Category Archives: Human Genetics

NUTLEY, N.J., Jan. 17, 2020 /PRNewswire/ --Genomic medicine's groundbreaking treatments, and its future promise, will be the focus of a full-day symposium at the Hackensack Meridian Health Center for Discovery and Innovation (CDI) on Wednesday, February 19.

This emerging discipline for tailoring active clinical care and disease prevention to individual patients will be the focus of presentations given by eight experts from medical centers in the U.S.A. and Canada.

"The Genomic Medicine Symposium convenes a diverse group of scientific experts who help serve as a vanguard for precision medicine," said David Perlin, Ph.D., chief scientific officer and vice president of the CDI. "At the Center for Discovery and Innovation, we are working to make genomics a central component of clinical care, and we are delighted to host our peers and partners from other institutions."

"The event is one-of-a-kind," said Benjamin Tycko, M.D., Ph.D., a member of the CDI working in this area, and one of the hosts. "We are bringing together great minds with the hope it will help inform our planning for genomic medicine within Hackensack Meridian Health and inspire further clinical and scientific breakthroughs."

Cancer treatments, neuropsychiatric and behavioral disorders, cardiometabolic conditions, autoimmune disease, infectious disease, and a wide array of pediatric conditions are areas where DNA-based strategies of this type are already employed, and new ones are being tested and refined continually.

The speakers come from diverse medical institutions and will talk about a variety of clinical disorders in which prevention, screening, and treatment can be informed through genomic and epigenomic data.

Among the speakers are: Daniel Auclair, Ph.D., the scientific vice president of the Multiple Myeloma Research Foundation; Joel Gelernter, M.D., Ph.D., Foundations Fund Professor of Psychiatry and Professor of Genetics and of Neuroscience and Director, Division of Human Genetics (Psychiatry) at Yale University; James Knowles, M.D., Ph.D., professor and chair of Cell Biology at SUNY Downstate Medical Center in Brooklyn; Tom Maniatis, Ph.D., the Isidore S. Edelman Professor of Biochemistry and Molecular Biophysics, director of the Columbia Precision Medicine Initiative, and the chief executive officer of the New York Genome Center; Bekim Sadikovic, Ph.D., associate professor and head of the Molecular Diagnostic Division of Pathology and Laboratory Medicine at Western University in Ontario; Helio Pedro, M.D., the section chief of the Center for Genetic and Genomic Medicine at Hackensack University Medical Center; Kevin White, Ph.D., the chief scientific officer of Chicago-based TEMPUS Genetics; and Jean-Pierre Issa, M.D., Ph.D., chief executive officer of the Coriell Research Institute.

The event is complimentary, but registration is required. It will be held from 8 a.m. to 4:30 p.m. at the auditorium of the CDI, located at 111 Ideation Way, Nutley, N.J.

The event counts for continuing medical education (CME) credits, since Hackensack University Medical Center is accredited by the Medical Society of New Jersey to provide continuing medical education for physicians.

Hackensack University Medical Center additionally designates this live activity for a maximum of 7 AMA PRA Category 1 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

For more information, visit https://www.hackensackmeridianhealth.org/CDIsymposium.

ABOUTHACKENSACKMERIDIAN HEALTH

Hackensack Meridian Health is a leading not-for-profit health care organization that is the largest, most comprehensive and truly integrated health care network in New Jersey, offering a complete range of medical services, innovative research and life-enhancing care.

Hackensack Meridian Health comprises 17 hospitals from Bergen to Ocean counties, which includes three academic medical centers Hackensack University Medical Center in Hackensack, Jersey Shore University Medical Center in Neptune, JFK Medical Center in Edison; two children's hospitals - Joseph M. Sanzari Children's Hospital in Hackensack, K. Hovnanian Children's Hospital in Neptune; nine community hospitals Bayshore Medical Center in Holmdel, Mountainside Medical Center in Montclair, Ocean Medical Center in Brick, Palisades Medical Center in North Bergen, Pascack Valley Medical Center in Westwood, Raritan Bay Medical Center in Old Bridge, Raritan Bay Medical Center in Perth Amboy, Riverview Medical Center in Red Bank, and Southern Ocean Medical Center in Manahawkin; a behavioral health hospital Carrier Clinic in Belle Mead; and two rehabilitation hospitals - JFK Johnson Rehabilitation Institute in Edison and Shore Rehabilitation Institute in Brick.

Additionally, the network has more than 500 patient care locations throughout the state which include ambulatory care centers, surgery centers, home health services, long-term care and assisted living communities, ambulance services, lifesaving air medical transportation, fitness and wellness centers, rehabilitation centers, urgent care centers and physician practice locations. Hackensack Meridian Health has more than 34,100 team members, and 6,500 physicians and is a distinguished leader in health care philanthropy, committed to the health and well-being of the communities it serves.

The network's notable distinctions include having four hospitals among the top 10 in New Jersey by U.S. News and World Report. Other honors include consistently achieving Magnet recognition for nursing excellence from the American Nurses Credentialing Center and being named to Becker's Healthcare's "150 Top Places to Work in Healthcare/2019" list.

The Hackensack Meridian School of Medicine at Seton Hall University, the first private medical school in New Jersey in more than 50 years, welcomed its first class of students in 2018 to its On3 campus in Nutley and Clifton. Additionally, the network partnered with Memorial Sloan Kettering Cancer Center to find more cures for cancer faster while ensuring that patients have access to the highest quality, most individualized cancer care when and where they need it.

Hackensack Meridian Health is a member of AllSpire Health Partners, an interstate consortium of leading health systems, to focus on the sharing of best practices in clinical care and achieving efficiencies.

For additional information, please visit http://www.HackensackMeridianHealth.org.

About the Center for Discovery and Innovation:

The Center for Discovery and Innovation, a newly established member of Hackensack Meridian Health, seeks to translate current innovations in science to improve clinical outcomes for patients with cancer, infectious diseases and other life-threatening and disabling conditions. The CDI, housed in a fully renovated state-of-the-art facility, offers world-class researchers a support infrastructure and culture of discovery that promotes science innovation and rapid translation to the clinic.

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Hackensack Meridian Health Center for Discovery and Innovation to Host Genomic Medicine Symposium - P&T Community

When Wellcome Sanger Institute geneticist Eugene Gardner set out to look for a specific type of genetic mutation in a massive database of human DNA, he figured itd be a long shot. Transposonsalso known as jumping genes because they can move around the genomecreate a new mutation in one of every 15 to 40 human births, but thats across the entire 3 billion base pairs of nuclear DNA that each cell carries. The sequencing data that Gardner was working with covered less than two percent of that, with only the protein-coding regions, or exons, included. Doing a quick calculation, he determined that, in the best-case scenario, he could expect to find up to 10 transposon-generated variants linked to a developmental disease. And we really might get zero, he says. This whole thing might be for naught.

But Gardner had recently developed the perfect tool to find the sort of de novo mobile element insertions that come about as a result of transposon movements and are often overlooked in genetic screens and analyses. As a graduate student in Scott Devines lab at the University of Maryland, Baltimores Institute for Genome Sciences, he had spent many hours making the software for the mobile element locator tool he dubbed MELT. The program was easy to use, so when Gardner moved across the Atlantic for a postdoc in Matthew Hurless lab at Sanger near Cambridge and gained access to a database of exomes from 13,000 patients with developmental disorders, he figured running the tool was worth a try.

There is tremendous value for these families that get a diagnosis.

Dan Koboldt, Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Childrens Hospital

Of those 13,000, Gardner focused on 9,738 people in the Deciphering Developmental Disorders (DDD) study whose parents exomes had also been sequenced, making it easier to single out variants present in the child but not in mom and dad. And as it turned out, he did get some hits. MELT picked up 40 potentially transposon-generated variants, which Gardner sat down at his computer to review using the raw sequencing data. Nine appeared to be true de novo mobile element insertions. I remember being in my desk doing the visualization of all the putative de novo variants after I got the first results off the pipeline, he recalls. I remember being excited: I think I might have found a diagnostic de novo!

Discussing the literature on the genes affected by such insertions with clinicians and other colleagues, Gardner narrowed the list down to four insertions found in genes that may be causing or contributing to four different patients disorders. He sent these results off to the physicians who had referred each of the patients to the database, and all the doctors confirmed that the results made sense to them given what had been published on those genes and what they knew about other cases involving patients with mutations in the same sequences. In one case, the physician had already linked the patients disorder to the gene Gardner had identified; in the other three cases, the patients were still undiagnosed.

There is tremendous value for these families that get a diagnosis, says human geneticist Dan Koboldt, who has collaborated with Hurles in the past and has used MELT in his studies of rare disease at the Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Childrens Hospital in Columbus, Ohio, but who was not involved in Gardners recent study. A genetic answer not only can help physicians connect patients to appropriate medical and counseling resources; it puts an end to the diagnostic odyssey that families affected by rare disease often endure.

Whats more, the finding of four potentially causative hits out of the nearly 10,000 cases provides first estimate of how commonly such mobile element insertions underlie developmental disorders. Whats interesting about this study is that its taking a very broad approach, says Ian Adams, a developmental biologist at the University of Edinburghs MRC Human Genetics Unit who was not involved in the research. Rather than look for transposon activity in a specific disorder, its casting a much broader net in trying to find what type of diseases this class of mutations could be contributing to.

This approach is important, agrees Adamss MRC Human Genetics Unit colleague Jose Garcia-Perez, a transposable elements expert who was also not involved in the new research. In the last few years, two studies have used a tool developed around the same time as MELT to search for de novo mobile elements in people with autism spectrum disorder, but neither identified any that were likely to be responsible for the patients symptoms. [Gardners] study shows that, no matter whats [been found] recently, its something that should be explored in further detail in the future, says Garcia-Perez. [The study] actually shows a real connection between . . . transposition with that particular [type of] disorder. Koboldt adds: The reason this is an important study is that it establishes [that these] variants do occur and [that] they can be pathogenic.

Gardner says he hopes that his methods can be used to explore other diseases, from both a research and a clinical perspective. Adams says MELT does appear to be widely applicable to other datasets. Such a tool could be a boon to research on transposons, given that their movements are often missed by normal screening tools, Adams adds. I think [MELT is] something that could be readily built into existing pipelines.

Jef Akst is managing editor ofThe Scientist. Email her atjakst@the-scientist.com.

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Transposons Identified as Likely Cause of Undiagnosed Diseases - The Scientist

In November 2018, Chinese biophysics researcher He Jiankuimade a historic announcement.

Two twin girls nicknamed Lulu and Nana had become the worlds first genetically modified human beings.

Using a gene-editing technology known as CRISPR, He had manipulated the DNA of the embryos that would become the girls in an effort to make them immune to the HIV virus.

What first seemed like a historic triumph of science, however, quickly became one of the most infamous scandals in medical history.

The researcher was swiftly fired from his university, put under police investigation, and denounced by experts around the world who said he jumped the gun and carried out an experiment that was unsafe and unethical.

In December, He was sentenced to three years in prison for illegally carrying out human embryo gene-editing intended for reproduction. Its unclear whether the experiment caused any genetic damage to Lulu and Nana or if they are even resistant to the HIV virus.

Kiran Musunuru, one of the worlds foremost genetics researchers, was the first expert to publically condemn Hes experiment.

Nonetheless, Musunuru says the birth of the Chinese twins marks the beginning of a new human era, the possibilities of which are boundless.

Potential future implications of gene-editing technology range from preventing genetic diseases to producing designer babies with custom traits to creating superhumans and controlling our own evolution.

With the release of his new book, The CRISPR Generation: The story of the Worls First Gene-Edited Babies, The Globe Posts Bryan Bowmanspoke to Musunuru about where this technology could go from here and what it could mean for the future of humanity.

The following interview is lightly condensed and edited for length and clarity.

Bowman: Could you explain what CRISPR is broadly and how that technology evolved to where it is today?

Musunuru: CRISPR is one type of gene-editing tool. Gene editing is a technology that allows us to make changes to genes in the DNA and in the cells in the body. If were talking about human beings, typically were talking about changes that are related to health or disease.

There are several types of gene editing tools, but CRISPR is by far the most popular one. CRISPR is interesting because it wasnt invented. It actually exists naturally in all sorts of bacteria. It evolved as a sort of an immune system that can fight off viral infections. Just like we can get viral infections, it turns out bacteria can get viral infections as well. And so bacteria created a system by which they can fight off viruses. So thats where CRISPR came from.

Over the past couple of decades, a variety of very talented scientists identified it, discovered it in bacteria, and then were able to adapt it into a gene-editing tool that can now be used in human cells.

What we can do with CRISPR is either turn off genes and thats easier to do or we can make more precise changes to genes such as correcting a mutation that causes disease.

Bowman: Last year, there was the famous or infamous case where Dr. He Jiankui in China covertly created the first gene-edited babies. And I understand that you were the first expert to publicly condemn the experiment. What exactly did Dr. He do and why did you feel it was so unethical?

Musunuru: What he was trying to do was use CRISPR to turn off a gene called CCR5. By turning off this gene, he was hoping to make the babies that were born resistant to HIV infection, HIV being the virus that causes AIDS.

There are many people who are naturally born with this chain turned off and theyre resistant to HIV. So the rationale was, well, Im going to try to create babies who have the same trait.

What he did was problematic for two reasons. One, it was, to put it lightly, a scientific disaster. Everything you worry about going badly with CRISPR actually did happen. Any technology has a potential for a lot of good with the potential for bad. I compare it to fire. It can be very useful. But if youre not careful, it can cause wildfires and a lot of damage and hurt a lot of people. Its the same with CRISPR. It can do a lot of good. It can help patients who have bad diseases. But if youre irresponsible with it, it could actually cause unintended genetic damage.

Its not clear whether these kids that were born they were twin girls nicknamed Lulu and Nana its not clear whether theyre actually protected against HIV infection. Its not clear whether they might have suffered some genetic damage that might have health consequences for them. Its not clear whether the genetic damage if it did occur could get passed down to their children and affect future generations.

So scientifically, there are a lot of problems with it. The work was very premature. I would say that if we were ever going to do this in a reasonable, rational, safe way, were years away from doing it. But he went ahead and just did it anyway. You can call him a rogue scientist, as clich as it is. And he did it in conditions of secrecy. There was essentially no oversight. And potentially these twins and future generations might suffer the consequences.

The other problem is a problem of ethics. The way in which he did it basically violated every principle of ethical medical research in the textbook. Basically, everything that you could do wrong, he did it wrong.

Whenever we do an experimental procedure, we hope that the benefits greatly outweigh the risks. What he was trying to do was protect these kids from HIV. But the truth is, they were in no particular danger of getting HIV compared to the average person. In China, the prevalence of HIV is about 0.1 percent. So there wasnt really much for them to gain. Even if they did somehow during their lifetime get the HIV infection, we have good treatments to prevent it from proceeding to full-blown AIDS.

So what was the benefit of doing this procedure? You have to balance that against the harms. And the genetic damage thats possible that raises risks of things like cancer and heart disease and other diseases. When you have those risks and very little benefit, then its just not a favorable ratio. And thats intrinsically unethical.

Bowman: Seeing as you said that were years away from doing something like this in a more responsible and ethical way, what are the greatest challenges to getting to a point where parents will have the option to go forth with a gene-editing procedure that might prevent their children from suffering from some kind of genetic disease?

Musunuru: There are really two aspects to this. One is a scientific or medical aspect. Can we get to a place where gene-editing of embryos is well-controlled? Where we know that what were doing is truly safe and appropriate from that perspective?

The second issue is really a decision more for broader society. Is this something that we should be doing, something we want to be doing? This is less about the science and more about ethics and morality and legality and religious values and all sorts of other things. Reasonable people can disagree on whats appropriate and whats not appropriate.What complicates things here is that its not really an all or nothing decision. There are different scenarios where you could see parents using gene-editing on behalf of their unborn children.

I like to break it down is three scenarios. The first scenario is with parents who have medical issues that make it so that theres no way they can have natural biological children or healthy babies if they both have a bad disease and theyre going to pass it on to all of their kids unless you do something like editing. These are unusual situations, but they do exist.

The second scenario is one where parents might want to quite understandably reduce the risk of their child having some serious illness at some point in their lifetime. Im talking about things that are fairly common, like Alzheimers disease or breast cancer or heart disease or whatnot. Theres no guarantee that the editing will eliminate that risk. But you can see how parents might want to stack the odds in their kids favor. Its still medical, but its not perhaps as severe a situation with a kid whos definitely going to get the disease unless you do something.

The third scenario would be cases in which parents want to make changes that are not really medical but are more of what we would think of as enhancements. These could be cosmetic changes like hair color, eye color, things like that.

But it could potentially be much more serious things like intelligence or athletic ability or musical talent. Now, to be fair, thats theoretical. I dont think we are anywhere near knowing enough about how genes influence these things to be able to do it anytime soon. You might actually have to change hundreds of genes in order to make those changes. But you can imagine how certain parents might want to do that, might want to advance their children in the ways that they feel personally are desirable.

Bowman: Can gene editing only be performed on embryos or is it possible to edit genes in later stages of pregnancy or even post-birth?

Musunuru: Theres actually a lot of exciting work going on using gene editing to help patients, whether its adults or children. Right now its been focused mostly on adults who have terrible diseases and its really being used as a treatment to alleviate their suffering or potentially cure the diseases.

Just recently, we got the exciting news that two patients one in the U.S. and one in Europe were participating in a clinical trial. They each had a severe blood disorder. One of them had sickle cell disease. The other had a disease called beta-thalassemia. Earlier this year, they got a CRISPR-based treatment. And whats very exciting is that it looks like not only have their conditions improved significantly, it looks like they might actually be cured.

If that bears out, it would really be historic because these are diseases that affect millions of people around the world and were previously incurable. This treatment is also being explored for things ranging from cancer to liver disease to heart disease.

So theres enormous potential for benefit for living people who have serious diseases. But its a very different situation than editing embryos because youre talking about a person who is in front of you. We are trying to alleviate their suffering. That patient has the ability to freely give consent to the procedure, to weigh the benefits and risks and come up with a decision.

Bowman: How does that work? Is it some kind of cell transplant where the new cells then replicate throughout the rest of the body?

Musunuru: Yeah. It depends on the situation. I mentioned those two patients with the blood disorders. The way it worked there was the medical team used bone marrow stem cells. They basically took bone marrow as if they were going to do a transplant and then edited blood stem cells in a dish outside of the body to fix the genetic problem. And then they took those edited stem cells and put them back into the same patient. Those cells start making the blood cells that are now corrected or repaired. And by doing that, to cure the disease.

Another potential implementation is I work on heart disease. And what wed like to be able to do is turn off cholesterol genes in the liver. So what I envision is that a patient with heart disease would get a single treatment and it would deliver CRISPR into the liver and just the liver. It would turn off genes that produce cholesterol in the liver. The effect of that is permanent reduction of cholesterol levels and lifelong protection against heart disease.

This actually works really well in mice. Ive been working on this in my own laboratory for six, almost seven years now experimenting with it in monkeys. And if looks like it works and Im pretty confident that it will work we could be looking at clinical trials in a few years where were taking patients who have really bad heart disease or a very high risk for heart disease and actually giving them the single treatment within their own bodies that would turn off these cholesterol genes.

Bowman: In terms of more cosmetic applications, theres this popular idea that designer babies will be a reality at some point in the future. But how feasible would it be to use gene-editing for something very basic like choosing eye color or hair color? Are there many genes involved in determining traits like that? Are we close to being able to do that if we choose to?

Musunuru: Well, eye color, hair color, those actually turned out to be fairly simple. Theres only a small number of genes that control those. So in theory, if you wanted to do it, it wouldnt be that difficult.

Personally, my point of view is thats a trivial thing. Like why would you go through all that trouble? Do I care if your kid has blue eyes versus green eyes versus brown eyes? Maybe some parents feel that thats very important. So I think simple things like hair color, like eye color, it could be done fairly readily. I just dont see it as serious enough to warrant doing it.

The more complex things like intelligence, gosh, thats going to be so challenging. I mean, intelligence is just such a complex phenomenon. Theres some genetics involved in it, but there are so many other factors that come into that like upbringing and environment. Were not even getting close to an understanding of how someones intelligence comes about, to be perfectly honest about it.

I will point out that even though some of these things are simpler, in general, the vast majority of people are very, very uncomfortable with the idea of using gene editing of embryos for enhancements.

And I think this reflects a couple of things. I think this reflects the fact that people are more sympathetic if something like this is being used for medical purposes and much less comfortable if its being done to give a child an advantage in a way thats not medical.

It brings to mind the recent scandal where wealthy parents were trying to get their kids into good colleges by actively bribing admissions officers, faking test scores, fabricating resums. That kind of thing makes people very uncomfortable that certain people, particularly wealthy people, might try to use this technology to an extreme to advantage their children.

Theres an economic aspect to that. Wealthy parents might have better access to this technology than those who are not as wealthy. And what does that mean? If wealthy parents are somehow able to make designer babies who somehow are advantaged and other people are not, does that exacerbate socio-economic inequalities in our society?

So I think there are a few reasons why people are uncomfortable with the idea of enhancement, whereas on the whole, the majority seem to be at least somewhat open to the idea that there might be good medical uses.

Bowman: Im really happy that you brought up that socio-economic inequality aspect because I was going to ask you about that. But if we table those concerns for a moment and go way out there, theres this notion you write about that we could ultimately, theoretically, control our own evolution.

Ive heard it suggested that it could be theoretically possible to incorporate traits from other organisms that could be advantageous into our own DNA and essentially enter a new post-human stage of evolution. Is that total science fiction or do you think were entering a period where that is increasingly possible?

Musunuru:Well, with the way things are going with this technology. I mean, weve taken a step towards that. But there are many, many, many, many steps that would need to be taken to actually get to that point. But I think youre right. You see the path. We have the technology. Then its a question of perfecting the technology. A question of learning more about what genes from other species might be advantageous.

The cats out of the bag. The technology is here. Whether its five years from now or 10 years from now or 50 years from now or 100 years from now, these sorts of things will inevitably start to happen. And Im not sure theres much that those who would like to not see that happen will be able to do to stop it in the long run.

China Jails Scientist Who Gene-Edited Babies

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Controlling Our Own Evolution: What is the Future of Gene-Editing? - The Globe Post

Iowa State researchers have looked to flies and their cardiac muscles as a way to develop new therapies for heart disease.

Researchers studying fruit flies and their hearts found a connection between fly hearts and human hearts.

Hua Bai, assistant professor of genetics, development and cell biology, led a study and was published recently in the academic journal "Autophagy" that explores the genetic mechanism that causes fly cardiac muscles to deteriorate with age.

Bai said the research team restored much of the cardiac function in middle-aged flies, which experience many of the same heart maladies as middle-aged humans.

To measure cardiac function parameters, semi-intact adult fly hearts were prepared by exposing abdominal heart tubes by cutting off the head and ventral thorax of the fly and then removing the ventral abdominal cuticle and all internal organs.

The researchers approach started with autophagy, a cellular cleanup process that removes and recycles damaged proteins and organelles. The autophagy process slows with age, which can lead to the weakening of cardiac muscles.

Bais research team looked at a key genetic pathway conserved in virtually all organisms on Earth related to autophagy that balances organism growth with nutrient intake. This pathway, called mechanistic target of rapamycin (mTOR), has long been linked to tissue aging, Bai said.

One of two complexes that underlie the mTOR pathway,mechanistic target of rapamycin complex two or mTORC2, decreases with age as autophagy declines. But the researchers found that transgenically boosting mTORC2 strengthens heart muscles of older fruit flies.

Boosting the complex almost fully restored heart function, Bai said.

The discovery that enhancing mTORC2 slows the decline of the critical autophagy process could have big implications for how doctors treat patients with heart disease, one of the leading causes of the death of humans in the United States.

While flies and humans might seem to be worlds apart evolutionarily, Bai said the two species hearts age in a similar fashion. By middle age, cardiac muscles in both species tend to contract with less strength and regularity.

The fly model can be useful for developing drug target discoveries that could have a big impact on human health, Bai said.

The researchers arrived at their conclusions after conducting thousands of video recordings on cardiac muscles in fruit flies of various ages. High-resolution, high-speed cameras measured the activity of the flies cardiac muscles.

The experiments showed that boosting mTORC2 could restore a five-to-six-week-old flys heart function to that of a fly between one and two weeks old. Thats like restoring a middle-aged heart to how it functioned during young adulthood, Bai said.

Because flies live only between two and three months, its much easier for scientists to study aging and longevity in flies than in more long-lived species, Bai said, and the ability to manipulate the fly genome also makes them ideal for genetic study and a common model organism.

Flies were maintained at 25 degrees Celsius, 60 percent relative humidity and 12 hour light/dark, and adults were reared on agar-based diet with 0.8 percent cornmeal, 10 percent sugar and 2.5 percent yeast.

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Study looks into connection of fruit fly hearts and those of humans - Iowa State Daily

Adult bone repair relies on the activation of bone stem cells, which still remain poorly characterized. Bone stem cells have been found both in the bone marrow and in the outer layer of tissue, called periosteum, that envelopes the bone. Of the two, periosteal stem cells are the least understood.

Having a better understanding of how adult bones heal could reveal new ways of repair fractures faster and help find novel treatments for osteoporosis. Dr. Dongsu Park and his colleagues at Baylor College of Medicine investigate adult bone healing and recently uncovered a new mechanism that has potential therapeutic applications.

Previous studies have shown that bone marrow and periosteal stem cells, although they share many characteristics, also have unique functions and specific regulatory mechanisms, said Park, who is assistant professor of molecular and human genetics and of pathology and immunology at Baylor.

It is known that these two types of bone stem cells comprise a heterogeneous population that can contribute to bone thickness, shaping and fracture repair, but scientists had not been able to distinguish between different subtypes of bone stem cells and study how their different functions are regulated.

In the current study, Park and his colleagues developed a method to identify different subpopulations of periosteal stem cells, define their contribution to bone fracture repair in live mouse models and identify specific factors that regulate their migration and proliferation under physiological conditions.

The researchers discovered specific markers for periosteal stem cells in mice. The markers identified a distinct subset of stem cells that showed to be a part of life-long adult bone regeneration.

We also found that periosteal stem cells respond to mechanical injury by engaging in bone healing, Park said. They are important for healing bone fractures in the adult mice and, interestingly, they contribute more to bone regeneration than bone marrow stem cells do.

In addition, the researchers found that periosteal stem cells also respond to inflammatory molecules called chemokines, which are usually produced during bone injury. In particular, they responded to chemokine CCL5.

Periosteal stem cells have receptors molecules on their cell surface called CCR5 that bind to CCL5, which sends a signal to the cells to migrate toward the injured bone and repair it. Deleting the CCL5 or the CCR5 gene in mouse models resulted in marked defects or delayed healing. When the researchers supplied CCL5 to CCL5-deficient mice, bone healing was accelerated.

The findings suggested potential therapeutic applications. For instance, in individuals with diabetes or osteoporosis in which bone healing is slow and may lead to other complications resulting from limited mobility, accelerating bone healing may reduce hospital stay and improve prognosis.

Our findings contribute to a better understanding of how adult bones heal. We think this is one of the first studies to show that bone stem cells are heterogeneous, and that different subtypes have unique properties regulated by specific mechanisms, Park said. We have identified markers that enable us to tell bone stem cell subtypes apart and study what each subtype contributes to bone health. Understanding how bone stem cell functions are regulated offers the possibility to develop novel therapeutic strategies to treat adult bone injuries.

Find all the details of this study in the journal journal Cell Stem Cell.

Other contributors to this work include Laura C. Ortinau, Hamilton Wang, Kevin Lei, Lorenzo Deveza, Youngjae Jeong, Yannis Hara, Ingo Grafe, Scott Rosenfeld, Dongjun Lee, Brendan Lee and David T. Scadden. The authors are affiliated with one of the following institutions: Baylor College of Medicine, Texas Childrens Hospital, Pusan National University School of Medicine and Harvard University.

This study was supported by the Bone Disease Program of Texas Award and The CarolineWiess Law Fund Award, the NIAMS of the National Institutes of Health under award numbers 1K01AR061434 and 1R01AR072018 and U54 AR068069 and the NIDDK of the NIH.

By Ana Mara Rodrguez, Ph.D.

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There is a new player in adult bone healing - Baylor College of Medicine News

Some people's hearts stay strong well into their 60s, but their kidneys begin to fail. Others may have the kidneys of a 30-year-old but fall victim to constant infection.

Now, scientists may be one step closer to understanding why the aging process varies so drastically between people.

Even within a single person, aging unfolds at different rates in different tissues, sometimes striking the liver before the heart or kidney, for example. People fall into distinct categories depending on which of their biological systems ages fastest, and someday, doctors could use this information to recommend specific lifestyle changes and design personalized medical treatments, according to a new study, published Jan. 13 in the journal Nature Medicine.

The research team behind the study sorted 43 people into aging categories, or "ageotypes," based on biological samples collected over the course of two years. The samples included blood, inflammatory substances, microbes, genetic material, proteins and by-products of metabolic processes. By tracking how the samples changed over time, the team identified about 600 so-called markers of aging values that predict the functional capacity of a tissue and essentially estimate its "biological age."

So far, the team has identified four distinct ageotypes: Immune, kidney, liver and metabolic. Some people fit squarely in one category, but others may meet the criteria for all four, depending on how their biological systems hold up with age.

"Now, it's going to be a lot more than just four categories," said senior author Michael Snyder, a professor and the chair of genetics at the Stanford University School of Medicine in California. For instance, one participant in the study appeared to be a cardiovascular ager, meaning their cardiac muscle accumulates wear-and-tear at a greater rate than other parts of their body. "If we [surveyed] 1,000 people, I'm sure we'll find other cardio agers and that category will become better defined." And with more research, even more patterns of aging may emerge, Snyder added.

Related: 8 Tips for Healthy Aging

In the past, scientists have hunted for markers of aging in enormous datasets for large populations, Snyder, told Live Science. Researchers pinpointed markers of aging by comparing data from young people to that of older people, but for individuals, that kind of data captures only a specific moment in time. It cannot reveal how a given person might change as they age, Snyder said.

In a clinical setting, that means population-based markers might not be the best measure to determine how a patient is aging, or what combination of medical treatments might suit them best, he added.

"Population-based decisions are crude at best," Synder said. They won't necessarily hold up for you, per se."

By tracking specific people through time, Snyder and his co-authors hoped to learn how aging markers differ between individuals. Their study participants ranged in age from 29 to 75 and provided at least five biological samples over the course of two years. Even within that relatively short time frame, several patterns of aging emerged.

For example, immunological agers accumulated more markers of inflammation through time, while metabolic agers accrued more sugar in their blood, indicating that their bodies were metabolizing glucose less efficiently. Similar to scores on a personality test, each individual's aging "profile" included a combination of traits, mixed and matched from different ageotypes.

Snyder and his co-authors plan to follow the study participants to see how their aging profiles morph over time. They also aim to develop a simple ageotype test that could be used in the doctor's office to quickly assess a patient's health status, and potentially point them toward the best possible treatment options.

"There are drugs and various kinds of dietary interventions and lifestyle interventions through which it may be possible to modulate some of these aging processes," Dr. James Kirkland, a gerontologist and head of the Kogod Center on Aging at the Mayo Clinic in Rochester, Minnesota, told NBC News.

"But in order to apply those correctly, we have to know which people to apply which drugs or which dietary interventions in order to get the most bang for the buck," said Kirkland, who was not involved in the new study.

Related: 7 Ways the Mind and Body Change With Age

While existing drugs, diets and exercise regimes can target some signs of aging, other markers aren't fully understood yet.

For example, over the course of Snyder's study, a marker of poor kidney function decreased in 12 individuals, eight of whom took statins. The marker, a waste product called creatinine, accumulates in the blood as muscle tissue naturally breaks down, but the kidneys typically filter the substance and expel it through the urine. Creatinine levels fell in the eight individuals on statins, suggesting that the medication improved their kidney function, though it's unclear why levels also dipped in four additional people, the authors noted.

The team also found that concentrations of several microbes seem to change with age, but we don't yet know how that may affect health. Certain microbes may proliferate in response to age-related changes in the body, while others help drive them, Snyder said. The authors also spotted differences in how diabetic and pre-diabetic people aged as compared to insulin-sensitive people, but it's unclear whether these markers indicate meaningful differences in health status. Many studies suggest that insulin plays a central role in aging throughout the animal kingdom, but more research is needed to clarify its exact influence over human aging.

For now, ageotypes present as many questions as they do answers about human aging. Until scientists understand what various aging markers really mean, clinicians will continue to rely on standard vital sign assessments to track patients' health over time. In the near future, perhaps ageotypes could serve to motivate people to take better care of areas of their body that appear to be aging faster than others, Snyder said. For instance, if someone fits the profile of a cardiovascular ager, they might focus on improving their cardiovascular health and undergoing relevant medical tests to check on their progress.

"As we collect a lot more information, we are going to be better able to follow how people are aging, [as well as] what interventions they did that actually reduced their aging," Snyder said.

Originally published on Live Science.

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Scientists Discover 4 Distinct Patterns of Aging - Livescience.com

DNA inherited from Neanderthals and Denisovans may have provided humans with protection against infectious diseases, including malaria, a study published in Neuron suggests.

Researchers also found added evidence that these inherited genes could affect biological processes and neurological conditions like autism and attention deficit/hyperactivity disorder (ADD).

For over a decade, scientists have suggested modern humans interbred with other hominin species, including Neanderthals. Evidence of this interbreeding can still be found in the DNA of people living today.

Genomic introgression is where DNA is swapped when two species interbreed. This can result in traits and characteristics being passed from one species to the other.

An example of this is Tibetans' unique aptitude for high altitude living, which is thought to have stemmed from their early ancestors interbreeding with Denisovansanother extinct archaic species from the Homo genus.

Less advantageous traits that we may have inherited from our non-Homo sapien ancestors include depression and social anxiety, as well as an increased susceptibility to inflammatory diseases like type 2 diabetes.

It is thought that Neanderthal ancestry for non-African populations sits somewhere between the 1 and 4 percent mark, though ranges vary. Melanasians and East Asian populations are also thought to carry Denisovan DNA, with up to 5 percent of Melanesian DNA derived from Denisovans by some estimates.

Typically, scientists have attempted to understand these genomic introgressions by studying the genes themselves, the researchers say. In this research, they focused on the relationships and interactions between genes, which were sourced from the 1000 Genomes Projecta catalogue of human genomesand 35 Melanesian individuals.

"Our results suggest that gene interactions and associations between different archaic mutations have played an important role in human evolution," Alexandre Gouy, one of the study authors, from the University of Bern, Switzerland, told Newsweek.

Some of the inherited genes analyzed in the study have been linked to autism and ADD. Others are thought to influence biological processes, such as energy metabolism. But some of the most intriguing mutations looked at were those related to protections against infectious diseasesand malaria in particular, said Gouy.

"When looking at immunity genes ... it was interesting to see that they were involved in the response to all kinds of pathogens: virus, bacteria and protozoanssuch as the malaria parasite," he said.

This suggests DNA inherited from extinct hominids bolstered the human immunity to infectious diseases, adding to existing research that suggests interbreeding with Neanderthals improved humans resistance to infections and susceptibility to allergies.

One of the "most striking" findings was evidence of an adaption in the genes of Papua New Guineans inherited from ancient hominids, which may provide some kind of protection against malaria.

However, the researchers are keen to stress their findings are preliminary. While it is becoming increasingly evident that humans have adopted genes from ancient hominids, it is unclear how this affects people in the 21st century.

"It remains very difficult to quantify precisely the effect of those mutations," Gouy said. "Health and behaviour result from the interaction of a complex genetic background and the environment. Hence, the impact of genetics on the immune system and behaviour is difficult to assess."

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Ancient Hominids May Have Helped Protect Humans From Malaria - Newsweek

Zika virus infection can stunt neonatal brain development, a condition known as microcephaly, in which babies are born with abnormally small heads. To determine how best to prevent and treat the viral infection, scientists first need to understand how the pathogen gets inside brain cells.

Employing different approaches to answer different questions, two research teams at University of California San Diego School of Medicine independently identified the same molecule v5 integrin as Zika virus key to entering brain stem cells.

In a pair of papers published January 16, 2020 by Cell Press, the researchers also found ways to take advantage of the integrin to both block Zika virus from infecting cells and turn it into something good: a way to shrink brain cancer stem cells.

Integrins are molecules embedded in cell surfaces. They play important roles in cell adherence and communication, and are known to be involved in cancer progression and metastasis. Several other integrins are known entry points for other viruses, including adenovirus, foot-and-mouth disease virus and rotavirus, but v5 was not previously known for its role in viral infections.

One team, led by Tariq Rana, PhD, professor and chief of the Division of Genetics in the Department of Pediatrics at UC San Diego School of Medicine and Moores Cancer Center, used CRISPR gene editing to systematically delete every gene in a 3D culture of human glioblastoma (brain cancer) stem cells growing in a laboratory dish. Then they exposed each variation to Zika virus to determine which genes, and the proteins they encode, are required for the virus to enter the cells. The virus was for the first time labeled with green fluorescent protein (GFP) to allow the researchers to visualize viral entry into the cells.

Their study, published in Cell Reports, uncovered 92 specific human brain cancer stem cell genes that Zika virus requires to infect and replicate in the cells. But one gene stood out, the one that encodes v5 integrin.

Integrins are well known as molecules that many different viruses use as doorknobs to gain entry into human cells, Rana said. I was expecting to find Zika using multiple integrins, or other cell surface molecules also used by other viruses. But instead we found Zika uses v5, which is unique. When we further examined v5 expression in brain, it made perfect sense because v5 is the only integrin member enriched in neural stem cells, which Zika preferentially infects. Therefore, we believe that v5 is the key contributor to Zikas ability to infect brain cells.

The second study, published in Cell Stem Cell, was led by Jeremy Rich, MD, professor in the Department of Medicine at UC San Diego School of Medicine and director of neuro-oncology and of the Brain Tumor Institute at UC San Diego Health. Knowing that many viruses use integrins for entry into human cells, Richs team inhibited each integrin with a different antibody to see which would have the greatest effect.

When we blocked other integrins, there was no difference. You might as well be putting water on a cell, said Rich, who is also a faculty member in the Sanford Consortium for Regenerative Medicine and Sanford Stem Cell Clinical Center at UC San Diego Health. But with v5, blocking it with an antibody almost completely blocked the ability of the virus to infect brain cancer stem cells and normal brain stem cells.

Richs team followed up by inhibiting v5 in a glioblastoma mouse model with either an antibody or by deactivating the gene that encodes it. Both approaches blocked Zika virus infection and allowed the treated mice to live longer than untreated mice. They also found that blocking the v5 integrin in glioblastoma tumor samples removed from patients during surgery blocked Zika virus infection.

Ranas team also blocked v5 in mice, treating them daily with cilengitide or SB273005, two experimental cancer drugs that target the integrin. Six days after Zika virus infection, the brains of their drug-treated mice contained half as much virus as mock-treated mice.

The neat thing is that these findings not only help advance the Zika virus research field, but also opens the possibility that we could similarly block the entry of multiple viruses that use other integrins with antibodies or small molecule inhibitors, Rana said.

Rana and team are now engineering a mouse model that lacks v5 integrin in the brain a tool that would allow them to definitively prove the molecule is necessary for Zika viral entry and replication.

Rich is a neuro-oncologist who specializes in diagnosing and treating patients with glioblastoma, a particularly aggressive and deadly type of brain tumor. When he first saw how the Zika virus shrinks brain tissue, it reminded him of what he hopes to achieve when hes treating a patient with glioblastoma. In 2017, he and collaborators published a study in which they determined that Zika virus selectively targets and kills glioblastoma stem cells, which tend to be resistant to standard treatments and are a big reason why glioblastomas recur after surgery and result in shorter patient survival rates.

Richs latest study helps account for the virus preference for glioblastoma stem cells over healthy brain cells. The v5 integrin is made up of two separate subunits v and 5. The team found that glioblastoma stem cells produce a lot of both the v subunit (associated with stem cells) and 5 subunit (associated with cancer cells). Together, these units form the v5 integrin, which, the team discovered, plays an important role in glioblastoma stem cell survival. Those high levels of v5 integrin also help explain why, in the study, glioblastoma stem cells were killed by Zika virus at much higher rates than normal stem cells or other brain cell types.

It turns out that the very thing that helps cancer cells become aggressive cancer stem cells is the same thing Zika virus uses to infect our cells, Rich said.

To see how this might play out in a more realistic model of human disease, Richs team partnered with an expert in human brain disease modeling Alysson Muotri, PhD, professor at UC San Diego School of Medicine, director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine, and team. Pinar Mesci, PhD, a postdoctoral researcher in Muotris lab, generated a new brain tumor model, where human glioblastoma tumors were transplanted into human brain organoids, laboratory mini-brains that can be used for drug discovery. The researchers discovered that Zika virus selectively eliminates glioblastoma stem cells from the brain organoids. Inhibiting v5 integrin reversed that anti-cancer activity, further underscoring the molecules crucial role in Zika virus ability to destroy cells.

Now Richs team is partnering with other research groups to perform targeted drug studies. In addition to searching for drugs to block Zika virus, as Ranas group is doing, Rich is interested in genetic modifications to the virus that could help better target its destruction to brain cancer cells, while leaving healthy cells alone.

While we would likely need to modify the normal Zika virus to make it safer to treat brain tumors, we may also be able to take advantage of the mechanisms the virus uses to destroy cells to improve the way we treat glioblastoma, Rich said. We should pay attention to viruses. They have evolved over many years to be very good at targeting and entering specific cells in the body.

Zika virus was perhaps best known in 2015-16, when a large outbreak affected primarily Latin America, but also several other regions of the world. While that particular epidemic has passed, Zika virus has not gone away. Smaller, local outbreaks continue and this past summer, the first few cases of native Zika virus infection were recorded in Europe. Scientists warn Zika could continue to spread as climate change affects the habitat range of the mosquito that carries it. The virus can also be transmitted from pregnant mother to fetus, and via sexual contact. More than half of all people on Earth are at risk for Zika virus infection, and there is no safe and effective treatment or vaccine.

Co-authors of Ranas study, published January 16, 2020 in Cell Reports, include: Shaobo Wang, Qiong Zhang, Shashi Kant Tiwari, Gianluigi Lichinchi, Edwin H. Yau, Hui Hui, Wanyu Li, UC San Diego; and Frank Furnari, UC San Diego and Ludwig Institute for Cancer Research.

This research was funded, in part, by the National Institutes of Health (grants AI125103, CA177322, DA039562, DA046171 and DA049524).

Co-authors of Richs study, published January 16, 2020 in Cell Stem Cell, also include: Zhe Zhu, Jean A. Bernatchez, Xiuxing Wang, Hiromi I. Wettersten, Sungjun Beck, Alex E. Clark, Qiulian Wu, Sara M. Weis, Priscilla D. Negraes, Cleber A. Trujillo, Jair L. Siqueira-Neto, David A. Cheresh, UC San Diego; Ryan C. Gimple, Leo J.Y. Kim, UC San Diego and Case Western Reserve University; Simon T. Schafer, Fred H. Gage, Salk Institute for Biological Studies; Briana C. Prager, UC San Diego, Case Western Reserve University and Cleveland Clinic; Rekha Dhanwani, Sonia Sharma, La Jolla Institute for Allergy and Immunology; Alexandra Garancher, Robert J. Wechsler-Reya, Sanford Burnham Prebys Medical Discovery Institute; Stephen C. Mack, Baylor College of Medicine, Texas Childrens Hospital; Luiz O. Penalva, Childrens Cancer Research Institute; Jing Feng, Zhou Lan, Rong Zhang, Alex W. Wessel, Michael S. Diamond, Hongzhen Hu, Washington University School of Medicine; Sanjay Dhawan, and Clark C. Chen, University of Minnesota.

The research was funded, in part, by the National Institutes of Health (grants CA217065, CA217066, CA203101, CA159859, CA199376, NS097649-01, CA240953-01, NS096368, R01DK103901,R01AA027065, MH107367, N5105969, CA045726, CA050286, CA197718, CA154130, CA169117, CA171652, NS087913, NS089272), California Institute for Regenerative Medicine (CIRM, grants FA1-00607, DISC209649) and International Rett Syndrome Foundation.

Disclosures: Tariq Rana is a co-founder of, member of the scientific advisory board for, and has equity interest in ViRx Pharmaceuticals. Alysson Muotri is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis focusing on therapeutic applications customized for autism spectrum disorder and other neurological disorders. David Cheresh is a co-founder of TargeGen and AlphaBeta Therapeutics, a new but currently unfunded company developing an antibody to integrin v5 involved in cancer treatment. The terms of these arrangements have been reviewed and approved by UC San Diego in accordance with its conflict of interest policies. In addition, Michael Diamond, of Washington University School of Medicine, is a consultant for Inbios and Atreca and serves on the Scientific Advisory Board of Moderna.

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Zika Virus' Key into Brain Cells ID'd, Leveraged to Block Infection and Kill Cancer Cells - UC San Diego Health

SAN DIEGO--(BUSINESS WIRE)--Empirico Inc. announced today that it has entered into a strategic collaboration with Ionis Pharmaceuticals. During the three-year collaboration, Empirico will utilize its Precision Insights Platform, which incorporates huge biological data sets, human genetics and advanced algorithmic approaches, to identify therapeutic targets for indications and tissues that are amenable to Ionis industry-leading antisense technology. Under the terms of the agreement, Ionis can advance up to ten targets identified by Empirico and assume responsibility for all preclinical and clinical development activities. Empirico and Ionis will also work together to incorporate human genetics evidence into ongoing efforts with existing Ionis programs, including work on target validation, indication and biomarker selection, and patient stratification.

Empiricos Precision Insights Platform was purpose-built for therapeutic target discovery and incorporates one of the largest datasets of its kind in the world to interrogate the role of genes and proteins in health and disease and find opportunities for novel therapeutic interventions. By combining expert data curation, customized data models, and statistical and machine learning algorithms, the platform enables Empiricos scientists to systematically generate, interrogate, and prioritize high-confidence therapeutic hypotheses that are then validated experimentally.

Empiricos approach to human genetics provides a much-needed opportunity to improve the success rate of drug discovery and development by leveraging experiments of nature, said Omri Gottesman, M.D., CEO of Empirico. Antisense oligonucleotides are an ideal translational partner for human genetics-focused target discovery, allowing us to precisely mimic or interfere with the mechanisms by which functional genetic variants influence health and disease. We are excited to work with Ionis, the leader in RNA-targeted drug discovery and development, in discovering new medicines for patients in need.

As part of this new collaboration, Ionis has made a $10 million equity investment in Empirico, with additional near-term commitments of up to $30 million based on operational and preclinical milestones. Empirico will be eligible to receive in excess of $620 million for the achievement of clinical development, regulatory and commercial milestones, and royalties on net sales. Empirico also has the option to license, develop, and commercialize an Ionis development candidate directed toward a collaboration target for which Ionis will receive milestone payments and royalties on net sales.

In connection with this new collaboration, Empirico also announced today the closing of its $17 million Series A-2 financing, led by Ionis and with participation by DCVC Bio and Neotribe Ventures. This was a follow-on round to Empiricos $12.5 million Series A financing, co-led by DCVC Bio and Neotribe Ventures and completed In November 2018.

About Empirico

Empirico is a next-generation therapeutics company founded on utilizing human genetics, data science and programmable biology to power novel target discovery and development. Empiricos Precision Insights Platform, a proprietary human genetics-focused discovery platform, leverages a world-leading dataset and advanced algorithmic approaches to identify and prioritize therapeutic targets with a higher probability of translational success. All potential therapeutic targets are subjected to rigorous experimental validation to elucidate the mechanism by which genetic variation impacts disease risk and provide insights about which therapeutic modality could be programmed to mimic or interfere with that mechanism. Empirico has active preclinical development programs across several immune, dermatological, cardiometabolic, and ophthalmic indications based on targets identified with the Precision Insights Platform. Empirico is headquartered in San Diego, Calif. with laboratories in Madison, Wis. To learn more about Empirico, visit http://www.empiricotx.com.

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Empirico Announces Strategic Collaboration to Harness Human Genetics for the Discovery and Development of Novel Antisense Oligonucleotide Therapeutics...

Jesse Bloom, left, and Lea Starita are genetic scientists pursuing advances with the technique known as Deep Mutational Scanning, which will be the subject of a symposium and workshop at the University of Washington in Seattle on Jan. 13 and 14. (GeekWire Photo / Todd Bishop)

It has been nearly two decades since scientists accomplished the first complete sequencing of the human genome. This historic moment gave us an unprecedented view of human DNA, the genetic code that determines everything from our eye color to our chance of disease, unlocking some of the biggest mysteries of human life.

Twenty years later, despite the prevalence of genetic sequencing, considerable work remains to fulfill the promise of these advances to alleviate and cure human illness and disease.

Scientists and researchers are actually extremely good at reading genomes, but were very, very bad at understanding what were reading, said Lea Starita, co-director of Brotman Baty Institute for Precision Medicines Advanced Technology Lab, and research assistant professor in the Department of Genome Sciences at the University of Washington.

But that is changing thanks to new tools and approaches, including one called Deep Mutational Scanning. This powerful technique for determining genetic variants is generating widespread interest in the field of genetics and personalized medicine, and its the subject of a symposium and workshop on Jan. 13 and 14 at the University of Washington.

I think approaches like Deep Mutational Scanning will eventually allow us to make better countermeasures, both vaccines and drugs that will help us combat even these viruses that are changing very rapidly said Jesse Bloom, an evolutionary and computational biologist at the Fred Hutchinson Cancer Research Center, the Howard Hughes Medical Institute and the University of Washington Department of Genome Sciences.

Bloom, who researches the evolution of viruses, will deliver the keynote at the symposium, held by the Brotman Baty Institute and the Center for the Multiplex Assessment of Phenotype.

On this episode of the GeekWire Health Tech Podcast, we get a preview and a deeper understanding of Deep Mutational Scanning from Bloom and Starita.

Listen to the episode above, or subscribe in your favorite podcast app, and continue reading for an edited transcript.

Todd Bishop: Lets start with the landscape for precision medicine and personalized medicine. Can you give us a laypersons understanding of how personalized medicine differs from the medicine that most of us have encountered in our lives?

Lea Starita: One of the goals of precision medicine is to use the genomic sequence, the DNA sequence of the human in front of the doctor, to inform the best course of action that would be tailored to that person given their set of genes and the mutations within them.

TB: Some people in general might respond to certain treatments in certain ways and others might not. Today we dont know necessarily why thats the case, but personalized medicine is a quest to tailor the treatment or

Starita: To the individual. Exactly. Thats kind of personalized medicine, but you could also extend that to infectious disease to make sure that youre actually treating the pathogen that the person has, not the general pathogen, if you would. How would you say that, Jesse?

Jesse Bloom: I would elaborate on what Lea said when it comes to infectious diseases and other diseases. Not everybody gets equally sick when they are afflicted with the same underlying thing, and people tend to respond very differently to treatments. That obviously goes for genetic diseases caused by changes in our own genes like cancer, and it also happens with infectious diseases. For instance, the flu virus. Different people will get flu in the same year and some of them will get sicker than others, and thats personalized variation. Obviously wed like to be able to understand what the basis of that variation is and why some people get more sick in some years than others.

TB: Where are we today as a society, as a world, in the evolution of personalized medicine?

Starita: Pretty close to the starting line still. Theres been revolutions in DNA sequencing, for example. Weve got a thousand dollar genome, right? So were actually extremely good at reading genomes, but were very, very bad at understanding what were reading. So you could imagine youve got a human genome, its three billion base pairs times two, because youve got two copies of your genome, one from your mother, one from your father, and within that theres going to be millions of changes, little spelling mistakes all over the genome. We are right now very, very, very I cant even use enough verys bad at predicting which ones of those spelling mistakes are going to either be associated with disease or predictive of disease, even for genes where we know a lot about it. Even if that spelling mistake is in a spot in the genome we know a lot about, say breast cancer genes or something like that, we are still extraordinarily bad at understanding or predicting what effects those changes might have on health.

Bloom: In our research, were obviously also interested in how the genetics of a person influences how sick they get with an infectious disease, but we especially focus on the fact that the viruses themselves are changing a lot, as well. So theres changes in the virus as well as the fact that were all genetically different and those will interact with each other. In both cases, it really comes back to what Lea is saying is that I think weve reached the point in a lot of these fields where we can now determine the sequences of a humans genome or we can determine the sequence of a virus genome relatively easily. But its still very hard to understand what those changes mean. And so, thats really the goal of what were trying to do.

TB: What is deep mutational scanning in this context?

Lea Starita: A mutation is a change in the DNA sequence. DNA is just As, Cs, Ts and Gs. Some mutations which are called variants are harmless. You can think of a spelling mistake or a difference in spelling that wouldnt change the word, right? So the American gray, which is G-R-A-Y versus the British grey, G-R-E-Y. If you saw that in a sentence, its gray. Its the color.

But then it could be a spelling mistake that completely blows up the function of a protein, and then in that case, somebody could have a terrible genetic disease or could have an extremely high risk of cancer, or a flu virus could now be resistant to a drug or something like that, or resistant to your immune response. Or, mutations could also be beneficial, right? This is what allows evolution. This is how flu viruses of all the bacteria evolve to become drug resistant or gain some new enzymatic function that it needs to survive.

Bloom: For instance, in the case of mutations in the human genome, we know that everybody has mutations relative to the average human. Some of those mutations will have really major effects, some of them wont. The very traditional way or the way that people have first tried to understand what those mutations do is to sequence the genomes of a group of people and then compare them. Maybe here are people who got cancer and here are people who didnt get cancer and now you look to see which mutations are in the group that got cancer versus the group that didnt, and youll try to hypothesize that the mutations that are enriched in the group that did get cancer are associated with causing cancer.

This is a really powerful approach, but it comes with a shortcoming which is that theres a lot of mutations, and it gets very expensive to look across very, very large groups of people. And so the idea of a technique like deep mutational scanning is that we could simply do an experiment where we test all of the mutations on their own and we wouldnt have to do these sort of complicated population level comparisons to get at the answer. Because when youre comparing two people in the population, they tend to be different in a lot of ways, and its not a very well-controlled comparison. Whereas you can set up something in the lab where you have a gene that does have this mutation and does not have this mutation, and you can really directly see what the effect of that mutation is. Really, people have been doing that sort of experiment for many decades now. Whats new about deep mutational scanning is the idea that you can do that experiment on a lot of mutations all at once.

Starita: And its called deep because we try to make every possible spelling mistake. So every possible change in the amino acid sequence or the nucleotide sequence, which is the A, C, Ts and Gs, across the entire gene or the sequence were looking at.

Bloom: Lets say we were to compare me and Lea to figure out why one of us had some disease and other ones didnt. We could compare our genomes and theres going to be a lot of differences between them, and were not really going to know what difference is responsible. We dont even really know if it would be a change in their genomes thats responsible. It could be a change in something about our environment. So the idea behind deep mutational scanning is we would just take one gene. So in the case of Lea, she studies a particular gene thats related to breast cancer, and we would just make all of the individual changes in that gene and test what they do one by one. And then subsequently if we were to see that a mutation has some effect, if we were to then observe that mutation when we sequenced someones genome, we would have some idea of what it does.

Starita: The deep mutational scanning, the deep part is making all possible changes. We have all of that information at hand in an Excel file somewhere in the lab that says that this mutation is likely to cause damage to the function of the protein or the activity of the protein that it encodes. Making all of the possible mutations. Thats where the deep comes from.

TB: How exactly are you doing this? Is it because of advances in computer processing or is it because of a change in approach that has enabled this increase in volume of the different mutations you can look at?

Bloom: I would say that theres a number of technologies that have improved, but the really key one is the idea that the whole experiment can be done all at once. The traditional, if you were to go back a few decades way of doing an experiment like this, would be take one tube and put, lets say the normal or un-mutated gene variant in that, and then have another tube which has the mutant that you care about, and have somehow do an experiment on each of those two tubes and that works well.

But you can imagine if you had 10,000 tubes, it might start to become a little bit more difficult. And so the idea is that really the same way that people have gotten very good at sequencing all of these genomes, you can also use to make all of these measurements at once. The idea is you would now put all of different mutants together in the same tube and you would somehow set up the experiment, and this is really the crucial part of the whole thing, set up the experiment such that the cell or the virus or whatever youre looking at, how well it can grow in that tube depends on the effect of that mutation. And then you can just use the sequencing to read out how the frequencies of all of these mutations have changed. You would see that a good mutation that lets say helped the cell grow better would be more representative in the tube at the end, and a bad mutation would be less representative in the tube. And by doing this you could in principle group together tens of thousands or even hundreds of thousands or millions of mutations all at once and read it all out in one experiment.

Starita: This has been enabled by that same revolution that has given us the thousand dollar genome. These DNA sequencers that were now using, not really to sequence human genomes, but were using them as very expensive counting machines. So, were identifying the mutation and were counting it. Thats basically what were using the sequencers for. Instead of sequencing human genomes, were using them as a tool to count all of these different pieces of DNA that are in these cells.

TB: At what stage of development is deep mutational scanning?

Starita: It started about 10 years ago. The first couple of papers came out in 2009 and 2010 actually from the Genome Sciences department at University of Washington. Those started with short sequences and very simplified experiments, and we have been working over the years to build mutational scanning into better and more accurate model systems, but that are increasing the complexity of these experiments. And so weve gone from almost, Hey, thats a cute experiment you guys did, to doing impactful work that people are using in clinical genetics and things like that.

TB: When youre at a holiday party and somebody asks you what you do and then they get really into it and they ask you, Wait, what are the implications of not only personalized medicine but this deep mutational scanning? Whats this going to mean for my life?

Starita: Right now it hasnt been systematically used in the clinic, but well get phone calls from UW pathology that says, Hey, I have a patient that has this variant. We found the sequence variant and this patient has this phenotype. What does this mutation look like in your assay? And were like, Well, it looks like its damaging. And then they put all of that information together and they can actually go back to that patient and say, You are at high risk of cancer. Were going to take medical action. That has happened multiple times. Were working right now to try to figure out how to use the information that we are creating. So these maps of the effect of mutations on these very important proteins and how to systematically use them as evidence for or against their pathogenicity. Right now for a decent percentage of these people who are telling them, Well, youve got changes but we dont know what they do. We want those tests to be more informative. So you go, you get the test, they say, That is a bad one. That ones fine. That mutation is good. That ones OK. That one, though. That ones going to cause you problems. We want more people to have more informative genetic testing because right now in a decent proportion of tests come back with an I have no idea, answer.

Bloom: You can also think about mutations that affect resistance to some sort of drug. For many, many types of drugs, these include drugs against viruses, drugs against cancers and so on, the viruses and the cancers can become resistant by giving mutations that allow them to escape from that drug. In many cases there are even multiple drugs out there and you might have options of which drug to administer, but you might not really know which one. Clinicians have sort of built up lore that this drug tends to work more often or you try this one and then you try this other one, but because how well the drug works is probably in general determined by either the genetic mutations in lets say the cancer or the person or the genetic mutations in the virus or pathogen, if you knew what the effects of those mutations were ahead of time, you could make much more intelligent decisions about which drugs to administer. And there really shouldnt be a drug that works only 50 percent of the time; youre probably just not giving it in the right condition 50 perfect of the time. Wed like to be able to pick the right drug for the right condition all the time.

TB: And thats what precision medicine is about.

Starita: Yes.

TB: Deep mutational scanning as a tool.

Starita: To inform precision medicine.

Bloom: These deep mutational scanning techniques were really developed by people like Jay Shendure and Stan Fields, and Lea and Doug Fowler to look at these questions of precision medicine from the perspective of changes in our human genomes affecting our susceptibility to diseases. I actually work on mutations in a different context, which has mutations in the viruses that infect us and make us sick. These viruses evolve quite rapidly. In the case of flu virus, youre supposed to get the flu vaccine every year. The reason why you have to get it every year is the virus is always changing and we have to make the vaccine keep up with the virus. The same thing is true with drugs against viruses like flu or HIV. Sometimes the viruses will be resistant, sometimes the drugs will work. These again have to do with the very rapid genetic changes that are happening in the virus. So, were trying to use deep mutational scanning to understand how these mutations to these viruses will affect their ability to, lets say, escape someones immunity or escape a drug that might be used to treat that person.

TB: How far along are you on that path?

Bloom: Were making progress. One of the key things weve found is that the same mutation of the virus might have a different impact for different people. So we found using these approaches that the ways that you mutate a virus will allow the virus sometimes to escape from one persons immunity much better than from another persons immunity. And so were really right now trying to map out the heterogeneity across different people. And hopefully that could be used to understand what makes some people susceptible to a very specific viral strain versus other people.

TB: And so then would your research extend into the mutations in human genes in addition to the changes in the virus?

Bloom: You could imagine eventually wanting to look at all of those combinations together, and we are very interested in this, but the immediate research were focusing on right now actually probably is not so much driven by the genetics of the humans. In the case of influenza virus, like I was saying, we found that if theres a virus that has some particular mutation, it might, lets say, allow it to escape from your immunity but not allow it to escape from the immunity of me or Lea. That doesnt seem to be driven as much we think by our genetics, but rather our exposure histories. So in the case of influenza, were not born with any immunity to influenza virus. We build up that immunity over the course of our lifetime because we either get infected with flu or we get vaccinated with flu and then our body makes an immune response, which includes antibodies which block the virus. Each of us have our own personal history, not genetic history, but life history of which vaccinations and which infections weve gotten. And so, that will shape how our immune response sees the virus. As a result, we think that that doesnt really have so much of a genetic component as a historical component.

TB: Just going with the flu example, could this result in a future big picture where I go in to get my flu vaccine and its different than the one the next person might go in to get?

Bloom: What we would most like to do is use this knowledge to just design a vaccine that works for everybody. So that would just be the same vaccine that everyone could get. But its a very interesting I think at this point I would say its almost in the thought experiment stage to think about this. When you think of something like cancer, like Lea was saying, you can use these tools to understand when people have mutations that might make them at risk for a cancer, but thats actually often a very hard thing to intervene for, right? Its not so easy to prevent someone from getting cancer even if you know theyre at risk. But obviously if people are able to do that, theyre interested in spending a lot of money to do it, because cancer is a very severe thing and you often have a very long window to treat it.

Something like a flu virus is very much at the other end. If I had the omniscient capability to tell you that three days from now youre going to get infected with flu and youre going to get really sick, we could prevent that. We have the technology basically right now to prevent that, if its nothing else than just telling you to put on a bunch of Purell and dont leave your bedroom. But theres also actually some pretty good interventions including prophylactics to flu that work quite well. But the key thing is, right now we think of everyone in the world as being at risk all the time and you cant be treating everybody in the world all the time against flu. Theres just too many people and the risk that any person

Starita: Not that much Tamiflu on the market.

Bloom: Not that much, and the risk of it So I think to the extent that we could really identify whos at the most risk in any given year, that might allow us to use these interventions in a more targeted way. Thats the idea.

TB: And how does deep mutational scanning lead to that potentially?

Bloom: Yeah. So the idea, and at this point, this is really in the research phase, but the idea is if we could identify that say certain people or certain segments of the population, that because of the way their immunity, lets say, is working makes them very susceptible to the viral mutant that happens to have arisen in this particular year, we could then somehow either suggest that theyre more at risk or, as you suggested, design a vaccine thats specifically tailored to work for them. So thats the idea. I should make clear that that is not anywhere close to anybody even thinking of putting it into economic practice at this point because even the concepts behind it are really quite new. But I do think that theres a lot of potential if we think of these infectious diseases not so much as an act of God, where you just happened to someone sneezed on you as youre walking down the street, but actually a complex interaction between the mutations in the virus and your own either genetics or immune system, we can start to identify who might be more at risk for certain things in certain years, and that would at least open the door to using a lot of interventions we already have.

Starita: The first year was three years ago, and some very enthusiastic graduate students started it. Basically, it was almost like a giant lab meeting where everybody who is interested in this field came. Somebody tweeted it out and then all of a sudden people from UCSF were there and were like, What the heck? It was great and we all talked about the technology and how we were using it. The next year, the Brotman Baty Institute came in and were like, OK, well, maybe if we use some of this gift to support this, we can have a bigger meeting. And then it was 200 people in a big auditorium and that was great. And now this year, its a two-day symposium and workshop, and its also co-sponsored by a grant from the National Human Genome Research Institute. But now weve got hundreds of people, so about 200 people again, but now flying in from all over the world. Weve got invited speakers, and the workshop, which is Tuesday, is a more practical, If youre interested in this, how do you actually do these experiments?

TB: Whats driving the interest in deep mutational scanning?

Bloom: We are starting to have so much genetic information about really everything. It used to be, going back a couple of decades, a big deal to determine even the sequence of a single flu virus. It was totally unthinkable to determine the sequence of a human genome, right? If you dont know what mutations are there, you dont really care that much what they do. Now we can determine the sequence of tens of thousands of flu viruses. I mean, this is happening all the time, and we can determine the sequence of thousands, even tens of thousands of human genomes. So now it becomes, as Lea said, really important to go from just getting these sequences to understanding what the mutations that you observe in these sequences actually will mean for human health.

See this site for more on the Brotman Baty Institute for Precision Medicine and the Deep Mutational Scanning Symposium and Workshop, Jan. 13 and 14 in Seattle. The symposium is free to attend if youre in the Seattle area, and it will also be livestreamed, with archived video available afterward.

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Scientists pursue new genetic insights for health: Inside the world of deep mutational scanning - GeekWire