIT, where she taught from 1987 until 1991. Subsequently, she moved to the University of Michigan, where she is currently George E. Uhlenbeck Professor of Physics.

Freeses main area of research has been on the dark matter/dark energy problem. In particular, she has made several proposals for ways to detect dark matter experimentally, which have led directly to the IceCube Neutrino Observatory at the AmundsenScott South Pole Station in Antarctica, and a worldwide consortium of efforts to detect a dark matter wind as the Earth and the solar system orbit the Milky Way galaxy. Her work has definitely ruled out the MACHO (massive compact halo object) theory of dark matter, thus giving support to WIMPs (weakly interacting massive particles). In more recent theoretical work, Freese has advanced several conjectures regarding dark matter, including a model known as the Cardassian expansion which replaces dark matter with a modification of Einsteins field equations, and another hypothesis known as dark stars, which if confirmed would be a new type of star powered by dark matter annihilation rather than fusion. Finally, Freese has also worked on improving the inflationary version of the Big Bang model of the origin of the universe. Her proposal, known as natural inflation, is a theoretically well-motivated idea that uses axion-like particles to provide the required flat potentials to drive the cosmic expansion. In 2013, the European Space Agencys Planck Satellite observed data which are consistent with Freeses natural inflation model.

Geller was born in Ithaca, New York. She received her bachelors degree in physics in 1970 from University of CaliforniaBerkeley, and her Ph.D. in physics in 1975 from Princeton, where she worked with P.J.E. Peebles. After post-docs at the Harvard-Smithsonian Center for Astrophysics and the Institute for Astronomy at the University of Cambridge, she returned to Harvard, where she served as an Assistant Professor of Astronomy from 1980 until 1983. She then moved to the Smithsonian Astrophysical Observatory (a partner in the Harvard-Smithsonian Center for Astrophysics), where she has worked ever since as a member of the permanent scientific staff. Geller is a Fellow of the American Association for the Advancement of Science, of the American Physical Society, and of the American Academy of Arts and Sciences, as well as a member of the physics section of the US National Academy of Sciences. She has also received numerous prizes and lectureships, including the Newcomb Cleveland Prize (AAAS) in 1989, a MacArthur Foundation Fellowship in 1990, the Henry Norris Russell Lectureship (American Astronomical Society) in 2010, the Julius Edgar Lilienfeld Prize (American Physical Society) in 2013, and the Karl Schwarzschild Medal (German Astronomical Society) in 2014.

In order to help promote public interest in astronomy and physics, Geller lectures frequently all around the world, and has made a number of educational short films and videos. Her particular field of expertise is the large-scale structure of the universe, and her best-known scientific achievement is the creation of pioneering maps of galaxy clusters and other super-galactic structures. One such effort, the Second Center for Astrophysics Redshift Survey (CfA2) conducted in 1989 by a team of American astronomers headed up by Geller and John Huchra, led to the discovery of the Great Wall, an enormous filament of galaxies that is one of the largest known material objects in the universe.

Gianotti was born in Rome. She received her Ph.D. in experimental particle physics in 1989 from the University of Milan. After graduation, she occupied a number of post-doc positions. In 1994, she was appointed a research physicist in the Physics Department of the Conseil Europen pour la Recherche Nuclaire (CERN) near Geneva now known officially as the European Organization for Nuclear Research (but retaining the original acronym) and site of the Large Hadron Collider, currently the worlds largest particle accelerator. Gianotti has worked at CERN ever since. She has served on the scientific advisory boards or councils of numerous international organizations, including the Centre National de la Recherche Scientifique (CNRS) in France, Fermilab in the US, the Deutsches Elektronen-Synchrotron (DESY) in Germany, and the European Physical Society.

Gianotti is a corresponding member of the Accademia Nazionale dei Lincei the most prestigious scientific society in her native Italy, which traces its roots back to the time of Galileo as well as a foreign associate member of the US National Academy of Sciences and the French Academy of Science. Moreover, in 2013, she won the Italian Physical Societys prestigious Enrico Fermi Prize. Gianotti has been involved with many important experiments at CERN over the years, but she is no doubt best known for her work as project leader of one of the two teams at CERN which undertook the search for the Higgs boson, beginning in 2009. The team she led in preparing, running, and analyzing the experiment on the Large Hadron Collider comprised some 3000 physicists from thirty-eight different countries. In July of 2012, it fell to Gianotti to make the announcement to the world that the Higgs boson had indeed been detected. In 2016, she began a five-year term as Director-General of CERN.

Greider was born in San Diego, California, and raised mostly in Davis (where her father was a physics professor). She took her bachelors degree in biology in 1983 from University of CaliforniaSanta Barbara. During this period, she spent time at the University of Gttingen in Germany, where as an undergraduate she already made important discoveries. Greider obtained her Ph.D. in molecular biology in 1987 from University of CaliforniaBerkeley, where she worked under Elizabeth Blackburn (see above on this list). When she joined Blackburns laboratory for her doctoral work in April of 1984, Greider focused on the search for the enzyme believed to be implicated in adding new nucleotide bases to the ends of chromosomes to replace ones lost during DNA replication. Working with the fresh-water protozoan Tetrahymena thermophila as a model organism, Greider obtained the first results indicating that the enzyme now known as telomerase might be the molecule they were seeking on Christmas Day of 1984.

After six months of additional experimenting for the sake of verification, Greider and Blackburn published their ground-breaking paper on telomere terminal transferase (as they originally styled the molecule) in December of 1985. Many years later in 2009, the grad student and her advisor shared the Nobel Prize in Physiology or Medicine (along with Jack W. Szostak, who had been working along similar lines independently). After completing her dissertation, Greider worked at the world-renowned Cold Spring Harbor Laboratory on Long Island. During her time at CSHL, she worked extensively on the connection between telomeres and longevity in multicelluar aninmals, using so-called telomerase knockout mice (mice genetically altered not to produce telomerase) as her model organism. She also became involved in efforts to develop new technologies based on her discoveries, notably by joining the Scientific Advisory Board of Geron Corporation. Since 2014, Greider has been Bloomberg Distinguished Professor and Daniel Nathans Professor and Director of Molecular Biology and Genetics at Johns Hopkins University, as well as heading up the Greider Lab there.

Hau was born in the small city of Velje in Denmark. She received her bachelors, masters, and Ph.D. degrees in physics all from the University of Aarhus. While working on her dissertation (on using silicon crystals as electrical conductors), she did research for seven months at CERN near Geneva. After graduating in 1991, she joined the Rowlands Institute for Science in Cambridge, Massachusetts, as a scientific staff member. Both at the Rowlands and after moving to Harvard in 1999 on a two-year fellowship (at the end of which she was awarded tenure), Hau began working on a pair of exotic phenomena: Bose-Einstein condensates (BEC), which occur in certain materials at ultra-low temperatures (~2 K), giving rise to unusual properties such as superfluidity; and slow light, in which the group velocity of photons interacting with a medium may be reduced far below the familiar value c the speed of light in a vacuum. Haus original application to the National Science Foundation (NSF) to fund her work on BEC was rejected on the grounds that her background was in theoretical physics and she did not have the experience to do such difficult experimental work.

Nothing daunted, she plunged ahead, gained alternative funding, and became one of the first researchers in the world to create a so-called pure BEC from a highly dilute gas (as opposed to helium-4, which is a liquid). However, she is best known for her pathbreaking work on slow light. In 1999, she and her team at Harvard used a BEC to slow a beam of light down to seventeen meters per second. Two years later, they succeeded in stopping light in its tracks. In her more recent work, Hau has been exploring novel interactions between ultracold atoms, slow light, and nanoscale systems. Her new work is thought to have great potential to revolutionize a number of different fields, from energy (photovoltaic cells, synthetic biofuels) to advanced forms of astronomical instrumentation to quantum computing. Hau is currently the Mallinckrodt Professor of Physics and of Applied Physics at Harvard University.

Jablonka (ne Tavori) was born in Poland. With her family, she emigrated to Israel in 1957. She received her bachelors degree in biology in 1976 and her masters degree in microbiology in 1980, both from Ben-Gurion University. Her masters thesis won Israels Landau Prize for outstanding masters of science work. In 1988, she earned her Ph.D. in Genetics from the Hebrew University in Jerusalem, where she worked under the supervision of Howard Cedar. Her dissertation won her nations Marcus Prize for outstanding Ph.D. work. While a Ph.D. student, Jablonka served as an Assistant Professor at Ben-Gurion University, teaching courses on genetics, microbiology, and biochemistry. Both before and after obtaining her PhD, she had a series of research assistantships and teaching fellowships, notably at the Van Leer Institute in Jerusalem, the Medical Research Councils Mammalian Development Unit in London, and the Edelstein Center for the History and Philosophy of Science, Technology, and Medicine at the Hebrew University.

After teaching for several years in the Biology Department at Tel Aviv University, Jablonka moved to the Cohn Institute for the History and Philosophy of Science and Ideas there, where she is currently a Professor and lectures mainly on the history and philosophical foundations of biology. In the years since, she has had numerous visiting professorships, including at Bielefeld University in Germany and University of CaliforniaBerkeley in the US. Jablonka is mainly known for her pathbreaking work on the integration of epigenetics (AKA Lamarckian inheritance) and evolutionary theory. She is a major contributor to what has come to be called the the extended evolutionary synthesis (EES). The author or co-author of more than fifty peer-reviewed papers, Jablonka has co-authored three influential textbooks: (with Marion J. Lamb) Epigenetic Inheritance and Evolution: The Lamarckian Dimension (Oxford University Press, 1995); (also with Lamb) Evolution in Four Dimensions: Genetic, Epigenetic, Behavioral, and Symbolic Variation in the History of Life, 2nd ed. (MIT Press, 2005); and (with Eytan Avital) Animal Traditions: Behavioural Inheritance in Evolution (Cambridge University Press, 2000).

Al-Kharafi was born in Kuwait. She received her bachelors of science degree in 1967 from Ain Shams University in Cairo. She then received her masters degree in 1972 and her Ph.D. in 1975, both from Kuwait University. While still in graduate school, she helped organize the new Corrosion and Electrochemistry Research Laboratory at Kuwait University. After graduating, she taught in the same universitys Department of Chemistry from 1975 until 1981, where she became department Chair in 1984 and a full Professor of Chemistry in 1987. From 1986 until 1989, she served as Dean of the Faculty of Science. In 1993, she was appointed Rector (an office later known as President) of Kuwait University, to help reconstruct the university in the aftermath of the trauma of the First Gulf War (19901991). The first woman to lead a major university in the Middle East, al-Kharafi remained in the post of President until 2002.

In her scientific work, al-Kharafi was primarily engaged in the study of corrosion in various technological systems, including engine cooling systems, distillation units for crude oil, and high temperature geothermal brines. She also worked on the electrochemical behavior of a wide variety of metals and metal alloys, from aluminum to vanadium to cadmium to low-carbon steel. Moreover, she collaborated in the discovery of a new class of molybdenum-based catalysts, which can be used to enhance the octane rating of gasoline without the use of undesirable benzene by-products. Al-Kharafi currently serves as a member of several boards of directors, including those of the Kuwait Foundation for the Advancement of Science and of the Kuwait-MIT Center for Natural Resources and the Environment. In addition, she is Vice-President of the World Academy of Sciences.

King was born in Evanston, Illinois, a suburb of Chicago. She received her bachelors degree in mathematics in 1966 from Carlteon College, and her Ph.D. in genetics in 1973 from University of CaliforniaBerkeley, where she worked under Allan Wilson. Kings dissertation consisted of a comparative protein analysis of humans and chimpanzees, on the basis of which she was the first researcher to determine that the two species share the vast majority of their genes in common. (Her original figure of 99% has been revised downward only slightly over the years to around 97%.) After a post-doc at University of CaliforniaSan Francisco, King joined the University of CaliforniaBerkeley faculty as a professor of genetics and epidemiology, a position she held from 1976 until 1995, when she moved to the University of Washington. In 1990, while still at Berkeley, she discovered that a single gene on chromosome seventeen (later called BRCA-1) plays an important role in many types of breast cancer.

Not only did Kings discovery lead to genetic tests that have enabled women with a family history of breast cancer to obtain more complete information about their own prospects for coming down with the disease, the techniques she developed in the isolation of BRCA-1 have also proven extremely useful to countless other researchers working on a host of other genetic illnesses. In the intervening years, King has branched out considerably, working on the genetics of other conditions, such as deafness, but also on projects such as using genetics to help identify the remains of those killed in civil conflicts in Argentina, El Salvador, and elsewhere, as well as to reconstruct prehistoric human migration patterns. A member of the National Academy of Sciences since 2005, and recipient of the Gruber Foundation Genetics Prize (2004), the Lasker Award (2014), and honorary doctorates too numerous to mention, King is currently the American Cancer Society Research Professor at the University of Washington.

Klein was born in Wilmington, Delaware. She obtained her bachelors degree in metallurgy in 1973 and her Ph.D. in ceramics in 1977, both from the Department of Materials Science and Engineering at MIT. Upon graduating in 1977, she joined the School of Engineering at Rutgers University, receiving tenure there in 1981 (the first woman to do so). She has been a visiting scientist at Sandia National Laboratory in Albuquerque, New Mexico, at the University of Grenoble in France, and at the Hebrew University of Jerusalem in Israel. Kleins field of scientific expertise lies in the sol-gel process, a method for producing solid materials such as glasses, ceramics, and organic-inorganic hybrid compounds from small molecules. Sol-gel processing methods refined by her have been applied to the development of a host of new devices, including ceramic membranes, solid electrolytes, fuel cell components, and planar waveguides.

Kleins best-known scientific contribution is probably her work on electrochromic window coatings. These are ceramic coatings that can be lightened or darkened through the use of a manually controlled dimmer attached to a battery. Reflecting away heat while still transmitting light in summer, as well as permitting solar heating in winter, such coatings are more versatile and efficient than traditional blinds and tintings, thus saving on heating and cooling costs. Klein is currently Distinguished Professor of Materials Science and Engineering at Rutgers University, as well as Graduate Director of the university, President of the American Association of University Professors (AAUP) there, and co-editor of the Journal of the American Ceramics Society.

Klinman was born in Philadelphia. She took her bachelors degree in 1962 and her Ph.D. in 1966, both from the University of Pennsylvania. She did post-doctoral research at the Weizmann Institute of Science in Rehovot, Israel, where she worked with David H. Samuel, and at the Institute for Cancer Research in Philadelphia, where she worked with Irwin Rose. Klinman stayed on as a permanent scientific staff member of the Institute for Cancer Research, where she worked for many years, before moving to University of CaliforniaBerkeley in 1978. Klinmans scientific career has been devoted to the study of enzyme catalysis. In her early work, she developed kinetic isotope effects for use as an experimental probe for studying the extremely rapid individual steps involved in enzyme action. In 1990, while working with a particular copper-containing amine oxidase present in bovine blood plasma, her team discovered the presence of the topaquinone (TPQ) molecule at the enzymes active site, thus demonstrating the existence of a new class of enzymes (quinoenzymes) that require protein-derived cofactors for proper functioning.

Klinmans pathbreaking work on quinoenzymes has opened up a whole new field of study with significant theoretical and therapeutic implications. Her most recent work focuses on the role of quantum mechanical tunneling in enzyme-catalyzed hydrogen activation reactions a phenomenon she studies with new technological probes also developed by her team. In 2012, Klinman was awarded the National Medal of Science, while in 2015, she received the Mildred Cohn Award in Biological Chemistry from the American Society for Biochemistry and Molecular Biology. Klinman is currently Professor of the Graduate School and Chancellors Professor at University of CaliforniaBerkeley, where she leads the Klinman Lab in the College of Chemistry.

Liskov (ne Huberman) was born in Los Angeles, California, but grew up in the San Francisco area. She earned her bachelors degree in mathematics (with a minor in physics) in 1961 from University of CaliforniaBerkeley. She applied to the Mathematics Department at Princeton University for graduate school, but they were still not accepting female graduate students at the time. She was accepted by Berkeley, but Liskov chose instead to go to work for the Mitre Corporation, a not-for-profit, research-and-development government contractor based in the Boston area. It was at Mitre that Liskov became interested in the still-infant field of computer programming. After a year, she moved to Harvard, where she worked on the problem of automated natural language translation. After a time, she decided to go back to school, and earned her Ph.D. in computer science from Stanford University in 1968 one of the first women anywhere to earn a doctorate in that field. At Stanford, Liskov worked closely with the artificial intelligence (AI) pioneer, John McCarthy; her dissertation was titled A Program to Play Chess Endgames. Upon graduation, she returned to Mitre, where she worked for many years as a member of their permanent research staff.

Among Liskovs many achievements in the fields of computer science and engineering are the following: the Venus operating systems (a low-cost, interactive time-sharing system); implementation of the CLU programming language and its extension, Argus (the first high-level language to support distributed programs, employing the technique of promise pipelining); and Thor (an object-oriented database system). She is also known for the eponymous Liskov Substitution Principle, an important logical/mathematical procedure in the implementation of any object-oriented programming system. In 2004, Liskov received the John von Neumann Medal bestowed by the Institute of Electrical and Electronics Engineers (IEEE), while in 2008 she won the Alan M. Turing Award bestowed by the Association for Computing Machinery (ACM) two of the highest honors in her field. Liskov is currently Institute Professor at MIT, as well as Ford Professor of Engineering in MITs Electrical Engineering and Computer Science Department in the School of Engineering.

Luu (ne Luu Le Hang) was born in Saigon, in what is now the Socialist Republic of Vietnam but was at the time the Republic of Vietnam (South Vietnam). In April of 1975, the 11-year-old Luu fled South Vietnam with her family. After some time first in a refugee camp, then with relatives living in Paducah, Kentucky, the family finally settled in Ventura, California, where Luu attended high school. She obtained a bachelors degree in physics in 1984 from Stanford University. After some time at University of CaliforniaBerkeley, she moved to MIT, where she received her Ph.D. in the Department of Earth, Atmospheric, and Planetary Science in 1990. After several post-docs, Luu taught at Harvard and at Leiden University in the Netherlands, before returning to MIT, where she is currently a technical staff member in the Active Optical Systems Group at Lincoln Laboratory.

Mayer was born in Wausau, Wisconsin. She took her bachelors degree in symbolic systems in 1997 and her masters degree in computer science in 1999, both from Stanford University. For both degrees, she specialized in artificial intelligence (AI), including developing a travel advice software system with a natural language user interface. Upon graduation, Mayer interned at SRI International in Menlo Park, California, and at UBS Financials research lab based in Zurich, Switzerland. Next, she turned down an offer to teach at Carnegie Mellon University in order to join the then-new Google company as employee number twenty. Mayer was the companys first female engineer. She started out writing code, as well as supervising small teams tasked with the design and development of Googles search offerings. Mayer holds several patents in artificial intelligence and interface design. Moving quickly into management, Mayer placed her own personal stamp on the company, especially as the person mainly responsible for the elegant, minimalist look of Googles home page, with a single search bar centered on the page surrounded by white space. From there, she went on to oversee the launch and development of many of Googles iconic products, overseeing the development of a host of new AI-based initiatives, including Google AdWords, Google Search, Google Images, Google Maps, Google Product Search, Google Toolbar, iGoogle, and Gmail, among others.

In 2005, Mayer was named Vice President of Search Products and User Experience at Goggle. In 2011, she spearheaded Googles $125 million acquisition of the survey site, Zagat, to bolster Google Maps. During her years at Google, Mayer also frequently functioned as one of the companys most prominent spokespersons. In 2012, she was appointed President and CEO of Yahoo! However, as a result of an ultimately unsuccessful $1+ billion acquisition of Tumblr undertaken to buoy the companys sagging fortunes, as well as other controversial cost-saving and performance-enhancing measures, she became unpopular with the companys rank-and-file. Mayer resigned from Yahoo! in June of 2017, in conjunction with the companys sale to Verizon Communications. Mayer, who currently resides in San Francisco, has a net worth estimated to be around $540 million.

Miller was home-schooled in the small town of Niskayuna, near Schenectady in upstate New York. She competed on the US team at the 45th International Mathematical Olympiad in 2004 in Athens, Greece, where she won a gold medal a first ever for an American woman. She received her bachelors degree summa cum laude in mathematics in 2008 from Harvard University, where while still a undergraduate she published two papers on modular forms in number theory, and a third paper giving the best known upper bounds on superpatterns in the theory of permutation patterns. While at Harvard, she also won the Elizabeth Lowell Putnam Prize for three years running (2005 2007), equaling a record previously set by Ioana Dumitriu. Her senior thesis, Explicit Class Field Theory in Function Fields: Gross-Stark Units and Drinfeld Modules, won the Hoopes Prize. Following her bachelors degree, Miller attended Cambridge University in England for a year on a Churchill Scholarship.

Miller earned her Ph.D. in 2014 from Princeton University, where she worked under the supervision of Fields Medalist, Manjul Bhargava. Her dissertation was titled, Counting Simple Knots via Arithmetic Invariants. Knot theory is a sub-discipline of topology with potentially important applications in quantum field theory, condensed-matter theory, and other areas of theoretical physics. After receiving her PhD, Miller returned to Harvard where she is currently a Benjamin Peirce and NSF Postdoctoral Fellow. She continues to work on algebraic number theory, arithmetic invariant theory, and their connections with classical knot invariants.

Morel was born in Issy-les-Moulineaux, a southeastern suburb of Paris. She completed her undergraduate work at the cole Normale Suprieure, and earned her Ph.D. in 2005 at the Universit de Paris-Sud XI under the direction of Grard Laumon. Her dissertation, titled Complexes dintersection des compactifications de Baily-Borel - le cas des groupes unitaires sur Q [Intersection Complexes of Baily-Borel Compactifications The Case of Unitary Groups Over Q], relates to a problem in the Langlands Program, an ambitious group of conjectures which seeks to unite various fields of mathematics such as algebraic number theory, algebraic geometry, and representation theory (a generalization of group theory) into a sort of Grand Unified Theory of mathematics.

After completing her PhD, Morel spent three years (from 2006 until 2009) at the Institute for Advanced Study (IAS) in Princeton, New Jersey, in the US. In 2009, she accepted a teaching position at Harvard University. In 2012, Morel moved to Princeton University, where she is currently a Professor of Mathematics. Since moving to Princeton, she has also been the beneficiary of two years additional affiliation with the IAS (2010 2011; 2012 2013). Moreover, between 2006 and 2011, Morel was a Clay Research Fellow under the auspices of the Clay Mathematics Institute (CMI) in Peterborough, New Hampshire. Morel continues to do research and publish on the Langlands Program.

Moser was born in Fosnavg, a small town on one of the westernmost islands off the coast of Norway. She attended the University of Oslo, where she began to study the link between brain and behavior in the laboratory of Terje Sagvolden. It was also at this time that she met her future husband and close scientific collaborator, Edvard I. Moser (the couple married in 1985). She received her undergraduate degree in general sciences with a special emphasis on neurobiology in 1983. For her masters degree, she worked in the laboratory of Per Andersen, graduating in psychology and neurobiology in 1990. For her PhD, Moser continued working in the Andersen lab, where she now focused on the the role of the hippocampus and associated neural structures in learning. During this time, she also did a stint in the lab of Richard G. Morris at the University of Edinburgh. It was Morris who had originally conceived of the water maze a specialized device for studying the process of learning in rats which Moser adapted for her own work.

Moser received her doctorate in neurophysiology in 1995, after which she occupied a short post-doctoral visiting fellowship at University College London to study with the renowned neuroscientist, John OKeefe. In 1996, she was appointed Associate Professor of Biological Psychology at the Norwegian University of Science and Technology (NTNU) in Trondheim, where she advanced to the rank of full Professor in 2000. In 2002, the group she spearheaded at NTNU became known as the Centre for the Biology of Memory. Moser also helped establish the Institute for Systems Neuroscience at NTNU in 2007. She is currently Head of Department at NTNUs Centre for Neural Computation. In 2005, Moser and her team discovered what are now known as grid cells in the entorhinal cortex, a structure within the medial temporal lobe connecting the neocortex to the hippocampus. Basically, they demonstrated that when a rat learns to navigate a maze, an isomorphic pattern of neural circuitry is established in this structure. For this pathbreaking work, Moser shared in the 2014 Nobel Prize for Physiology or Medicine (along with her husband and John OKeefe).

Nsslein-Volhard (ne Volhard) was born near Magdeburg, Germany. She studied general science at the Johann-Wolfgang-Goethe-Universitt in Frankfurt, before moving to Eberhard-Karls-Universitt in Tbingen, where she received her undergraduate degree in biochemistry in 1968. For her graduate work, she remained in Tbingen; however, she now began attending the lectures of Gerhard Schramm, Heinz Schaller, and other eminent scientists at the Max Planck Institute for Virus Research (later rechristened the Max Planck Institute for Developmental Biology). She obtained her Ph.D. in genetics there in 1973 under the supervision of Schaller. For her dissertation, she studied the binding of RNA polymerase to the DNA molecule in Escherichia coli. Techniques she developed at this time for purifying RNA polymerase opened up new avenues for genetics research extending in many different directions.

After graduating, Nsslein-Volhard received a post-doc to work with world-renowned developmental biologist Walter Gehring at the University of Basel in Switzerland. It was in Gehrings laboratory that she undertook the painstaking work of genetic screening of mutations involving the bicaudal gene in the fruit fly (Drosophila melanogaster) on which her reputation is based. Her landmark 1977 paper, Genetic analysis of pattern-formation in the embryo of Drosophila melanogaster. turned the field of developmental biology on its ear. Scientists were now able to intervene in the development of the vertebrate embryo in a controlled way, allowing them for the first time to study the mechanistic details of embryonic development. In 1978, Nsslein-Volhard accepted a position at the European Molecular Biology Laboratory (EMBL) in Heidelberg, where she continued her groundbreaking work on Drosophila embryos, making many additional advances. In 1981, she moved to the Friedrich Miescher Laboratory, back in Tbingen, before being appointed in 1986 Director of the newly renamed Max Planck Institute for Developmental Biology, where she remains until today as an emerita researcher. In 1995, Nsslein-Volhard shared in the Nobel Prize for Physiology or Medicine (with Edward B. Lewis and Eric Wieschaus) for her work on the genetic control of early embryonic development.

Perlman was born in Portsmouth, Virginia, and grew up near Asbury Park, New Jersey. She entered MIT to study mathematics for her bachelors degree, but ended up debugging programs for the LOGO group within the Artificial Intelligence Laboratory (as it was then known) to earn some money. LOGO was an early educational robotics language. It was while working for this group under the supervision of Seymour Papert that Perlman was inspired to design a child-friendly version of LOGO called TORTIS (Toddlers Own Recursive Turtle Interpreter System), which was an interactive robot with a special keyboard that preschoolers could use to learn the basics of programming. Historians have acclaimed TORTIS as a pioneering example of tangible computing, as the field has come to be known. Perlman has stated that she failed to follow up on TORTIS for fear that the involvement of small children might prevent her from being taken seriously as a scientist. After earning her bachelors and masters degrees in mathematics from MIT, she obtained her Ph.D. in computer science in 1988 from the same institution.

After graduating, she went to work for Digital Equipment Corporation (DEC), where she made most of the conceptual innovations for which she is famous. These include protocols she designed in the 1980s (IS-IS), which continue to be used for routing Internet Protocol (IP) to this day. She is perhaps best known for inventing the Spanning Tree Algorithm, which transformed Ethernet from its originally limited scalability into a protocol capable of handling large clouds. She later improved on this work by designing TRILL (TRansparent Interconnection of Lots of Links), which allows Ethernet to make optimal use of bandwidth. On account of these and other fundamental contributions to digital network infrastructure, she is often referred to as the Mother of the Internet a sobriquet she modestly rejects. Perlman has written two influential college textbooks her 1992 classic, Interconnections: Bridges, Routers, Switches, and Internetworking Protocols, brought simplifying clarity to a confused field and holds over one hundred patents. She is currently employed by Dell EMC.

Porco was born in the Bronx, in New York City. She earned her bachelors degree in 1974 from State University of New York (SUNY) at Stony Brook. She received her Ph.D. in 1983 in the Division of Geological and Planetary Sciences from California Institute of Technology (CalTech), in Pasadena, California, where she wrote her dissertation on the discoveries made by NASAs unmanned spacecraft, Voyagers 1 and 2, while exploring the rings of Saturn. Immediately upon graduation, Porco joined the University of Arizonas Department of Planetary Sciences, and was appointed a member of the Voyager Imaging Team. In 1986, she was an active member of the team managing Voyager 2s encounter with Uranus, and in 1989, she headed up the Rings Working Group within the Imaging Team participating in Voyager 2s encounter with Neptune. Among the many Voyager-based discoveries attributable to Porco and her team are eccentric spokes among the rings of Saturn, the Uranian moons Cordelia and Ophelia, which shepherd Uranuss rings, and the Neptunian moon Galatea, which performs a similar function for Neptunes ring arcs.

In 1990, Porco was named leader of the Imaging Team for the Cassini space probe, which was inserted into orbit around Saturn and deployed the Huygens probe into the upper atmosphere of Saturns largest moon, Titan. During this mission, Porcos team discovered several new moons in orbit around Saturn, as well as new features of its ring system, a hydrocarbon lake on Titan, and water geysers on the moon Enceladus. In 1993, Porco coauthored a paper predicting that acoustic oscillations within Saturn are responsible for creating particular features in its ring system. This prediction was confirmed in 2013 by data collected by the Cassini spacecraft, proving that planetary rings can be used as a sort of seismograph to record oscillatory motions within a host planet. Most recently, Porco served as a member of the Imaging Team for the recent Pluto flyby mission. The author of more than 110 scientific papers, and one of the worlds experts on planetary ring formations, Porco is currently Senior Research Scientist at the Space Science Institute in Boulder, Colorado.

Randall was born in Queens, in New York City. She received her bachelors degree in physics from Harvard University in 1983, and her Ph.D. in theoretical particle physics in 1987 from the same university, where Howard Georgi served as her dissertation advisor. After graduating, Randall held a postdoctoral fellowship at University of CaliforniaBerkeley and at the Lawrence Berkeley Laboratory until 1990, after which she returned to Harvard for a year as a member of the exclusive Junior Fellows program there. In 1991, she accepted a position as Assistant Professor of Physics at MIT, where she was promoted to Associate Professor in 1995. In 1998, Randall moved to the Princeton Department of Physics as a full Professor. After another brief stint at MIT, in 2001 she joined the Harvard Physics Department, which has been her home base ever since. She is currently the Frank B. Baird, Jr., Professor of Science in the Physics Department at Harvard, where she is also a member of the Center for the Fundamental Laws of Nature/High Energy Theory Group.

Randall works on elementary particles and fundamental forces, and has studied a wide variety of theories and models, the most recent of which involve extra dimensions of space. Moreover, she has made major contributions to such areas of theoretical physics as the standard model, the Higgs boson, supersymmetry, grand unified theories (GUTs), general relativity, cosmological inflation, baryogenesis, and dark matter. With more than 160 scientific papers to her credit, Randall is also the author of four books aimed at a popular audience, including most recently Dark Matter and the Dinosaurs: The Astounding Interconnectedness of the Universe (Ecco, 2015). In addition, she wrote the libretto for an opera, Hypermusic Prologue by Hctor Parra, based on an earlier book of hers, Warped Passages: Unraveling the Mysteries of the Universe's Hidden Dimensions (Ecco, 2005). Elected a member of the National Academy of Sciences in 2008, for a time in the early 2000s Randall was one of the worlds most-cited active theoretical physicists.

Raymo was born in Los Angeles. She received her bachelors degree in geology in 1982 from Brown University. She went on to earn two masters degrees, in 1985 and 1988, from Columbia Universitys Lamont-Doherty Earth Observatory, as well as a Ph.D. in 1989 from the same institution. After graduating, she spent a year at the University of Melbourne in Australia. Between 1991 and 2011, Raymo taught at University of CaliforniaBerkeley (briefly), at MIT, and at Boston University. For a number of years during this period, she was also an Adjunct Scientist at the Woods Hole Oceanographic Institute. In 2011, she returned to the Lamont-Doherty Earth Observatory, where she is currently Lamont Research Professor and Director of the Lamont-Doherty Core Repository.

Over the course of her career, Raymo has participated in or led field expeditions to Tibet, Patagonia, South Africa, southern India, and Western Australia, among other places. Her particular area of interest lies in understanding the causal factors responsible for the earths climate variation over geological time. This involves many different factors, including variations in the earths orbit (and thus distance from the sun), variations in solar activity, plate tectonics, and the evolution of life (and thus its contribution to the physics and the chemical composition of the land surface, the oceans, and the atmosphere). One of Raymos signal contributions to the field is her Uplift-Weathering Hypothesis (developed with William Ruddiman and Philip Froehlich). This hypothesis states that during mountain formation (tectonic uplift), such as on the Tibetan plateau, many minerals that become exposed at the surface interact with atmospheric CO2 in a process of chemical weathering, leading to a net loss of carbon to the atmosphere and a lowering of the earths mean surface temperature. The hypothesis has proved to be quite complicated in its details, and thus difficult to test. It is still being hotly debated. In 2014, Raymo received two of the most prestigious awards in her field: the Milutin Milankovic Medal of the European Geosciences Union and the Wollaston Medal of the Geological Society of London. In 2016, she was elected a member of the National Academy of Sciences.

Seager was born in Toronto, Ontario, in Canada. She earned her bachelors degree in mathematics and physics in 1994 from the University of Toronto. For he graduate work, she moved to Harvard University, where she received her Ph.D. in astronomy in 1999. For her dissertation, Extrasolar Planets under Strong Stellar Irradiation, she worked on developing theoretical models of the atmospheres of extrasolar planets, or exoplanets, under the direction of Dimitar Sasselov. After graduating, she was a Postdoctoral Research Fellow for three years at the Institute for Advanced Study in Princeton, New Jersey. She also held a position as a Senior Research Staff member at the Carnegie Institution of Washington through 2006. In 2007, Seager joined MIT as a Associate Professor; she became a full Professor there in 2010. She is currently the Class of 1941 Professor of Physics and Planetary Science at MIT.

Seager has been at the forefront of efforts to discover and study exoplanets, particularly by analyzing their atmospheres through spectroscopic analysis. The difficulty this presents lies in the extreme faintness of the light reflected by extrasolar planets in relation to the light from the nearby stars they orbit. Seager has worked on several NASA missions past, ongoing, and in the planning stages. A future mission she is currently involved in developing will deploy a novel mechanical device to occlude starlight in order to make the closer study of exoplanets feasible. (See the video clip below for details.) Named a MacArthur Fellow in 2013, Seager is also known for the Seager Equation, a revised version of the famous Drake Equation, which provided a formula for estimating the probability of the existence of extraterrestrial life in the universe. She has co-edited (with L. Drake Deming) the volume of conference proceedings, Scientific Frontiers in Research on Extrasolar Planets (Astronomical Society of the Pacific, 2003), and authored two popular college textbooks: Exoplanets (University of Arizona Press, 2010) and Exoplanet Atmospheres: Physical Processes (Princeton UP, 2010).

Shotwell was born in Libertyville, Illinois. She received her bachelor of science degree from Northwestern University, and her masters degree in in mechanical engineering and applied mathematics from the same university. She is currently the President and Chief Operating Officer of SpaceX, a private corporation which provides spacecraft- and rocket-manufacturing and -launching services to both government and private-sector customers. SpaceX, founded in 2002 by the companys current CEO, Elon Musk, was the first private company to send a liquid-fuel rocket into earth orbit (2008) and to reach the International Space Station (2012), as well as the first group, period, to effect a propelled vertical landing of a rocket booster (2015) and to develop an integrated, vertical take-off and landing, reusable rocket system (2017).

Shotwell has been with SpaceX from the companys inception in 2002, when she was brought on board as Vice President of Business Development. Before joining SpaceX, she had worked briefly for the Chrysler Corporation, and, from 1988 until 1998, for the Aerospace Corporation, a federally funded, non-profit, research and development center. During this time, she wrote dozens of technical papers developing new concepts and analyzing operational risks in many different fields of space flight, from small spacecraft design to space shuttle integration, and from infrared signature target modeling to thermal analysis in relation to reentry vehicles. Between 1998 and 2002, she served as Director of the space systems division of Microcosm, Inc. During her early years at SpaceX, Shotwell oversaw the development of the highly successful Falcon family of launch vehicles, culminating in a commercial resupply services contract with the International Space Station. The first resupply mission was launched atop a fully reusable Falcon-9 rocket in 2012. She is currently overseeing ambitious plans to send a manned spacecraft into earth orbit next year (2018), with the eventual goal of a manned mission to Mars by 2024.

Silverstein earned her bachelors degree in physics in 1992 from Harvard University, and her Ph.D. in physics in 1996 from Princeton University, where she studied with Ed Witten. After a post-doc at Rutgers University, in 1997 she was appointed an Assistant Professor at the Stanford Linear Accelerator Center (SLAC) now known as the SLAC National Accelerator Laboratory which is a federally owned particle accelerator laboratory operated by Stanford University. During this early stage of her career, Silverstein was also appointed a MacArthur Fellow and a Member of the Institute for Advanced Study, both in 1999. In 2001, she was promoted to Associate Professor status at SLAC, where she became a full Professor in 2006. During a sabbatical year (2009 2010), she was a Visiting Professor at the Kavli Institute for Theoretical Physics and in the Department of Physics in University of CaliforniaSanta Barbara.

Silversteins work focuses on the nature of the fundamental laws of physics, as well as the origin and early evolution of the universe. She has made important theoretical contributions to a number of different areas of current research, including the cosmic microwave background radiation, cosmic inflation, dark energy, supersymmetry breaking, the dynamics of interacting scalar fields, the unification of string vacua, and the origin of the hierarchical structure of the universe from the Planck scale to the cosmological horizon. Silverstein is perhaps best known for her work (with Allan Adams and Joseph Polchinski) on closed string tachyon condensation, resulting in the resolution of certain spacetime singularities. She is currently Professor of Physics at SLAC. Sycara has also been very active professionally, serving

Solomon was born in Chicago, Illinois. She received her bachelors degree in chemistry in 1977 from the Illinois Institute of Technology and her Ph.D. in chemistry in 1981 from University of CaliforniaBerkeley. Upon graduating, Solomon went to work for the National Oceanic and Atmospheric Administration (NOAA) in Boulder, Colorado, where she spent the bulk of her career. There, she worked in the Aeronomy Laboratory, the Earth System Research Laboratory, and at the time of her retirement in 2011, was head of the Chemistry and Climate Processes Group. That year, she joined MITs Department of Earth, Atmospheric and Planetary Sciences. It was while working for NOAA during the 1980s that Solomon did the work upon which her reputation primarily rests. In the 1970s, it had been observed that the ozone layer on the stratosphere which screens deadly cosmic radiation and upon which all life on earth depends was becoming depleted. The problem was especially acute over Antarctica, giving rise to the phrase ozone hole.

Solomon and her team at NOAA began to study the problem and came up with what proved to be the correct causal mechanism: the interaction of atmospheric ozone with man-made chlorofluorocarbons (CFCs), which were present at that time in a wide variety of refrigerants and aerosol propellants. To test the theory, Solomon led expeditions to Antarctica in 1986 and 1987, personally carrying out observations showing that the abundance of chlorine compounds there is about one hundred times greater than expected, thus confirming the CFC theory of the etiology of the Antarctic ozone hole. As a result of Solomons work (as well as that of James Lovelock and others), several international treaties were signed in the late 1980s phasing out the production and commercial use of CFCs. By the early twenty-first century, it had become clear that the strategy was working stratospheric ozone depletion was being reversed. Solomon, who is a member of the National Academy of Sciences and was awarded the National Medal of Science in 1999, is currently the Ellen Swallow Richards Professor of Atmospheric Chemistry and Climate Science at MIT.

Soto received her bachelors degree in biology from the Colegio Padre Elizalde in Buenos Aires, Argentina, and her MD from the University of Buenos Aires. After obtaining her MD, Soto took a research position with the Institut National de la Sant et de la Recherche Mdicale (INSERM), Unit 34, in Lyon. It was there, in 1976, that Soto together with her lifelong scientific collaborator and partner, Carlos Sonnenschein first became convinced that the received view of the endocrine regulation of cell proliferation was seriously flawed. In a nutshell, Soto and Sonnenschein argued that cell proliferation occurs, not as a result of direct endocrine (especially, sex hormone) stimulation, but rather by means of a default homeodynamic process that is foundational to all cellular life. According to their theory, the endocrine system exercises only negative feedback control by blocking the action of blood plasma borne inhibitors. The implications of their ideas, which have received experimental confirmation but remain controversial, are wide-ranging.

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50 Top Women in STEM - TheBestSchools.org

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The Conrad Prebys Foundation to Support the Discovery and Development of Personalized ASO Medicines for Nano-rare Patients – Business Wire

Posted: March 25, 2022 at 2:18 am

SAN DIEGO--(BUSINESS WIRE)--n-Lorem, a nonprofit foundation, is the recipient of a $300,000 grant from The Conrad Prebys Foundation that will support n-Lorems discovery and development efforts to provide personalized experimental antisense oligonucleotide (ASO) medicines for nano-rare patients (1 to 30 patients worldwide) for free, for life.

We are grateful to be a part of the San Diego community and to be working with the Foundation whose support may have a profound impact on the lives of several of our nano-rare patients. Nano-rare patients have a genetic mutation that is unique to them, and therefore they have few, if any therapeutic options. Today ASO technology and n-Lorem represent the only option for the treatment for many of these nano-rare patients, who are desperate and isolated, said Stanley T. Crooke, M.D., Ph.D., Founder, CEO and Chairman of n-Lorem Foundation. We have more than 40 nano-rare patients at n-Lorem, eight of whom are located in San Diego county. Out of this work, we hope to advance several programs from discovery into development. This work will lead us one step closer to providing a personalized ASO medicine for each nano-rare patient.

The funding will support n-Lorems efforts to discover optimal ASO candidates for several nano-rare patients. Once identified, n-Lorem will conduct preclinical studies necessary to support clinical development for each optimized ASO.

Through significant investments in medical research during his lifetime, Conrad Prebys helped pave the way for private philanthropy to play a meaningful role in the advancement of the field. The Conrad Prebys Foundation is proud to continue this legacy by supporting n-Lorem Foundations unique and vitally important work in rare genetic disease treatment, said Erin Decker, Director of Grantmaking at The Conrad Prebys Foundation. Beyond the significant communities of rare disease patients, n-Lorems research has the potential to accelerate important breakthroughs in the biomedical understanding of diseases in general for the benefit of all.

Learn more about n-Lorems mission at http://www.nlorem.org, and please consider giving to n-Lorem to bring hope, possibility and treatment options to these needy patients and families.

The Conrad Prebys Foundation

The Conrad Prebys Foundation was established by real estate entrepreneur Conrad Prebys to perpetuate his commitment to philanthropic endeavors. The Conrad Prebys Foundation inspires transformational change by funding projects in alignment with Conrad Prebys legacy interests and continuing his efforts that spark meaningful advancement in our communities. For more information, visit http://www.ConradPrebysFoundation.org.

About n-Lorem

n-Lorem Foundation is a non-profit organization established to apply the efficiency, versatility and specificity of antisense technology to charitably provide experimental antisense oligonucleotide (ASO) medicines to treat nano-rare patients diagnosed with diseases that are the result of a single genetic defect unique to only one or very few individuals. Nano-rare patients describe a very small group of patients (1-30 worldwide) who, because of their small numbers, have few if any treatment options. n-Lorem Foundation was created to provide hope to these nano-rare patients by developing individualized ASO medicines, which are short strands of modified DNA that can specifically target the transcripts of a defective gene to correct the abnormality. The advantage of experimental ASO medicines is that they can be developed rapidly, inexpensively and are highly specific. To date, n-Lorem has assisted in the development and treatment of 14 nano-rare patients and received over 130 applications for treatment with more than 50 nano-rare patients approved. n-Lorem was founded by Stanley T. Crooke, M.D., Ph.D., former chairman and CEO of Ionis Pharmaceuticals, who founded Ionis Pharmaceuticals in 1989 and, through his vision and leadership, established the company as the leader in RNA-targeted therapeutics. Follow us on Twitter, Facebook, LinkedIn, YouTube and Instagram.

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The Conrad Prebys Foundation to Support the Discovery and Development of Personalized ASO Medicines for Nano-rare Patients - Business Wire

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Space the next frontier for cancer treatment? – Australian Jewish News

Posted: March 25, 2022 at 2:17 am

AN Israeli cancer drug has returned to Earth after a series of tests on the International Space Station (ISS), conducted in the hope it may prove more effective in micro-gravity.

Prof. Yehezkel Bernholtz of the Hebrew University is analysing results from the experiment to see whether there is any truth to his hypothesis that treating cancer patients with his drug in space-like conditions, where gravity is lower than normal, could have benefits.

Bernholtz, an expert in biochemistry, nanotechnology and drug development, is the inventor of Doxil, which became the first nano drug to receive approval from the US Food and Drug Administration, back in 1995.

Almost a million people around the world are believed to have been treated with the drug, including patients suffering from ovarian cancer and multiple myeloma. Bernholtz, the founder of Ayana Pharma, designed an experiment in which the drug meets tumour cells on the ISS, and packaged it in a container the size of two cigarette boxes.

It was blasted into space in early January on a SpaceX Falcon 9, as part of a smart laboratory developed by Israeli company SpacePharma, and recently arrived back on Earth.

What we want to check is whether the active molecules that kill the tumour cells are released, when in microgravity, at a rate and in a manner that makes them more effective, Bernholtz told The Times of Israel.

Prof. Yehezkel Bernholtz of the Hebrew University and founder of ay Pharma, holding a vial of Doxil (courtesy of Ayana Pharma)

He said that the microgravity of space is the best place to test the possibility, but if microgravity is found to boost the medicine, then the conditions of space can be replicated, to a degree, on Earth. If this idea proves correct, we already have equipment to imitate microgravity on Earth, and we can use it with cells, then to test with small animals, and if relevant we can try to apply microgravity to humans undergoing cancer treatment.

The samples will now undergo a series of tests, and its results will be examined and analysed so that we can better understand the effects that zero gravity has on Doxil and whether there is a change in the drug itself or in its action against cancer cells under zero-gravity conditions.

NASA and others are deeply interested in the potential of exomedicine, the study of medicine in zero gravity. NASA has explained the rationale in apost: Without gravity, cells, molecules, protein crystals, and microbes behave in very different ways.

Microgravity thus presents opportunities to explore new and potentially game-changing discoveries in areas such as human tissue regeneration, drug development, treatments for diseases such as cancer and other life-threatening and chronic conditions, as well as energy and novel materials.

The potential of exomedicine for impacting regular drugs like aspirin is thought to be limited, but its believed that some drugs with complex structures that are easily impacted by changing environments could show significant differences in zero gravity.

Bernholtz said that Doxil is well suited for space studies as it has a complex structure with qualities that could conceivably change in zero gravity. Complex drugs are much more likely to go through changes that other drugs dont go through, he said.

Bernholtz added: This is a highly exciting progress in the world of cancer treatment research as well as in our understanding of the impact of microgravity conditions on the structure and perforce of complex drugs. We are all hoping for encouraging results.

Times of Israel

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MorphoSys and Incyte Announce Swissmedic Temporary Approval of Minjuvi(R) (tafasitamab) in Combination with Lenalidomide for the Treatment of Adults…

Posted: March 25, 2022 at 2:16 am

MorphoSys and Incyte Announce Swissmedic Temporary Approval of Minjuvi(R) (tafasitamab) in Combination with Lenalidomide for the Treatment of Adults with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

PLANEGG and MUNICH, GERMANY and MORGES, SWITZERLAND / ACCESSWIRE / March 22, 2022 / MorphoSys AG (FSE:MOR) (NASDAQ:MOR) and Incyte (INCY) today announced that the Swiss agency for therapeutic products (Swissmedic), has granted temporary approval for Minjuvi(R) (tafasitamab) in combination with lenalidomide, followed by Minjuvi monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), after at least one prior line of systemic therapy including an anti-CD20 antibody, who are not eligible for autologous stem cell transplant (ASCT). Incyte holds exclusive commercialization rights for Minjuvi in Switzerland.

The approval of Minjuvi by Swissmedic is excellent news, said Jonathan Dickinson, Executive Vice President and General Manager, Incyte Europe. There are a substantial number of people living with relapsed or refractory DLBCL in Switzerland and were pleased to be able to offer them a new treatment option.

DLBCL is a fast-growing cancer and can be very hard to treat. Up to 40% of DLBCL patients either relapse after they have been treated or dont respond to initial treatment at all, said Mike Akimov, M.D., Ph.D., Head of Global Drug Development, MorphoSys. Minjuvi addresses this unmet need and its approval in Switzerland is a crucial milestone for these patients.

The approval is based on the results from the L-MIND study evaluating the safety and efficacy of tafasitamab in combination with lenalidomide as a treatment for patients with relapsed or refractory DLBCL who are not eligible for autologous stem cell transplant (ASCT). The results showed a best objective response rate (ORR) of 56.8% (primary endpoint), including a complete response (CR) rate of 39.5% and a partial response rate (PR) of 17.3%, as assessed by an independent review committee. The median duration of response (mDOR) was 43.9 months after a minimum follow up of 35 months (secondary endpoint). Tafasitamab together with lenalidomide was shown to provide a clinically meaningful response and the side effects were manageable.[2]

Incyte and MorphoSys share global development rights to tafasitamab; Incyte has exclusive commercialization rights to tafasitamab outside the U.S. Tafasitamab is co-marketed by Incyte and MorphoSys under the brand name Monjuvi(R) (tafasitamab-cxix) in the U.S., and is marketed by Incyte under the brand name Minjuvi in Europe, the UK and Canada.

About Diffuse Large B-Cell LymphomaDLBCL is the most common type of non-Hodgkin lymphoma in adults worldwide, comprising 40% of all cases[3]. Each year around 16,000 patients in Europe are diagnosed with relapsed or refractory DLBCL[4],[5],[6]. The condition is characterized by rapidly growing masses of malignant B-cells in the lymph nodes, spleen, liver, bone marrow or other organs[7]. It is an aggressive disease with about one in three patients not responding to initial therapy or relapsing thereafter[8],[9],[10],[11].

About L-MINDThe L-MIND trial is a single arm, open-label Phase 2 study (NCT02399085) investigating the combination of tafasitamab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have had at least one, but no more than three prior lines of therapy, including an anti-CD20 targeting therapy (e.g., rituximab), who are not eligible for high-dose chemotherapy (HDC) or autologous stem cell transplant (ASCT). The studys primary endpoint is overall response rate (ORR). Secondary outcome measures include duration of response (DoR), progression-free survival (PFS) and overall survival (OS). The study reached its primary completion in May 2019.

For more information about L-MIND, visit https://clinicaltrials.gov/ct2/show/NCT02399085.

About Minjuvi(R) (tafasitamab)Tafasitamab is a humanized Fc-modified CD19 targeting monoclonal antibody. In 2010, MorphoSys licensed exclusive worldwide rights to develop and commercialize tafasitamab from Xencor, Inc. Tafasitamab incorporates an XmAb(R) engineered Fc domain, which mediates B-cell lysis through apoptosis and immune effector mechanism including Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP).

In the U.S., Monjuvi(R)(tafasitamab-cxix) is approved by the U.S. Food and Drug Administration in combination with lenalidomide for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT). This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

In Europe, Minjuvi(R) (tafasitamab) received conditional approval, in combination with lenalidomide, followed by Minjuvi monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT).

Tafasitamab is being clinically investigated as a therapeutic option in B-cell malignancies in several ongoing combination trials.

Minjuvi(R) and Monjuvi(R) are registered trademarks of MorphoSys AG. Tafasitamab is co-marketed by Incyte and MorphoSys under the brand name Monjuvi(R) in the U.S., and marketed by Incyte under the brand name Minjuvi(R) in Europe, the UK and Canada.

XmAb(R) is a registered trademark of Xencor, Inc.

About MorphoSysAt MorphoSys, we are driven by our mission to give more life for people with cancer. As a global commercial-stage biopharmaceutical company, we use groundbreaking science and technologies to discover, develop, and deliver innovative cancer medicines to patients. MorphoSys is headquartered in Planegg, Germany, and has its U.S. operations anchored in Boston, Massachusetts. To learn more, visit us at http://www.morphosys.com and follow us on Twitter and LinkedIn.

About Incyte Incyte is a Wilmington, Delaware-based, global biopharmaceutical company focused on finding solutions for serious unmet medical needs through the discovery, development and commercialization of proprietary therapeutics. For additional information on Incyte, please visit Incyte.com and follow @Incyte.

MorphoSys Forward-Looking StatementsThis communication contains certain forward-looking statements concerning the MorphoSys group of companies. The forward-looking statements contained herein represent the judgment of MorphoSys as of the date of this release and involve known and unknown risks and uncertainties, which might cause the actual results, financial condition and liquidity, performance or achievements of MorphoSys, or industry results, to be materially different from any historic or future results, financial conditions and liquidity, performance or achievements expressed or implied by such forward-looking statements. In addition, even if MorphoSys results, performance, financial condition and liquidity, and the development of the industry in which it operates are consistent with such forward-looking statements, they may not be predictive of results or developments in future periods. Among the factors that may result in differences are that MorphoSys expectations may be incorrect, the inherent uncertainties associated with competitive developments, clinical trial and product development activities and regulatory approval requirements, MorphoSys reliance on collaborations with third parties, estimating the commercial potential of its development programs and other risks indicated in the risk factors included in MorphoSys Annual Report on Form 20-F and other filings with the U.S. Securities and Exchange Commission. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements. These forward-looking statements speak only as of the date of publication of this document. MorphoSys expressly disclaims any obligation to update any such forward-looking statements in this document to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statement is based or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements, unless specifically required by law or regulation.

Incyte Forward-looking Statements Except for the historical information set forth herein, the matters set forth in this press release, including statements regarding whether and when Minjuvi might provide a successful treatment option for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), the Companys ongoing clinical development program for tafasitamab, and its DLBCL program generally, contain predictions, estimates, and other forward-looking statements.These forward-looking statements are based on the Companys current expectations and subject to risks and uncertainties that may cause actual results to differ materially, including unanticipated developments in and risks related to: unanticipated delays; further research and development and the results of clinical trials possibly being unsuccessful or insufficient to meet applicable regulatory standards or warrant continued development; the ability to enroll sufficient numbers of subjects in clinical trials and the ability to enroll subjects in accordance with planned schedules; the effects of the COVID-19 pandemic and measures to address the pandemic on the Companys clinical trials, supply chain, and other third-party providers and development and discovery operations; determinations made by Swissmedic and other regulatory authorities; the Companys dependence on its relationships with its collaboration partners; the efficacy or safety of the Companys products and the products of the Companys collaboration partners; the acceptance of the Companys products and the products of the Companys collaboration partners in the marketplace; market competition; sales, marketing, manufacturing, and distribution requirements; and other risks detailed from time to time in the Companys reports filed with the Securities and Exchange Commission, including its annual report for the year ending December 31, 2021. The Company disclaims any intent or obligation to update these forward-looking statements.

# # #

For more information, please contact:

MorphoSys

Media contactsThomas BiegiVice PresidentTel.: +49 (0)89 / 89927 26079[emailprotected]

Investor contactsDr. Julia NeugebauerSenior DirectorTel: +49 (0)89 / 899 27 179[emailprotected]

Jeanette BressiDirector, U.S. CommunicationsTel: +1 617-404-7816[emailprotected]

Myles CloustonSenior DirectorTel: +1-857-772-0240[emailprotected]

Incyte

Media contactsEla ZawislakTel: + 41 21 581 5200[emailprotected]

Investor contactChristine ChiouSenior Director, Investor RelationsTel: +1 302 274 4773[emailprotected]

Catalina Loveman Executive Director, Public AffairsTel: +1 302 498 6171[emailprotected]

[1] Nationaler Krebsbericht; published 14th October 2021; https://www.bfs.admin.ch/bfs/de/home/aktuell/neueveroeffentlichungen.assetdetail.19305696.html;Accessed: March 2022[2] Duell et al. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica. 2021. 106(9): 2417-2426. Doi: 10.3324/haematol.2020.275958[3] Cancer Research UK. Diffuse large B cell lymphoma. Available at https://www.cancerresearchuk.org/about-cancer/non-hodgkin-lymphoma/types/diffuse-large-B-cell-lymphoma. Accessed: October 2021.[4] DRG Epidemiology data.[5] Kantar Market Research (TPP testing 2018).[6] Friedberg, Jonathan W. Relapsed/Refractory Diffuse Large B-Cell Lymphoma. Hematology Am Soc Hematol Educ Program 2011; 2011:498-505. doi: 10.1182/asheducation-2011.1.498[7] Sarkozy C, et al. Management of relapsed/refractory DLBCL. Best Practice Research & Clinical Haematology. 2018 31:209-16. doi.org/10.1016/j.beha.2018.07.014.[8] Skrabek P, et al. Emerging therapies for the treatment of relapsed or refractory diffuse large B cell lymphoma. Current Oncology. 2019 26(4): 253-265. doi.org/10.3747/co.26.5421.[9] DRG Epidemiology data[10] Kantar Market Research (TPP testing 2018).[11] Friedberg, Jonathan W. Relapsed/Refractory Diffuse Large B-Cell Lymphoma. Hematology Am Soc Hematol Educ Program 2011; 2011:498-505. doi: 10.1182/asheducation-2011.1.498.

The DGAP Distribution Services include Regulatory Announcements, Financial/Corporate News and Press Releases.Archive at http://www.dgap.de

SOURCE: MorphoSys AG

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MorphoSys and Incyte Announce Swissmedic Temporary Approval of Minjuvi(R) (tafasitamab) in Combination with Lenalidomide for the Treatment of Adults...

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Adeno-Associated Virus (AAV) as a Vector for Gene Therapy …

Posted: March 25, 2022 at 2:16 am

BioDrugs. 2017; 31(4): 317334.

1Janssen Research and Development, 200 McKean Road, Spring House, PA 19477 USA

1Janssen Research and Development, 200 McKean Road, Spring House, PA 19477 USA

1Janssen Research and Development, 200 McKean Road, Spring House, PA 19477 USA

2BiStro Biotech Consulting, LLC, Bridgewater, NJ 08807 USA

1Janssen Research and Development, 200 McKean Road, Spring House, PA 19477 USA

2BiStro Biotech Consulting, LLC, Bridgewater, NJ 08807 USA

Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

There has been a resurgence in gene therapy efforts that is partly fueled by the identification and understanding of new gene delivery vectors. Adeno-associated virus (AAV) is a non-enveloped virus that can be engineered to deliver DNA to target cells, and has attracted a significant amount of attention in the field, especially in clinical-stage experimental therapeutic strategies. The ability to generate recombinant AAV particles lacking any viral genes and containing DNA sequences of interest for various therapeutic applications has thus far proven to be one of the safest strategies for gene therapies. This review will provide an overview of some important factors to consider in the use of AAV as a vector for gene therapy.

The discovery of DNA as the biomolecule of genetic inheritance and disease opened up the prospect of therapies in which mutant, damaged genes could be altered for the improvement of the human condition. The recent ability to rapidly and affordably perform human genetics on hundreds of thousands of people, and to sequence complete genomes, has resulted in an explosion of nucleic acid sequence information and has allowed us to identify the gene, or genes, that might be driving a particular disease state. If the mutant gene(s) could be fixed, or if the expression of overactive/underactive genes could be normalized, the disease could be treated at the molecular level, and, in best case scenarios, potentially be cured. This concept seems particularly true for the treatment of monogenic diseases, i.e. those diseases caused by mutations in a single gene. This seemingly simple premise has been the goal of gene therapy for over 40years.

Until relatively recently, that simple goal was very elusive as technologies to safely deliver nucleic acid cargo inside cells have lagged behind those used to identify disease-associated genes. One of the earliest approaches investigated was the use of viruses, naturally occurring biological agents that have evolved to do one thing, i.e. deliver their nucleic acid (DNA or RNA) into a host cell for replication. There are numerous viral agents that could be selected for this purpose, each with some unique attributes that would make them more or less suitable for the task, depending on the desired profile [1]. However, the undesired properties of some viral vectors, including their immunogenic profiles or their propensity to cause cancer have resulted in serious clinical adverse events and, until recently, limited their current use in the clinic to certain applications, for example, vaccines and oncolytic strategies [2]. More artificial delivery technologies, such as nanoparticles, i.e. chemical formulations meant to encapsulate the nucleic acid, protect it from degradation, and get through the cell membrane, have also achieved some levels of preclinical and clinical success. Not surprisingly, they also have encountered some unwanted safety signals that need to be better understood and controlled [3].

Adeno-associated virus (AAV) is one of the most actively investigated gene therapy vehicles. It was initially discovered as a contaminant of adenovirus preparations [4, 5], hence its name. Simply put, AAV is a protein shell surrounding and protecting a small, single-stranded DNA genome of approximately 4.8kilobases (kb). AAV belongs to the parvovirus family and is dependent on co-infection with other viruses, mainly adenoviruses, in order to replicate. Initially distinguished serologically, molecular cloning of AAV genes has identified hundreds of unique AAV strains in numerous species. Its single-stranded genome contains three genes, Rep (Replication), Cap (Capsid), and aap (Assembly). These three genes give rise to at least nine gene products through the use of three promoters, alternative translation start sites, and differential splicing. These coding sequences are flanked by inverted terminal repeats (ITRs) that are required for genome replication and packaging. The Rep gene encodes four proteins (Rep78, Rep68, Rep52, and Rep40), which are required for viral genome replication and packaging, while Cap expression gives rise to the viral capsid proteins (VP; VP1/VP2/VP3), which form the outer capsid shell that protects the viral genome, as well as being actively involved in cell binding and internalization [6]. It is estimated that the viral coat is comprised of 60 proteins arranged into an icosahedral structure with the capsid proteins in a molar ratio of 1:1:10 (VP1:VP2:VP3) [6]. The aap gene encodes the assembly-activating protein (AAP) in an alternate reading frame overlapping the cap gene. This nuclear protein is thought to provide a scaffolding function for capsid assembly [7]. While AAP is essential for nucleolar localization of VP proteins and capsid assembly in AAV2, the subnuclear localization of AAP varies among 11 other serotypes recently examined, and is nonessential in AAV4, AAV5, and AAV11 [8].

Although there is much more to the biology of wild-type AAV, much of which is not fully understood, this is not the form that is used to generate gene therapeutics. Recombinant AAV (rAAV), which lacks viral DNA, is essentially a protein-based nanoparticle engineered to traverse the cell membrane, where it can ultimately traffic and deliver its DNA cargo into the nucleus of a cell. In the absence of Rep proteins, ITR-flanked transgenes encoded within rAAV can form circular concatemers that persist as episomes in the nucleus of transduced cells [9]. Because recombinant episomal DNA does not integrate into host genomes, it will eventually be diluted over time as the cell undergoes repeated rounds of replication. This will eventually result in the loss of the transgene and transgene expression, with the rate of transgene loss dependent on the turnover rate of the transduced cell. These characteristics make rAAV ideal for certain gene therapy applications. Following is an overview of the practical considerations for the use of rAAV as a gene therapy agent, based on our current understanding of viral biology and the state of the platform. The final section provides an overview for how rAAV has been incorporated into clinical-stage gene therapy candidates, as well as the lessons learned from those studies that can be applied to future therapeutic opportunities.

The main point of consideration in the rational design of an rAAV vector is the packaging size of the expression cassette that will be placed between the two ITRs. As a starting point, it is generally accepted that anything under 5kb (including the viral ITRs) is sufficient [10]. Attempts at generating rAAV vectors exceeding packaging cassettes in excess of 5kb results in a considerable reduction in viral production yields or transgene recombination (truncations) [11]. As a result, large coding sequences, such as full-length dystrophin, will not be effectively packaged in AAV vectors. Therefore, the use of dual, overlapping vector strategies (reviewed by Chamberlain et al.) [12], should be considered in these cases. An additional consideration relates to the biology of the single-stranded AAV-delivered transgenes. After delivery to the nucleus, the single-stranded transgene needs to be converted into a double-stranded transgene, which is considered a limiting step in the onset of transgene expression [13]. An alternative is to use self-complementary AAV, in which the single-stranded packaged genome complements itself to form a double-stranded genome in the nucleus, thereby bypassing that process [13, 14]. Although the onset of expression is more rapid, the packaging capacity of the vector will be reduced to approximately 3.3kb [13, 14].

AAV2 was one of the first AAV serotypes identified and characterized, including the sequence of its genome. As a result of the detailed understanding of AAV2 biology from this early work, most rAAV vectors generated today utilize the AAV2 ITRs in their vector designs. The sequences placed between the ITRs will typically include a mammalian promoter, gene of interest, and a terminator (Fig.). In many cases, strong, constitutively active promoters are desired for high-level expression of the gene of interest. Commonly used promoters of this type include the CMV (cytomegalovirus) promoter/enhancer, EF1a (elongation factor 1a), SV40 (simian virus 40), chicken -actin and CAG (CMV, chicken -actin, rabbit -globin) [15]. All of these promoters provide constitutively active, high-level gene expression in most cell types. Some of these promoters are subject to silencing in certain cell types, therefore this consideration needs to be evaluated for each application [16]. For example, the CMV promoter has been shown to be silenced in the central nervous system (CNS) [16]. It has been observed that the chicken -actin and CAG promoters are the strongest of these constitutive promoters in most cell types; however, the CAG promoter is significantly larger than the others (1.7kb vs. 800bp for CMV), a consideration to take into account when packaging larger gene inserts [15].

Schematic representation of the basic components of a gene insert packaged inside recombinant AAV gene transfer vector. AAV adeno-associated virus, ITR inverted terminal repeat

Although many therapeutic strategies involve systemic delivery, it is often desirable to have cell- or tissue-specific expression. Likewise, for local delivery strategies, undesired systemic leakage of the AAV particle can result in transduction and expression of the gene of interest in unwanted cells or tissues. The muscle creatine kinase and desmin promoters have been used to achieve high levels of expression, specifically in skeletal muscle, whereas the -myosin heavy chain promoter can significantly restrict expression to cardiac muscle [15, 17]. Likewise, the neuron-specific enolase promoter can attain high levels of neuron-specific expression [18, 19]. Often is the case, systemic delivery of AAV results in a significant accumulation in the liver. While this may be desirable for some applications, AAV can also efficiently transduce other cells and tissues types. Thus, in order to restrict expression to only the liver, a common approach is to use the 1-antitrypsin promoter [20, 21]. Finally, there are now technologies that have the ability to generate novel, tissue-specific promoters, based on DNA regulatory element libraries [22].

Over the course of the past 1015years, much work has been done to understand the correlation between codon usage and protein expression levels. Although bacterial expression systems seem to be most affected by codon choice, there are now many examples of the effects of codon engineering on mammalian expression [23]. Many groups have developed their own codon optimization strategies, and there are many free services that can similarly provide support for codon choice. Codon usage has also been shown to contribute to tissue-specific expression, and play a role in the innate immune response to foreign DNA [24, 25]. With regard to the gene of interest, codon engineering to support maximal, tissue-specific expression should be performed.

Additionally, terminator/polyadenylation signal choices, the inclusion of post-transcriptional regulator elements and messenger RNA (mRNA) stability elements, and the presence of microRNA (miRNA) target sequence in the gene cassette can all have effects on gene expression [26]. The human factor IX 3 UTR, for example, was shown to dramatically increase factor IX expression in vivo, especially in the context of additional cis regulatory elements [27]. Likewise, synthetic miRNA target sequences have been engineered into the 3 UTR of AAV-delivered genes to make them susceptible to miRNA-122-driven suppression in the liver [28]. Although there is much known about these individual components that needs to be considered when designing an AAV vector, the final design will most likely need to be determined empirically. It is not yet possible to know how a particular design will function by just combining the best elements together based on published reports, therefore considerable trial and error will eventually be required for deciding on the final construct. In addition, one also needs to consider the differences between in vitro and in vivo activity. Although it is possible to model rAAV expression in rodents, there is still significant concern about the translatability to humans.

AAV has evolved to enter cells through initial interactions with carbohydrates present on the surface of target cells, typically sialic acid, galactose and heparin sulfate [29, 30]. Subtle differences in sugar-binding preferences, encoded in capsid sequence differences, can influence cell-type transduction preferences of the various AAV variants [3133]. For example, AAV9 has a preference for primary cell binding through galactose as a result of unique amino acid differences in its capsid sequence [34]. It has been postulated that this preferential galactose binding could confer AAV9 with the unique ability to cross the bloodbrain barrier (BBB) and infect cells of the CNS, including primary neurons [35, 36].

In addition to the primary carbohydrate interactions, secondary receptors have been identified that also play a role in viral transduction and contribute to cell and tissue selectivity of viral variants. AAV2 uses the fibroblast/hepatocyte growth factor receptor and the integrins V5 and 51; AAV6 utilizes the epidermal growth factor receptor; and AAV5 utilizes the platelet-derived growth factor receptor. Recently, an uncharacterized type I membrane protein, AAVR (KIAA0319L), was identified as a critical receptor for AAV cell binding and internalization [37].

As a result of these subtle variations in primary and secondary receptor interactions for the various AAV variants, one can choose a variant that possesses a particular tropism and preferentially infects one cell or tissue type over others (Table). For example, AAV8 has been shown to effectively transduce and deliver genes to the liver of rodents and non-human primates, and is currently being explored in clinical trials to deliver genes for hemoglobinopathies and other diseases [38]. Likewise, AAV1 and AAV9 have been shown to be very effective at delivering genes to skeletal and cardiac muscle in various animal models [3946]. Engineered AAV1 is currently being explored as the gene transfer factor in clinical trials for heart failure, and has been approved for the treatment of lipoprotein lipase deficiency [47]. However, although different AAV vectors have been identified that preferentially transduce many different cell types, there are still cell types for which AAV has proven difficult to transduce.

Selected AAV vectors, known receptors, and known tropisms

With the strong desire to utilize AAV to deliver genes to very selective cell and tissue types, efforts to clone novel AAV variants from human and primate tissues have identified a number of unique capsid sequences that are now being studied for tropism specificities [48]. In addition, recombinant techniques involving capsid shuffling, directed evolution, and random peptide library insertions are being utilized to derive variants of known AAVs with unique attributes [4951]. In vivo-directed evolution has been successfully used to identify novel AAV variants that preferentially transduce the retinal cells of the eye, as well as other cell populations, including those in the CNS [50, 52, 53]. In addition, these techniques have been employed to identify novel AAV variants with reduced sensitivities to neutralizing antibodies (NAbs) [5457].

Alternatively, other investigators have inserted larger binding proteins into different regions of AAV capsid proteins to confer selectivity. For example, DARPins (designed ankyrin repeat proteins), portions of protein A, and cytokines, have all been engineered into the capsid of AAV for the purpose of greater cell specificity and targeting [58, 59]. Employing this concept, others have been able to selectively target AAV to tumors and CD4+ T cells, as examples of engineered tropism [60, 61].

As we continue to learn more about the biology of AAV with regard to the mechanisms involved in membrane translocation, endosomal escape, and nuclear entry, we will undoubtedly find opportunities to engineer unique properties into viral vectors through modulating one or more of these functions. For example, it has been hypothesized that surface-exposed serine and tyrosine residues could be phosphorylated upon viral cell entry, resulting in their ubiquitination and proteolytic degradation [6264]. Studies have shown that mutation of tyrosine to phenylalanine, which prevents this phosphorylation, results in dramatically improved transduction efficiencies [63]. Similar efforts have been made in attempts to limit the effects of NAbs, as discussed below.

The choice of a particular AAV to use as a gene transfer vector is heavily reliant on several critically important criteria: (1) which cell/tissue types are being targeted; (2) the safety profile associated with the delivered gene; (3) the choice of systemic versus local delivery; and (4) the use of tissue-specific or constitutively active promoters. As one gives careful consideration to these selection criteria, it is possible to narrow the choices of which AAVs (natural or engineered) to profile. Alternatively, one can begin the path of exploring fully engineered versions of AAV for truly selective cell targeting and optimized transduction. Because our understanding of AAV biology is in relative infancy, many of these efforts will remain empirical for quite some time as optimization for one activity could have a negative impact on another. Nonetheless, the future looks promising for this highly adaptable platform.

One of the appealing aspects of using rAAV as a gene transfer vector is that it is composed of biomolecules, i.e. proteins and nucleic acids. Fortunately, a full-package virus lacks engineered lipids or other chemical components that could contribute to unwanted toxicities or immunogenicities that may not be predictable or fully understood. In general, AAV has been shown to be less immunogenic than other viruses. Although not completely understood, one possible reason for this may hinge on the observation that certain AAVs do not efficiently transduce antigen-presenting cells (APCs) [65]. Additionally, unlike previous viral delivery strategies, rAAV does not contain any viral genes, therefore there will be no active viral gene expression to amplify the immune response [66]. Although AAV has been shown to be poorly immunogenic compared with other viruses (i.e. adenovirus), the capsid proteins, as well as the nucleic acid sequence delivered, can trigger the various components of our immune system. This is further complicated by the fact that most people have already been exposed to AAV and have already developed an immune response against the particular variants to which they had previously been exposed, resulting in a pre-existing adaptive response. This can include NAbs and T cells that could diminish the clinical efficacy of subsequent re-infections with AAV and/or the elimination of cells that have been transduced. It should be of no surprise that the formidable challenge is how to deliver a therapeutically efficacious dose of rAAV to a patient population that already contains a significant amount of circulating NAbs and immunological memory against the virus [67]. Whether administered locally or systemically, the virus will be seen as a foreign protein, hence the adaptive immune system will attempt to eliminate it.

The humoral response to AAV is driven by the uptake of the virus by professional APCs, and their presentation of AAV capsid peptides in the context of class II major histocompatibility proteins (MHCs) to B cells and CD4+ T cells [68, 69]. This leads to plasma cell and memory cell development that has the capacity to secrete antibodies to the AAV capsid. These antibodies can either be neutralizing, which has the potential to prevent subsequent AAV infection, or non-neutralizing. Non-NAbs are thought to opsonize the viral particles and facilitate their removal through the spleen [70].

Upon entry of the virus into target cells during the course of the natural infection process, the virus is internalized through clathrin-mediated uptake into endosomes [71]. After escape from the endosome, the virus is transported to the nucleus where the ITR-flanked transgene is uncoated from the capsid [72]. The pathway and mechanism of AAV intracellular transport and processing is not fully understood, and there are quite a few areas of debate with regard to current understanding. The most current hypothesis is that following endosomal escape, capsid breakdown and uncoating occurs after subsequent nuclear translocation. However, it is thought that cytosolic ubiquitination of the intact virus can occur during transport to the nucleus [73]. This would be a critical step in directing capsid proteins to the proteasome for proteolytic processing into peptides for class I MHC presentation. This hypothesis is supported by data in which proteasome inhibitors, or mutations in capsid residues that are sites for ubiquitination, can limit class I presentation and T-cell activation [7376]. However, apparent differences have been observed for T-cell activation to different AAV variants with significant sequence identity. At this time, it is unclear whether this is due to subtle capsid sequence differences and susceptibility to MHC I presentation or differential cellular processing that is innate to the different AAV variants, or simply due to contaminants in vector preparations [76].

In addition to an adaptive immunological reaction to the capsid of AAV, the transgene can elicit both an adaptive and an innate response. If the transgene encodes a protein that can be recognized as foreign, it too can generate a similar B- and T-cell response. For example, in replacement therapy applications in which the protein to be replaced is the consequence of a null genotype, the immune system will have never selected against precursor B and T cells to that protein [70, 77]. Likewise, if the transgene is an engineered variant, the engineered sequence can be recognized as foreign. Even the variable regions of antibodies can activate an adaptive response that can result in deletion of target cells that are expressing transgene as a result of AAV delivery. Finally, a transgene with a significant number of CpG dinucleotides can activate innate responses through toll-like receptor (TLR) molecular pattern receptors [78].

Pre-existing immunity to AAV, especially the presence of circulating NAb, can have a dramatic effect on AAV clinical efficacy. To date, this represents one of the biggest therapeutic challenges to the use of systemically delivered AAV, and is thought to be one of the factors in early clinical failures [79]. Pre-existing immunity to AAV can often be overcome by selecting a particular AAV variant that has not circulated throughout the human population, and, therefore, does not have any memory responses elicited against it, including NAbs and T cells [80]. Additionally, some of the AAV evolution technologies discussed above have been used to identify AAVs that are resistant to the effects of NAbs [50, 57]. Although not optimal, it is possible to prescreen subjects for the presence of NAbs to the particular AAV variant to be used. In addition, the impact of this immunological response can sometimes be minimized by the particular route of administration employed for the particular therapeutic strategy, as discussed in Sect. 6 [80].

Like most biotherapeutics, AAV needs to be produced in a living system (Fig.). The parallels with recombinant antibody production during the 1990s and 2000s, with regard to the upstream challenges of robust production levels, are important to understand where the industry currently is, and where we need to strive to be.

Overview of AAV production/purification. Cell platform: HEK-293T, Sf9, or other suitable cell system can be grown on a small scale on 150mm tissue culture-treated culture dish, hyperflasks, or shake flasks. Cells are then transfected with adenovirus helper virus, rep/cap, and ITR-transgene plasmids for 293T, or infected with baculovirus for Sf9. Producer lines with integrated expression of rep/cap and ITR-transgene can be infected with adenovirus and grown to scale. Scale-up: For larger-scale culture volumes, virus can be produced in roller bottles, continuous perfusion, or WAVE Bioreactor systems. Purification/polishing: Affinity or heparin chromatography are optimal for isolation of virus from culture supernatants with or without cell pellet harvesting. Benzonase/DNAse treatment of eluted virus is required for removal of extraviral DNA contamination, followed by anion-exchange chromatography to fractionate empty vs. full AAV particles. QC/release: Upper left of far right panel: image depicts a silver stain analysis of culture FT next to affinity/anion exchange purified AAV (pure). The three bands represent the viral capsid proteins VP1, VP2, and VP3. Upper right of far right panel: Dynamic light scattering analysis of purified AAV1 indicates a uniform particle distribution of approximately 2530nM. Bottom half of far right panel: Analytical ultracentrifugation can resolve the proportion of empty vs, full particles of purified material. Additional assays that should be employed are digital drop polymerase chain reaction for determining titer in GC/mL, cryo or transmission electron microscopy for visual representation of purified particles, endotoxin testing, and other assays to evaluate the presence of residual host-cell protein contamination. AAV adeno-associated virus, FT flow-through, GC genome copies, rep/cap replication/capsid, QC quality control

Current methods to produce rAAV are still expensive despite years of research (Table). The most widely used platform for producing rAAV involves transfecting HEK293 cells with either two or three plasmids; one encoding the gene of interest, one carrying the AAV rep/cap genes, and another containing helper genes provided by either adeno or herpes viruses [6]. While most robust production rates have been achieved with adherent cells in either roller bottles or cell stacks, similar rates are now achievable in suspension-adapted HEK293 cells (Table). Production rates of approximately 105 genome copies (GC)/cell are now common, resulting in 1014 GC/L [81]. While this has proven to be sufficient to support early clinical trials, and could supply marketed product for small patient population indications, the deficiencies in scalability with this platform are a significant limitation [82, 83]. As one could surmise, successfully delivering three plasmids to one cell is a relatively inefficient process. For larger-scale manufacturing efforts, transient delivery of plasmid requires excess quantities of DNA, adding to the overall cost of production and purification. Moreover, transient delivery of rep/cap genes in the presence of helper genes can also contribute to product heterogeneity, including AAV vectors lacking a transgene. These empty capsids represent a significant proportion of virus produced in transient transfection assays. Thus, it is critically important to develop robust analytical quality control (QC) methods that are able to distinguish between these viral variants in order to ensure similarities between production lots [82, 83].

Current manufacturing platforms being employed to generate rAAV for clinical use

In three other AAV manufacturing platforms, one or more genetic components for the AAV manufacturing has been integrated into the genome of mammalian or insect production cell lines. While most viral helper genes needed for AAV production cannot be stably transfected, the adenoviral E1a and E1b genes are exceptions. These genes have been used to transform HEK293 cells, however they induce expression of the AAV rep gene, which is toxic to mammalian and insect cells [84, 85]. Hence, two different approaches have been used to develop mammalian cell lines. The first uses co-infection of BHK cells with two replication-defective HSVs engineered to encode the ITR-flanked transgene and the rep/cap genes. The second is based on stable producer cell lines in HeLa cells carrying the ITR-flanked transgene and the rep/cap genes. Rep proteins are not expressed in these cells since HeLa carries no adenoviral genes. However, infection with wild-type adenovirus is required for AAV production. The inclusion of replication-competent viral agents into a production process is a concern that needs to be addressed and also requires additional steps during the downstream processing [82, 83].

More recently, the Sf9 insect cell system in combination with baculovirus infection has been utilized to produce bulk quantities of rAAV. In this system, two or three baculovirus particles may be used to infect the Sf9 cells and initiate AAV production. In one example, one virus contains the rep gene, a second contains the cap gene, and the final virus carries the ITR-flanked gene of interest. In an alternative system, the Sf9 cells can be engineered to have the ITR-flanked gene of interest integrated into their genome, upon which production is initiated with only two baculovirus preps [81, 82]. A further improvement has recently been shown whereby the rep/cap genes are stably integrated into the Sf9 cell line genome, but are under the control of a promoter/enhancer that is induced by subsequent baculovirus infection. In this system, infection can occur, with only one baculovirus containing the ITR-flanked gene of interest, simplifying the system significantly [86, 87].

Production levels of approximately 105 GC/cell and 1015 GC/L have routinely been achieved with these Sf9 systems. Because of their ease of manipulation and their ability to grow to very high cell densities, the Sf9 system is rapidly becoming the platform of choice for AAV manufacturing. Concerns regarding baculovirus instability and differences in post-translational modifications between mammalian and insect cell systems are now beginning to be understood and controlled. These concerns are offset by the fact that baculovirus cannot efficiently infect mammalian cells which makes it inherently safer then other viral-based production systems [8183, 86, 87].

Unlike antibody manufacturing that relied on a single protein A-based purification platform early in the development of the downstream process, AAV is still rapidly evolving in that area. The products of an AAV production run will contain not only cellular debris (protein/lipids/nucleic acids) but also two main populations of AAV particles: particles that contain (full capsids) or those lacking (empty capsids) the ITR-flanked transgene. Although still widely debated in the field, the presence of empty capsids represents another contaminant that must be removed or controlled. Initial attempts to separate these two populations originally relied on the cumbersome and non-scalable method of density ultracentrifugation. In addition to the scalability issue, there are also concerns about the physiochemical effects of this method on the particles. Regardless, this method is still employed by many organizations as either a primary or secondary step in AAV purification [83].

Current technologies utilizing various affinity resins and/or ion exchange chromatography are being adopted by the industry. As mentioned above, AAV uses cell membrane-associated carbohydrates as the primary cell receptor for transduction. This affinity for carbohydrates can be exploited as an initial capture step in AAV purification. Indeed, heparin columns are frequently used in many downstream processing steps for AAV [88]. However, because of the lack of specificity, alternative affinity columns based on AAV-specific binding proteins such as scFvs and antibody single domains from llamas (camelids) have started to dominate the field. Improvements in generating these AAV-specific resins confers many advantages in downstream purification. These resins have the ability to bind to more than one AAV variant, have very high binding capacities (>1014GC/mL resin), and are stable against harsh clean-in-place and regeneration methods, making them suitable for use multiple times. Some of these commercial resins are already Good Manufacturing Practice (GMP) compliant, making them ideal for downstream manufacturing at commercial scales. Polishing steps using anion exchange chromatography are now routinely included after affinity capture steps, and can efficiently separate full capsids from empty capsids [8992].

As with any new therapeutic platform, and, again, similar to antibody-based therapeutic evolution, details on product specification and regulatory requirements are still evolving. With still very limited clinical experience, the impact of empty particles, host-cell impurities, post-translational modifications from different production platforms, fidelity of the packaged transgene, capsid ratio integrity, and probably many other specifications are still not known. However, over time, and as more clinical experience is gained, the field will be able to better relate these details to product performance and safety [83].

The use of rAAV as a delivery vector for gene therapies has been rapidly gaining interest over the past 35years. As approvals begin to increase (see Sect.6), efforts to optimize and maximize clinical manufacturing technologies will see a burst of activity. This will most likely mirror what occurred with antibody therapeutics in the 1990s and 2000s, in which early technologies were quickly overcome by next-generation technologies, resulting in significant cost savings and increased clinical supplies.

AAV has been shown to be a very stable vector able to withstand wide temperature and pH changes with little to no loss in activity [93]. To date, the only limitation seems to be the concentration with which it can be formulated, currently maximized around 51013 particles per milliliter [83]. With the resurgence in clinical use, this formulation limit will most likely be overcome in the near future. However, the robust stability of these vectors provides ample opportunities to attempt different routes of administration and specialized delivery strategies (Table).

Selected examples of more than 50 clinical candidates employing rAAV

Other than the European Medicines Agency (EMA)-approved AAV-based product alipogene tiparvovec (Glybera), the most advanced current clinical trial using AAV is sponsored by Spark Therapeutics and utilizes local injection of AAV2 into the eye for inherited retinal diseases (voretigene neparvovec-RPE65) (Table) [94]. Phase III studies have just been completed on this candidate and a Biologics License Application (BLA) submission is expected this year. This type of local delivery has proven to be safe and efficacious, but requires specialized surgical techniques and/or devices to deliver the vector [94, 95]. Similar strategies are being conducted by Applied Genetic Technologies Corporation (AGTC), targeting X-linked retinoschisis and achromatopsia, X-linked retinitis pigmentosa, and age-related macular degeneration. These programs are at various stages of development, with the most advanced for X-linked retinoschisis and achromatopsia in phase I safety studies (http://www.AGTC.com) (Table).

Several clinical trials are being run in which systemic administration is being used to target the liver, a tissue that is readily accessible through this route of administration and a tissue type that is readily transduced by many well-understood AAV variants [96]. These trials are mostly for monogenic, inherited diseases, in which the goal is gene replacement for defective genes, including those mutated in hemophilia A and B. Currently, these trials are in phase I/II, and are sponsored by academic groups, as well as biopharmaceutical companies such as Spark Therapeutics (SPK-9001, SPK-8011), Sangamo Therapeutics (SB-525), UniQure (AMT-060), Dimension Therapeutics (DTX101, DTX201), and Biomarin (BMN 270) (Table) [97]. Unlike local administration to the eye, which is considered an immune-privileged site that might not be affected by the existence of NAbs, systemic administration will require patient stratification for patient NAb levels. In addition, the possibility for re-administration becomes very difficult, should the need arise [80]. Although rare, there have been reports of rAAV vector integration into animal model genomes with subsequent genotoxicities [98, 99]. In addition, AAV genome sequences have been found in human hepatocellular carcinoma samples near known cancer driver genes, although at a low frequency [100]. There is an ongoing debate on these findings regarding cause and effect, and mouse/human translation. Regardless, hepatocellular, as well as other tissue genotoxicity, will need to be monitored in the course of AAV clinical development.

Another common delivery strategy is direct intramuscular injections. The only approved AAV gene therapy in Europe (Glybera) is an AAV1 encoding the gene for lipoprotein lipase deficiency [47, 101]. Skeletal muscle has been shown to be a target tissue type that is efficiently transduced by many AAV variants [39]. Once transduced, the muscle cells serve as a production site for protein products that can act locally or systemically, as is the case with Glybera. As a result of the low cellular turnover rate of the muscle cells, the transduced AAV gene product will be maintained in these cells as an episome for years, as has been shown in many studies in non-human primates [39]. Consequently, a single-dose regimen of an intramuscularly-delivered product may never need to be readministered unless there is significant damage or immune clearance of the transduced cells. This strategy is also being employed by Adverum and AGTC for 1-antitrypsin deficiency, as well as for certain muscular dystrophies (Table) [97].

Direct CNS administration is being utilized for Parkinsons disease, as well as various inherited diseases such as Batten disease, Canavan disease, and mucopolysaccharidosis (MPS) IIA and IIB, as well as MPS IIIa and MPS IIIb (Sanfilippo syndromes type A and type B, respectively). Phase I/II studies for these diseases using a variety of AAV variants, including AAV2, AAVrh10, and AAV9, are currently ongoing by various academic groups and biopharmaceutical companies, such as Abeona Therapeutics (ABO-101, ABO-102, ABO-201, ABO-202) [97, 102, 103]. Delivery strategies range from direct intraparenchymal administration into particular areas of the brain, intracerebroventricular, and cisternal and lumbar intrathecal routes [102]. The decision on the best route of administration is intimately related to the disease and affected areas. For example, for Parkinsons disease, according to our current understanding of disease pathogenesis and therapeutic strategies, direct injection into the putamen, substantia nigra or striatum is thought to be required. Similarly, for diseases that affect larger areas of the brain, such as Canavan disease or MPS, direct injection into the cerebellum is thought to be most beneficial [102, 103].

Alternatively, administration directly into the cerebrospinal fluid through an intrathecal route can result in wide CNS biodistribution, which is thought to be necessary for diseases such as spinal muscular atrophy (SMA) and Alzheimers disease [102106]. An alternative to cerebral spinal fluid (CSF)-based routes is the use of systemic administration of AAV variants that have been shown to cross the BBB. AAV9 has been shown to transcytosis across the BBB and transduce large sections of the CNS [36, 104, 107, 108]. This approach is currently being explored in the clinic for the treatment of SMA by AveXis (AVXS-101).

Neurodegenerative diseases represent a particular devastating health problem for which there is significant unmet medical need. These diseases of the CNS have proven to be very difficult to treat as a result of our poor understanding of their etiology and difficulty getting efficacious agents across the BBB. With regard to Alzheimers disease, although there is still some disagreement in the field, idiopathic amyloid plaque formation or generation of neurofibrillary tau tangles (NFTs), both of which are thought to be neurotoxic, are still the prevailing hypotheses behind the mechanism of many of these neuropathologies. Attempts to clear these plaques with plaque-specific antibodies have shown signs of limiting this process in animals and early-stage clinical trials [109, 110]; However, larger studies have all shown to be inconclusive at best, or failures at worst. It is unclear if these failures were because the plaque hypothesis is wrong, or if there was inefficient CNS exposure to the antibody therapeutic [110, 111]. Alternative strategies taking advantage of the safety and persistence of AAV would utilize either local administration of antibody-encoding AAVs directly to the CNS, or systemic delivery of AAVs that can cross the BBB, resulting in significantly higher CNS exposure levels of the antibody [112].

Local delivery of AAV to cardiac muscle for heart failure has been attempted in various clinical trials. In one case, Celladon failed in their attempt to deliver SERCA2A directly to the heart, and, in a second case, there is an ongoing program sponsored by UniQure to deliver S100A directly to the heart that is currently still in preclinical development [46, 113115]. Although it is not thoroughly clear why Celladon failed in the clinic, and why one would expect UniQure/BMS to succeed, there are significant differences in the delivery methods used by the two programs and the target gene delivered. Celladon used intracoronary infusion to deliver their AAV1 SERCA2A gene product, whereas UniQure is using retroinfusion and left anterior descending (LAD) coronary occlusion [41, 115]. This procedure is thought to better localize and restrict the delivered AAV9 S100A gene product to better target the heart tissue of interest. The reality of this suspected benefit will be realized in the clinic in the coming years.

Aerosolized AAV for inhaled pulmonary delivery was utilized in some of the earliest trials for cystic fibrosis (CF). Although none of these trials resulted in significant benefit or showed much of a pharmacodynamic response, they did help to show the safety of AAV when administered via this route [116118]. More importantly, the pathophysiology of CF, molecular biology of the CF transmembrane conductance regulator (CFTR) gene, and the target cell population for this type of indication exposed some key considerations when using AAV [117]. Congestion of the airways in these patients can limit AAV biodistribution after delivery, thus attenuating robust transduction [118]. In addition, the CFTR gene is over 4kb in size, putting it at the upper limit of the packaging capacity of AAV after also considering a required promoter and terminator. Finally, CFTR is expressed by the submucosal glands, which may be difficult to target efficiently [116, 117]. Nonetheless, these early efforts proved that AAV can safely deliver genes to the lung, which might be an ideal strategy for other diseases, such as influenza and other infectious diseases of the lung [119].

The field is just beginning to explore localized delivery of AAV for gene therapy applications. The stability of the virus and broad tropism for many different cell and tissue types make them ideal for most applications. There appears to be at least one AAV variant option for every tissue type of interest, with engineering and novel AAV discovery efforts sure to identify and create AAV variants with very specialized functions on demand. These efforts will undoubtedly result in new therapeutic strategies for many new indications.

The transfer of genes and other nucleic acids into cells has been a research tool in the laboratory for more than four decades. However, it was our growing understanding of the genetic components underlying certain diseases that has driven the search for true gene therapies. Progressively, research in other areas have identified other potential opportunities in which gene delivery could be applied therapeutically. In addition, limitations with current small molecule and protein therapeutic platforms have also driven the search for alternative therapeutic platforms that accommodate those limitations [120, 121]. Gene therapies accommodate all of those limitations, especially around target accessibility. As a result, the search for safe and effective gene delivery technologies has been a major focus in pharmaceutical research and development, and will hopefully represent a paradigm shift in how we approach disease-state intervention.

AAV was discovered over 50years ago and has since become one of the leading gene delivery vectors in clinical development. As a result of its unique biology, simple structure, and no known disease associations, AAV could become the vector of choice for most gene therapy applications. Gene therapy using rAAV has been demonstrated to be safe and well-tolerated in virtually every clinical setting in which it has been used. These studies, along with basic research on its biology, have revealed many facets of this vector that can be applied to future efforts.

Among the critical parameters to be considered are vector design, capsid selection, desired target cell and tissue type, and route of administration. The transgene to be delivered optimized for expression, the right AAV variant with an appropriate capsid for target cell transduction and immunoreactivity profile, and the appropriate delivery approach to maximize target tissue exposure while limiting off-tissue exposure are key focal points for AAV-based therapies.

All of these variables will be dictated by the overall therapeutic strategy which will be influenced by our understanding of the pathobiology of the disease to be treated. Will the transgene have the desired effect? Is the target cell driving the disease state? Is the turnover rate of the target cell high, requiring repeat dosing? This cannot be emphasized enough; without a strong understanding of the mechanisms driving the disease state, it will not be possible to design, discover, and develop the right gene therapeutic. Better designed trials, optimized vector construction, and novel AAV variants will certainly result in future regulatory approvals and improvements on patient outcomes and health.

Michael F. Naso, Brian Tomkowicz, and William L. Perry III are employees of Janssen Research and Development. William R. Strohl has no conflicts of interest to declare.

No funding was received for the preparation of this review.

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Adeno-Associated Virus (AAV) as a Vector for Gene Therapy ...

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