Category Archives: Genetic medicine

The Dindot Lab team. Front row (L to R): Research scientist Dr. Sarah Christian and Dr. Scott Dindot. Back row (L to R): Dr. Johnathan Ballard (Texas A&M Institute for Genomic Medicine) and biomedical sciences doctoral students Tom Jepp and Luke Myers

A treatment for a rare disease that was researched and developed in the laboratory of Texas A&M School of Veterinary Medicine & Biomedical Sciences (VMBS) associate professor Scott Dindot has not only produced encouraging interim data from a phase 1/2 clinical trial in the United States, United Kingdom, and Canada but has become the subject of a $75 million acquisition by Ultragenyx Pharmaceutical, Inc., which will continue to develop the treatment.

In an update last month, Ultragenyx announced that GTX-102, the drug originating in Dindots lab, had demonstrated meaningful improvement in pediatric patients afflicted with a genetic disorder called Angelman Syndrome (AS) and that the company is expanding patient enrollment in its ongoing phase 1/2 study of the drug.

AS is a rare genetic disorder that affects approximately one in 15,000 live births per year; the disorder is caused by a loss of function of the UBE3A gene, which leads to developmental delay, speech impairment, movement or balance disorder, and seizures.

Currently, there is no cure for AS. Available treatments for the disorder focus solely on behavioral therapy and controlling the symptoms, specifically the seizures that often affect patients with AS.

However, researchers have reported improvements in measurements of disease severity and quality of life for AS patients in the phase 1/2 study of GTX-102, leading Ultragenyx to believe that the novel, targeted therapeutic could be a promising treatment for the disorder.

This groundbreaking work not only highlights the strong science being conducted in our school but also demonstrates how researchers in the School of Veterinary Medicine & Biomedical Sciences are finding novel solutions to real-world problems that can improve the lives of both animals and human beings, said Dr. John R. August, the Carl B. King Dean of Veterinary Medicine at Texas A&M.

In developing the drug, Dindot and his Texas A&M research team identified a region on the UBE3A antisense (UBE3A-AS) transcript, which regulates the expression of the paternally inherited allele of the UBE3A gene. The drug an antisense oligonucleotide (ASO) inhibits UBE3A-AS and reactivates expression of the paternal UBE3A allele, restoring UBE3A protein in the brain.

We targeted a very specific region on the UBE3A-AS transcript that we believe is important for regulating its expression, said Dindot, who also is a Texas A&M University System Chancellors Enhancing Development and Generating Excellence in Scholarship (EDGES) Fellow. In theory, this treatmentgoes after the heart of the condition.

In natural conditions, only the copy of UBE3A inherited from the mother is expressed in the brain. Individuals living with AS have a mutation or deletion in the maternal copy of the gene, and thus, they lack the UBE3A protein in the brain.

Dindots drug, the first molecular therapeutic for AS to advance into clinical development, works by reactivating the paternal copy of UBE3A so it can compensate for the loss of function in the maternal copy.

After the initial discovery, which was supported by funding from the Foundation for Angelman Syndrome Therapeutics (FAST), Dindot continued the research and development of the drug in collaboration with the newly-formed biotech company GeneTx Biotherapeutics, LLC, (GeneTx) and later, Ultragenyx which conducted investigational-new-drug-enabling studies on the therapeutic as it moved into clinical trials in the US, UK and Canada.

That the drug made it to a clinical trial is an enormous milestone and now it is just amazing to hear the interim data suggesting that kids conditions are improving in multiple areas, Dindot said. Over the past decade, there have been probably over a dozen people who have worked on this in my lab undergraduate and graduate students and scientists and I really want to recognize them for the hard work they put into the research and development of this drug; it takes a lot of people to do this and Im proud of what we have accomplished together.

With the acquisition of GeneTx by Ultragenyx, Ultragenyx will now take the lead on advancing GTX-102 into late-stage development for AS by testing the effectiveness of the therapeutic at higher monthly doses.

This is a really great example of the successful commercialization of a technology from the research stage to the clinical development of a promising therapeutic with a company, said Janie Hurley, program director atTexas A&M AgriLifeResearch Intellectual Property & Commercialization, who oversees the development of commercialization and intellectual property protection strategies for technologies created by researchers affiliated with Texas A&M AgriLife and the CVMBS. We strive to ensure that new discoveries such as this one have the best chance possible to reach those in society who could benefit. Working with companies like GeneTx and Ultragenyx is how we accomplish this goal.

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Biopharmaceutical Company Expands Clinical Trials On Texas A&M-Developed Angelman Syndrome Treatment - Texas A&M University Today

During a pregnancy, women are offered prenatal genetic screening and diagnostic testing to determine whether a fetus is healthy or has certain genetic disorders or anomalies.

This information can help patients and their doctors prepare for the pregnancy. But some opt out of such testing, believing that babies should be born regardless of potential abnormalities.

For those who do choose to undergo such testing, maternal-fetal medicine specialists and genetic counselors usually work closely with the pregnant person or couple to explain in detail what the results mean for a birth, for mother and child, if a genetic disorder or fetal anomaly is detected. These health care providers can also provide the pregnant person or couple with guidance on what options are available to them after a diagnosis, which can include aborting apregnancy. That option, however, is limited or no longer available to women in many U.S. states.

Prenatal tests cant diagnose a genetic condition before 6 weeks

Without the protection of Roe v. Wade, the 1973 Supreme Court decision that legalized abortion nationwideand was overturnedin June, the procedure has become illegal or heavily restricted in at least 14 states. Six states Mississippi, Missouri, Tennessee, North Dakota, South Dakota and Ohio prohibit abortions when the fetus may have a genetic anomaly, and infive of those states, its now nearly impossible, because it is banned at about six weeks. This is so early in a pregnancy that many women at that point dont even know they are carrying a child.

A person's first [doctors] appointment in pregnancy doesn't usually happen until eight or 10 weeks, so never mind the rest of the story. That's when obstetric care begins, said Philip D. Connors, lead genetic counselor at Boston Medical Center.

Three [percent] to 4% of all pregnancies are going to be affected by some sort of complication related to a difference in fetal or embryonic development, a genetic condition. And essentially none of those can be screened for or diagnosed until after the gestational age limits that are being placed by some of these really discriminatory laws, Connors added.

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Dr. Tani Malhotra, a maternal-fetal medicine specialist in Cleveland,Ohio, a state where abortions are now illegal after six weeks and where there are no exceptions for cases of rape, incest or fatal fetal anomalies, said it is impossible to assess whether there are any issues with the fetus at such an early point in pregnancy.

The size of the embryo at six weeks is somewhere between 6 to 7 millimeters. It's less than 1 centimeter, and that centimeter is like the size of my finger, right? So it's just impossible for us to be able to detect abnormal findings on an ultrasound at that point, Malhotra said.

KatieSagaser, director of genetic counseling at Juno Diagnostics, a women's health company, told Yahoo News: Theres no genetic testing or screening that can be done prior to six weeks.

One method of testing which she said has revolutionized the landscape of prenatal chromosome screening and is mostly used today is a noninvasive prenatal screening technology known as NIPT or NIPS. This can detect genetic variations as early as nine weeks into pregnancy, using a blood sample from the mother. But the test, Sagaser said, can only indicate if there is a potential problem, and does not replace diagnostic testing, such as chorionic villus sampling (CVS) or amniocentesis, which study the cells from the fetus or placenta and can confirm a diagnosis.

The earliest a CVS diagnostic test can be performed is at the 10th week of pregnancy. Amniocentesisis usually conducted at between 15 and 20 weeks of pregnancy, but can technically be done up until a person gives birth, according to the American College of Obstetricians and Gynecologists.

WASHINGTON, DC - JUNE 24: Abortion-rights activists gather in front of the Supreme Court building following the announcement to the Dobbs v Jackson Women's Health Organization ruling on June 24, 2022 in Washington, DC. (Photo by Nathan Howard/Getty Images)

Aborting a pregnancy because of genetic anomalies

As prenatal screening testing like NIPS has become more common, selective terminations involving genetic conditions have too. Some studies have shown that parents often decide to terminate a pregnancy, even after finding a mild form of a genetic condition, including Turner and Klinefelter syndromes.

Down syndrome is the most common chromosomal disorder in the U.S., and about 6,000 babies are born with it in the U.S. each year, according to the Centers for Disease Control and Prevention.

A published review of studies, which included 24 publications studying pregnancy terminations after a prenatal diagnosis of Down syndrome in the U.S., found that 67% ofthose pregnancies end in abortion.

Terminating a pregnancy after the 2nd trimester because of medical complications

Its notable, however, that the majority of abortions in the U.S.(91%) occur at or before 13 weeks of gestation. Abortions late in pregnancy are rare,butMalhotra said some of the main reasons why they do happen include delays and other barriers in obtaining abortion care, or after discovering medical complications. Those complications often include the discovery of lethal fetal anomalies, which can be detected during a fetal anatomy scan that is usually performed at around 20 weeks of pregnancy. Terminations at this stage, Malhotra said, are difficult and traumatic, because these pregnancies are often desired.

It's really tragic, as you're telling these patients who have been continuing their pregnancy. They're at 20 weeks. They're excited about the pregnancy. They're planning their baby showers. They come to that ultrasound hoping to be able to find out the sex of the baby and you tell them this devastating news, that there is an abnormality that is either not compatible with life, or is going to have significant impact on the quality of life after birth, the Ohio doctor said.

Malhotra told Yahoo News that Ohios new abortion law has made her job even tougher, because she also has to tell patients in these situations who wish to terminate the pregnancy that they cannot receive such care in their state.

It is just horrible, because not only are you giving them this tragic, heartbreaking news, but you're stigmatizing their care, because you're saying, Oh, this thing is illegal here, but you could go to another state. So they have to travel to another state to do something that's illegal, which is a part of medical care, Malhotra said. If they're not able to go out of the state, then we're asking them to take on risks associated with a pregnancy, which we know inherently, pregnancy is not risk-free.

In addition, she explained, she needs to inform these patients that they must act rapidly. Abortions later in a pregnancy are more complex and also more expensive. Medication abortion, which can be taken at home, can only be safely used in the first 70 days, or 10 weeks of pregnancy. After that, women need a surgical abortion, which typically takes about two days and requires inpatient care. A patient who needs to go out of state to receive care must therefore also take into account additional costs related to travel and lodging.

Because of the abortion bans that have gone into effect in the Midwest, surrounding states where the procedure is protected have seen an increase in patients, Malhotra said. They are really backed up, currently complicating the scheduling of an abortion, she said.

Another important reason to act quickly in these situations, according to Malhotra, is because most states do not permit abortions after 24 weeks when a fetus has reached viability and can survive outside the uterus. According to the Guttmacher Institute, a research group focused on reproductive health, 17 states impose a ban at viability.

Little research has been conducted on what happens to women who are unable to terminate a pregnancy because of a fetal genetic condition or anomaly. However, one study conducted by the University of California, San Francisco, that tracked 1,000 women unable to get an abortion because they had passed the gestational limits, found they were more likely to fall into poverty, as well as have worse financial, health and family outcomes, than those who had terminated their pregnancies.

Opponents of abortions conducted as a result of screening for disabilities believe that such procedures are unjust, because all human beings have inherent value from the moment of conception. Malhotra, on the other hand, told Yahoo News that she finds it absolutely horrible to put patients in a position where they dont have a choice anymore.

There are multiple reasons women may choose to terminate a pregnancy because of a genetic condition or anomaly, ranging from the emotional and financial cost of raising a disabled child to the effect that this may have on the existing children in a family, as well as the feeling that it is cruel to give birth to a child who may need a lifetime of constant medical intervention.

Connors said that terminations due to genetic or fetal anomalies are comparatively rare, but are often emphasized unduly in conversations on abortion and abortion care. It inadvertently leads to a narrative about what makes a good or a bad abortion, he said.

Sagaser agreed, saying:There's no benefit to us as a society to say, Oh, there's this one population that really needs access to abortion care more so than other people.'

Everyone deserves to be able to make the choices that are right for them and their family in that unique situation, she added.

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Restrictive abortion laws are limiting the options parents have after receiving genetic test results, experts say - Yahoo News

The field of precision medicine blends molecular biology and systems biology to understand better and treat disease.

FREMONT, CA: The precision medicine industry integrates molecular biology and systems biology to identify illness prevention and treatment methods. It enables clinicians to select tailored treatments based on a genetic understanding of a patient's ailment and environmental and lifestyle factors. It uses big data technologies to help more precise and individualized therapy by finding correlations in vast data sets. This decreases the impacts of an overly comprehensive therapeutic approach, which may have unwanted side effects, and reduces treatment costs for physicians. It is especially crucial to discover medicines for neurological illnesses as life expectancy and population increase. It is also essential to better understand and treat cancer individually. Here are some precision medicine market trends to watch in 2022:

Oncology Will Continue to Hold the Largest Market Share: Oncological illnesses will likely continue to focus on precision medicine's efforts to develop new treatments. The United States is one of the primary locations where precision medicine and research oncological applications are conducted. It is utilized 30 percent more frequently as a treatment for oncological disorders than the next highest application of precision medicine. State funding is anticipated to accelerate the precision medicine sector's expansion to treat oncological disorders.

Increased Non-Oncology Therapeutic Research: As genetic research has expanded, there are indications that the emphasis on precision medicine may shift from oncology to non-oncology fields. Two-thirds of phase three pipelines are focused on non-oncology sectors, per Diaceutics Group. This gives researchers in precision medicine strong motivation to identify applications outside of oncology. Infectious disorders, central nervous system diseases, and cardiovascular diseases are where such uses may be found. Alzheimer's disease and Parkinson's disease, which have substantial genetic links, have been suggested as potential prospects for additional research within the precision medicine business.

The precision medicine market will continue to be competitive: The precision medicine market is neither competitive, with significant enterprises competing, nor monopolistic, with one or a few major corporations, dominating. Several major corporations, including Pfizer and Novartis, and mid-sized and smaller firms, are entering the market and introducing innovative technology. A competitive economy is more likely to produce lower-cost solutions without government intervention, which is beneficial for transmitting precision medicine advancements.

Better Diagnoses: In oncology, precision medicine can determine whether breast cancer patients have estrogen or progesterone receptors. By sequencing blood and detecting tumor DNA, researchers in precision medicine are now developing a blood test that might detect cancer in any part of the body. Physicians will also have a clearer understanding of whether the patient responds to treatment or is simply in remission. According to the medical community, the FDA is likely to approve additional precision medicine treatments that can detect the existence of cancer-based on genetic changes.

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Marketing and Industry Trends Influencing Precision Medicine in 2022 - Healthcare Tech Outlook

August 18, 2022

A study published in the British Journal of Cancer looks at the use of a genetic risk score to predict prostate cancer diagnosis in men with lower urinary tract symptoms.

Dr Chantal Babb de Villiers, PHG Foundation, said:

This paper looked at if genomic information can predict which men would develop prostate cancer after presenting at a GP with lower urinary tract symptoms. The study researchers found that, using age as well as a genetic risk score, they could stratify which men were most, and least, likely to develop prostate cancer after having symptoms. There are limitations to the study, notably that only men of European ancestry were included, which is a major limitation as black men are twice as likely to be diagnosed with prostate cancer, and have worse outcomes. The findings support the idea that accurate risk prediction using a genetic risk score along with other risk factors could improve symptomatic patient triaging in primary care, to determine which men could have further investigationto find out their possibility of prostate cancer. The PHG Foundation is following developments in these areas carefully to understand their implications for healthcare policy and delivery.

Dr James Ware, Cardiologist, Reader in Genomic Medicine at Imperial College London and MRC Investigator, MRC London Institute of Medical Sciences, said:

Overall I think this is an interesting study. I think the press release reflects the science in most important respects. I have reservations on one element: the press release emphasises that genetic risk scores (GRS) could identify people at highest risk, for fast-track referral. In fact in the paper they emphasise that the principle utility is in identifying low risk individuals who can avoid referral. The press release says that Only one in three men with a positive PSA test have cancer, but from this perspective the GRS arguably performs even worse figure 2 and table 2 shows that about 1 in 12 men with symptoms (8%) with a high genetic risk develop cancer in the next 2 years. Perhaps this difference is not hugely important for a lay audience, since there is potential utility either way, but I would emphasise that the real value is likely to be through reducing unnecessary invasive tests in low risk individuals. It does not have a high precision (positive predictive value) in this context. (Here the evaluation was done in men with symptoms, with an overall cancer risk of 3.7% in 2 years)

I did not identify any particular methodological problems. The authors acknowledge important limitations. An important limitation (in common with much similar work) is that the work was done in individuals with European ancestry, and utility is likely to be limited to this group.

My expertise is in genomic medicine more broadly I am not particularly expert in prostate cancer. The authors cite a previous high profile study in Nature Genetics (Conti et al, 2021) which showed how a GRS could be predictive of prostate cancer in the UK biobank population. So some of what is reported here is already known. The main advance here seems to be in assessing risk stratification in symptomatic men which simulates a real-world clinical problem, and the authors present specific data on utility in context

A Genetic Risk Score (GRS) that identifies low risk individuals who can avoid an invasive biopsy would likely be of clinical value.

At the moment the genetic data needed to calculate a GRS is not generally available in patients health records. If a sample needs to be sent for genetic testing then this would take some time so in the short term you would need to take this into account when designing a clinical referral pathway for patients with symptoms suggestive of possible prostate disease, and factor in the additional cost of this test.

Again I highlight that I am not a cancer expert specifically, but I note that prostate cancer represents a wide spectrum of disease, some of which is not clinically significant. The prior work from Conti et al. found that the GRS identified prostate cancer, but did not discriminate between aggressive and non-aggressive disease. Other studies have also found that GRS do not select for clinically-significant disease. So while the test may help to identify individuals with cancer, other approaches may be needed to discriminate which of the men with prostate cancer need active treatment.

Prof Shirley Hodgson, Emeritus Professor of Cancer Genetics, St Georges, University of London (SGUL), said:

This is a very interesting study of a cohort of men who attended their general practice because of urinary symptoms. The researchers used genetic profiling with 260 common genetic variants known to influence prostate cancer risk, and other data including self-reported family history of prostate cancer, BMI and smoking status. Nearly 5,000 men with symptoms that could indicate prostate cancer were enrolled in the study, and 400 were diagnosed with prostate cancer within 2 years of enrolment. The study outcome was diagnosis of prostate cancer within 2 years of the index date of interview.

The genetic risk score (GRS) appeared to be very useful for predicting the diagnosis of cancer, where the highest risk score quintile was highly predictive of cancer with an incidence rate of 8.1%, and the lowest score quintile with a risk of less than 1%.

This pilot study suggests that if this was implemented in general practice, it could mean that men with the highest risk scores could be targeted for increased screening by referral to secondary care, whereas those in the lowest quintile could be managed in primary care, thus saving anxiety and costs.

The study is limited by being biased to younger men and mostly white individuals, meaning that the outcomes could be different in the groups who were not included.

Prof Dusko Ilic, Professor of Stem Cell Science, Kings College London, said:

This is an interesting research paper. However, a much simpler and significantly cheaper blood test for prostate-specific antigen (PSA), that is already in place, has more value as a biomarker in diagnosis of prostate cancer. When PSA is moderately increased, it may not be easy to differentiate benign prostatic hyperplasia from cancer and in such cases, a genetic risk score might have potential application to improve diagnostic the pathway.

Applying a genetic risk score for prostate cancer to men with lower urinary tract symptoms in primary care to predict prostate cancer diagnosis, as implicated in the paper, would be an unnecessary waste of the NHS funds.

Applying a genetic risk score for prostate cancer to men with lower urinary tract symptoms in primary care to predict prostate cancer diagnosis: a cohort study in the UK Biobank by Harry D. Green et al. was published in British Journal of Cancer at 01:00 UK time on Thursday 18 August.

Declared interests

Dr James Ware: None directly relevant to this work. I have acted as a consultant for and/or received research funding from Pfizer, MyoKardia, Bristol-Myers Squibb, and Foresite Labs, related to work on genetic disease and/or genome-based risk stratification.

Prof Shirley Hodgson: No conflicts of interest.

Prof Dusko Ilic: I declare no conflict of interest.

For all other experts, no reply to our request for DOIs was received.

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expert reaction to study investigating use of genetic risk score for prostate cancer in men with lower urinary tract symptoms to predict diagnosis -...

When the Smithsonian National Museum of Natural History opened its genomics exhibit in 2013, the field was just celebrating the 10th anniversary of the completed Human Genome Project. Sequencing that first genome cost over $500 million. The genomes since cost $10,000.

In 2022, as the museum prepares to wrap up the landmark exhibit, much has changed. Gene names such as BRCA1 and HER2 have entered the public consciousness. Sequencing DNA has become faster, cheaper, and smaller-scale. Portable sequencers that were not even being sold commercially in 2013 have since been used to trace the evolution of the Ebola virus as it wreaked havoc in West Africa. The development of CRISPR-Cas9 landed a Nobel Prize. The cost of genome sequencing is rapidly approaching $100.

What seemed cutting edge maybe in 2013, now in 2022, were just things that were somewhat more routine, said Carla Easter, who helped organize the exhibit while at the National Human Genome Research Institute, which partnered with the Smithonian to launch the project.

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Nobody knew what CRISPR was ten years ago, added Easter, now at the Smithsonian. But now, people will mention it and theyll know what that is. They may not know understand the science behind it, but at least theyve heard the word.

Before the exhibit closes its doors later this year, STAT spoke with curators, educators, and leading scientists involved in its creation about how genomics has changed in the past decade.

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The field of genomics has gone way beyond genomics experts, people who would call themselves genomicists, and its applied everywhere, said Lawrence Brody, who leads the NHGRI Division of Genomics and Society. Weve done these analyses of the NIH budget, and theres way more genomics being done outside of our institute than there is inside our institute, because its such a powerful tool. And thats a great thing.

Most of those improvements have been with sequencing, he said. Were now talking about what genetic variation might be. If you study people who have a disease, [and] find a genetic variant that seems to be common in those people, you dont really know anything until you ask yourself, How common is that variant in people who dont have the disease? And you need to look at large numbers of people to understand that. This also means involving people who are not normally represented in research, a task the NIH-funded All of Us program has taken up.

Another change he sees is the newfound ability to broadly study the entire genome, rather than only specific genes, and to analyze how various parts of the genome are being turned on or off in individual cells.

Even though all cells but sperm and egg share the same genome, they do not all make the same proteins. A decade or two ago, studying these differences involved an arduous process, and scientists could only study a few specific genes at a time. But Brody said that has changed thanks to advances in RNA sequencing, which allow you to ask questions about all the genes completely, objectively, and agnostically. And to me, thats really the power and has always been the power of genetics is to ask the question and have the organism tell you whats important, as opposed to guess and saying It must be this gene or it must be that gene.

Now, he said, the field needs to understand how diseases are caused by a combination of genes and environmental exposures, manipulate the genome to treat diseases, and survey life on the planet because, as a geneticist, its really important for me to know the variations out there.

We often say Oh, in ten years, well be doing this, and if you look back at those predictions, were wrong a lot, said Brody. But we will get there.

To Stephen Palumbi, a professor of marine sciences at Stanford who studies corals, the biggest change in genomics is the speed and cost of sequencing.

The same questions are there, the same approaches are there, said Palumbi. But its like you took a garden hose that you were plenty of water flow and everything and you turned it into a firehose of information. That deluge of data that you can get right now is incredible. So the whole field, not just natural history or oceans, but the whole field of genomics, has become more and more and more tuned to being a high-flow data-rich, incredible science of whats now called bioinformatics. Bioinformatics at the time, a decade ago, was really important. Its probably increased in importance 50-fold because the data sets have increased 100-fold, and being able to actually pull information out of these data sets has become one of the most interesting, challenging, and rewarding parts of how genomes are used.

The human genome is the most traveled, well-mapped genome in the known universe, no big surprise. But I study organisms that are not humans and have genomes anyway. And so were always sort of scrambling a little bit behind that technology, but adopting it and adapting it, he said.

He pointed to work he is doing to study corals living on reefs in an archipelago in Palau that look strikingly similar, but have turned out to be genetically different. Being able to deeply mine the genomes of those corals offers valuable clues about their genetic capacity to adapt to environmental change.

So genomics gives me a map to their current patterns of adaptation that I would not get in any other way, he said. When this exhibit opened, I couldnt have done what I just told you because it would have been prohibitively expensive. And the people who can do the bioinformatics really werent there. And the genetic, genomic resources that I need to do this work werent there. But theyre there now. So thats where the whole field has changed so much. In that period of time, 2011 till now, the entire landscape, seascape, forestscape changed.

He said the fields advances like enabling handheld sequencing will make it even easier to reveal DNA in the environment, whether that is samples pulled from a kelp forest or fungus living in the soil of wetlands. Those insights are more critical than ever, as they can offer insights on monitoring pathogens and endangered species.

What I dont want to see in 50 years in a genome exhibit, is a whole lot of genomes of extinct species that weve lost because of climate change.

Harvard professor and genetics pioneer George Church was involved in the Human Genome Project from its earliest days, having joined the effort in 1984, years before the National Institutes of Health got involved. He saw the project pique the interest first of lawmakers, and then the public at large. Some projects that are highly technical, whether theyre expensive or not, are unpopular or ignored, said Church. But this one actually captured Congresss interest, around 1987 was really when they started paying attention. They liked this and they committed to $3 billion, which was quite a lot in 1987. And then they proceeded to get excited in all kinds of science and they ended up doubling the NIH budget, which is almost unprecedented and hasnt happened since then.

And despite the celebration of the sequencing of the human genome, Church said, the work is far from over.

[It] had been sort of declared done in 2001, and then was re-declared done in 2004. And its actually still not done in my opinion. This year marks the first year that weve finished one genome, one human genome, but in a way that really isnt generally applicable we did it to a haploid cell. Haploid cells have only a single set of chromosomes, in contrast to the typical human cell which is diploid and has two. So if you want to diagnose a patient, you have to be able to do a diploid genome. And no ones ever completed a diploid genome yet, although we are on our way, Church said.

Church said genomics has already made an impact in medical care. It played a role in the development of the Covid-19 vaccines, and can give prospective parents insight about when they carry a recessive gene for certain diseases. It also enabled the development of the first gene therapy to be approved by the Food and Drug Administration. Even when the exhibit was being developed a decade ago, he said, the idea of gene therapy wasnt that popular. In fact, it just barely was recovering from its 2001 setback, or 1999 to 2001 setbacks, plural.

In the future, Church would like to see a bioweather map that uses genomics to keep tabs on and track the evolution of viruses and bacteria, akin to a weather forecast. What flu just flew in the town? And what is happening at the daycare? Should you take your kid? he asked.

But for all his big ideas about genomics, Church also has his sticking points. Among them: One of my pet peeves is when people say, Oh, you know that humans share fill in your favorite number with fill in your favorite organism. So itd be like 46% related to plants or bananas, he said. I mean, its a completely meaningless statistic.

(It is a battle he did not win with the Smithsonian exhibit, which tells viewers that the human genome is 41% similar to a bananas.)

For Joann Boughman, a senior vice chancellor at the University System of Maryland, advances in genomics have changed how people perceive genetic diseases. From the historical perspective, if you will, in human genetics, we have understood and have always looked at variability as an essential theme, said Boughman. It wasnt until the human genome started and people started understanding about the variations at the DNA level that they made the connection between genes and ultimate phenotype, what we look like. And it has been really fascinating to see how these two worlds, as you will, collide and hopefully come together.

During the pandemic, Boughman served as the point person for the Maryland university systems Covid response, which included a community of over 200,000 students, staff, and faculty. And I realize Im working with an educated population, but all kinds of people really understood when we started talking about viral variants, they understood what had changed was the DNA in the virus, that there had been a mutation. These were not absolutely foreign concepts to people, and they, with very little explanation, would understand why one vaccine might fight this virus, but not a mutated form of that virus, Boughman said.

This is part of a growing awareness she had seen unfolding long before the pandemic hit. The fact that the double strand of DNA is not a foreign concept, even to relatively small children, really makes our conversation different. And thats been an incredible thing to watch over the last 40 years. Today, if people see an image of DNA, theyll recognize it.

Boughman said that shift struck her recently when she saw a commercial for a treatment for a rare genetic disease. It hit me right between the eyes that they actually have an ad on TV and named a genetic syndrome and talked about that drug that was helping these children. But 20 years ago, the idea of putting on television a picture of a child who has physical abnormalities and labeling them as having a genetic disease or a genetic syndrome just would have been devastating. But now that we are getting to the point where we understand enough about the genetics that we can start to intervene and treat, it becomes a very different perspective than somebody who is simply doomed. They labeled it genetic and they labeled it as a syndrome, and then they talked about hope that they had. And that simply was not the case 20 or 30 years ago, at all.

As a geneticist and professor at the University of Pennsylvania, Sarah Tishkoff originally got involved in the exhibit to share her expertise on what genetics and genomics can tell us about the evolutionary history of humans. Given her research, she is keenly aware of how much the field has changed in the past few decades.

She is also aware of how far the field still needs to go specifically when it comes to securing better representation in genomics research, which is overwhelmingly centered on white and European populations. What we dont really have are good reference genomes, she said. So there are populations or people in different parts of the world that might have insertions or deletions in their genome or things that arent even in that reference.

But if the Smithsonian were to open the exhibit again in 50 years, she said, we will have unraveled far more mysteries and the public will be far more familiar with the science.

I think at that point, most people are going to have their genome sequenced, she said. That would give scientists a far deeper trove of data to understand structural variation large-scale differences across the DNA of individuals, including duplications of certain genes and, in turn, knowledge of how humans have adapted to different environments and develop different levels of risk for disease. She added that by that time, were going to know more about what the genome variation actually does, similar to her findings that multiple different gene mutations can cause lactose tolerance.

She is also hopeful that we will have wide-ranging insights into ancient DNA and the origins of human history, including a far more complete picture. Right now, she noted, we are limited by the fact that ancient DNA is often poorly preserved. Someday, somebody is going to get ancient DNA from a fossil in Africa thats 50,000 years old or 100,000 or 200,000. Thats going to really help shed light on human history in that region, which is where we all evolved, Tishkoff said. Im hoping that were going to know a lot more examples of how people adapted to different environments.

In addition to his day job at the E.O. Wilson Biodiversity Foundation, Dennis Liu serves on the board of the American Chestnut Foundation, which has funded efforts to introduce a gene into American chestnut trees that can help them resist a group of diseases known as blight. To Liu, there are clear benefits that advances in genomics can bring to conservation efforts like this one.

But as the field ages, he also sees a downside to the growing distance from the Human Genome Project.

When the initiative launched, Liu said, there was a sense of a moonshot at the time. And I think that kind of new excitement isnt necessarily here. I havent done a survey or a poll, but I imagine that these things are now kind of all lumped together with big pharma and the pharmaceutical industry and sort of high-tech medicine. And I would imagine that a lot of people still would wonder, Oh, I dont know, what does this do for me? I do think theyd hope, of course, that this kind of information is going to help cancer treatments, for example, and those sorts of things.

For example: To the field, the increase in sequencing speeds is a huge advance. But I dont think that means much of anything to the general public, Liu said. Instead of feeling that genomics completed with the sequencing of the genome, he hopes we will continue to wonder about genomics. It is not like Oh, the genome, we did that, its over. Its like, No, its both that this work has continued and it continues to matter, said Liu, who was then with the Howard Hughes Medical Institute, And you should know something about it even if youre not a professional scientist.

Eric Green has served as the director of the NHGRI since 2009. The biggest difference he sees in genomics then, and genomics now? At the time I started as director, when this exhibition was being created, there was a lot of clarity around what had been accomplished and a lot of growing knowledge about how the human genome works. But the idea of actually using genomic information for the practice of medicine was pretty hypothetical.

When he stepped into his role, he wanted to close that gap and figure out how to use genomic information to improve the practice of medicine. And the biggest difference between then and now is then it was hypothetical and, while it is certainly not pervasive in medicine, there are a number of just very clear areas where now genomics is mainstream. Green highlighted the use of genomics to diagnose rare diseases. They were like the very first home runs in those areas, he said. But now its just routine practice. Another notable change, he added, is the proliferation of DNA genealogy tests from companies such as 23andMe and Ancestry.

Looking ahead, Green said he is a realist about the role of genomics in medicine.

The implementation of some aspects of genomic medicine are no longer scientifically difficult. Theyre sociological, because of the societal challenges associated with health care, said Green, who trained as a physician-scientist. What I would say going forward is that, Im actually quite optimistic were going to figure out a lot of these really valuable uses of genomics. But I cant claim to be as optimistic about the effective use of those tools in health care, because we all appreciate that health care is really complicated.

It is a hurdle he had not considered early on in research, he said. Science drives some things, but its not the only thing.

Read more:
As the Smithsonian wraps a genome exhibit, leaders in the field reflect - STAT

A large number of people are currently contracting COVID-19. Fortunately, most of them are experiencing only mild symptoms, largely thanks to the high vaccination rate. However, in some individuals the disease takes a much more severe cause and our understanding about the underlying reasons is still insufficient. The human genome may hold a key to why COVID-19 is more serious for some people than others. A team of scientists from the Berlin Institute of Health at Charit (BIH) together with colleagues from the United Kingdom and Canada have found genes and proteins that contribute to a higher risk of severe COVID-19. Their findings have now been published in the journal Nature Communications.

Doctors and scientists around the world are still in the dark as to why some people become severely ill when infected with SARS-CoV-2 (the virus that causes the COVID-19 disease), while others experience only mild symptoms. A team of scientists at the BIHs Digital Health Center has identified genes that - in addition known risk factors such as age and sex predispose people to experience a more serious infection.

It has been observed relatively early on that susceptibility to infection depends on a persons blood group, for example, which is inherited, explains Maik Pietzner, the studys lead author. So it was clear that the course of the disease is at least in part determined by genetics. Scientists at the BIH were given access to genetic data that researchers had collected from COVID-19 patients worldwide, which also included disease severity. At the time, there were some 17 genomic regions observed to be associated with a higher risk of severe COVID-19, Pietzner explains, but the causal genes and underlying mechanism remained unknown for many.

The Computational Medicine Group at BIH had previously developed a proteogenomic approach to link protein-encoding regions of DNA to diseases via the protein product. They applied this method to COVID-19 and came across eight particularly interesting proteins in this new study. One of these was a protein responsible for an individuals blood group, Claudia Langenberg, head of the Computational Medicine Group, explains. We were aware that this gene was associated with the risk of infection, so it was like a proof of concept. The protein ELF5, meanwhile, seemed like it could be much more relevant. We found that COVID-19 patients carrying a variant in the gene that encodes ELF5 were more much more likely to be hospitalized and ventilated, in some cases even died so we took a closer look.

The team turned to their colleagues from the Intelligent Imaging Group, led by Christian Conrad, because of their expertise in single-cell analyses. Lorenz Chua, a doctoral student in the group was immediately enthusiastic to find out which cells displayed a particular abundance of the ELF5 protein: We found that ELF5 is present in all surface cells of the skin and mucous membranes, but is produced in particularly large quantities in the lungs. Since this is where the virus causes most of its damage, this seemed very plausible.

But Conrad puts a damper on any hopes that the scientists may have identified a new target molecule for drug development: ELF5 is what is known as a transcription factor, and controls how frequently or infrequently other genes are switched on and off throughout the body, he explains. Unfortunately, it is difficult to imagine interfering with this protein in any way, as that would undoubtedly cause many undesirable side effects.

However, the scientists did identify another interesting candidate among the eight suspects: the protein G-CSF, which serves as a growth factor for blood cells. They found that COVID-19 patients who genetically produce more G-CSF tend to experience a milder disease course. Synthetic G-CSF has been available as a drug for a long time, so its use as a treatment for COVID-19 patients could be conceivable.

Translation of such genetic discoveries into clinical application is not an easy or rapid process. The work only possible through the support of many scientists and clinicans of the BIH and Charit, and open access results from studies around the world highlights how open science and an international team effort can step by step uncover how the smallest changes in our genetic make-up alter the course of disease, COVID-19 in this example. We started with global data from 100,000 participants and ended up looking at single molecules in individual cells. We believe that collaborations that allow us to rapidly move from the bigger picture and studying large populations to in depth molecular follow-up can help to better understand the clinical consequences of this virus and teach us important lessons for future pandemics, Pietzner concludes.

Maik Pietzner, Robert Lorenz Chua, Christian Conrad, Claudia Langenberg: ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19 Nature Communications (2022), DOI: 10.1038/s41467-022-31999-6

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About the Berlin Institute of Health at Charit (BIH)The mission of the Berlin Institute of Health at Charit (BIH) is medical translation: transferring biomedical research findings into novel approaches to personalized prediction, prevention, diagnostics and therapies and, conversely, using clinical observations to develop new research ideas. The aim is to deliver relevant medical benefits to patients and the population at large. As the translational research unit within Charit, the BIH is also committed to establishing a comprehensive translational ecosystem one that places emphasis on a system-wide understanding of health and disease and that promotes change in the biomedical translational research culture. The BIH was founded in 2013 and is funded 90 percent by the Federal Ministry of Education and Research (BMBF) and 10 percent by the State of Berlin. The founding institutions, Charit Universittsmedizin Berlin and Max Delbrck Center for Molecular Medicine in the Helmholtz Association (MDC),were independent member entities within the BIH until 2020. Since 2021 the BIH has been integrated into Charit as its so-called third pillar. The MDC is now the Privileged Partner of the BIH.

Contact

Dr. Stefanie SeltmannHead of CommunicationsBerlin Institute of Health at Charit (BIH)stefanie.seltmann(at)bih-charite.de

+49 (0)30 450 543019www.bihealth.org

Nature Communications

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Why some people suffer more from COVID-19 than others - EurekAlert

LogicBio Therapeutics, Inc. (NASDAQ:LOGC Get Rating) Equities researchers at William Blair boosted their Q3 2022 earnings per share (EPS) estimates for shares of LogicBio Therapeutics in a report issued on Tuesday, August 16th. William Blair analyst R. Prasad now expects that the company will post earnings per share of ($0.20) for the quarter, up from their previous forecast of ($0.25). William Blair has a Outperform rating on the stock. The consensus estimate for LogicBio Therapeutics current full-year earnings is ($0.88) per share. William Blair also issued estimates for LogicBio Therapeutics Q4 2022 earnings at ($0.22) EPS, Q4 2022 earnings at ($0.22) EPS, FY2022 earnings at ($0.77) EPS, FY2022 earnings at ($0.77) EPS, Q1 2023 earnings at ($0.32) EPS, Q2 2023 earnings at ($0.32) EPS, Q2 2023 earnings at ($0.32) EPS, Q3 2023 earnings at ($0.33) EPS, Q4 2023 earnings at ($0.34) EPS, Q4 2023 earnings at ($0.34) EPS, FY2023 earnings at ($1.29) EPS and FY2023 earnings at ($1.29) EPS.

LogicBio Therapeutics stock opened at $0.40 on Thursday. The stock has a market cap of $13.18 million, a PE ratio of -0.43 and a beta of 1.60. The company has a quick ratio of 2.74, a current ratio of 2.26 and a debt-to-equity ratio of 0.17. The businesss 50-day moving average price is $0.43 and its two-hundred day moving average price is $0.55. LogicBio Therapeutics has a 12-month low of $0.34 and a 12-month high of $5.15.

A number of hedge funds and other institutional investors have recently made changes to their positions in LOGC. Blair William & Co. IL acquired a new position in shares of LogicBio Therapeutics in the fourth quarter worth approximately $51,000. Samlyn Capital LLC lifted its stake in LogicBio Therapeutics by 2.5% in the fourth quarter. Samlyn Capital LLC now owns 1,511,417 shares of the companys stock valued at $3,492,000 after buying an additional 37,309 shares during the period. Acadian Asset Management LLC acquired a new position in LogicBio Therapeutics in the first quarter valued at approximately $32,000. Renaissance Technologies LLC acquired a new position in LogicBio Therapeutics in the first quarter valued at approximately $312,000. Finally, Virtu Financial LLC increased its holdings in shares of LogicBio Therapeutics by 312.4% during the first quarter. Virtu Financial LLC now owns 71,475 shares of the companys stock valued at $49,000 after acquiring an additional 54,145 shares in the last quarter. 55.20% of the stock is owned by institutional investors and hedge funds.

(Get Rating)

LogicBio Therapeutics, Inc, a genetic medicine company, focuses on developing and commercializing genome editing and gene therapy treatments using its GeneRide and sAAVy platforms. The company's GeneRide technology is a new approach to precise gene insertion harnessing a cell's natural deoxyribonucleic acid; and gene delivery platform, sAAVy is an adeno-associated virus, which is designed to optimize gene delivery for treatments in a range of indications and tissues.

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Q3 2022 Earnings Forecast for LogicBio Therapeutics, Inc. Issued By William Blair (NASDAQ:LOGC) - Defense World

image:Picture depicting Micro-organospheres (MOS) encapsulating primary tissue derived cells prior to demulsification. view more

Credit: Terasaki Institute for Biomedical Innovation

(LOS ANGELES) A team of scientists, led by Xiling Shen, Ph.D., Chief Scientific Officer, and Professor at the Terasaki Institute for Biomedical Innovation (TIBI), has reached new levels in patient model development. They have developed improved methods for generating micro-organospheres (MOS) and have shown that these MOS have superior capabilities for a variety of clinical uses. As documented in a recent publication in Stem Cell Reports, their MOS can be used as patient avatars for studies involving direct viral infection, immune cell penetration and high-throughput therapeutic drug screening, something that is not obtainable with conventional patient-derived models.

Dr. Shens team has developed emulsion microfluidic technology for creating MOS, tiny, nanoliter-sized basal membrane extract (BME) droplets composed of tissue cell mixtures which can be generated at a rapid pace from an automated device. After the droplets are created, excess oil is removed by an innovative membrane demulsification process, leaving behind thousands of viscous, uniformly sized droplets which contain tiny 3D tissue structures.

The team went on to demonstrate unique MOS capabilities and features in several first-of-its-kind experiments. They were able to show that the MOS could be created from a variety of different tissue sources and the resultant MOS had retention of histopathological morphology, capacity for differentiation and genetic expression, and the ability to be frozen and sub-cultured, as in conventional organoids.

Experiments were conducted to test the ability to infect MOS with viruses. Unlike with conventional organoids, MOS can be directly infected with viruses without the removal and suspension of cells from its surrounding BME scaffold, hence recapitulating the process of viral infection of the host tissue. Dr. Shens team was able to create a MOS atlas of human respiratory and digestive tissues from patient autopsies and infect them with SARS-COV-2 viruses, followed by drug screening to identify drugs that block viral infection and replication within those tissues.

MOS also provide a unique platform for studying and developing immune cell therapy. Within natural diffusion limit of vascularized tissue, tumor-derived MOS allowed sufficient penetration by therapeutic immune T-cells such as CAR-T, enabling a novel T cell potency assay to assess tumor killing by the engineered T-cells. Such a model would be highly useful in investigating tumor responsiveness and in developing anti-tumor immune cell therapies.

MOS could be further integrated with deep-learning imaging analysis for rapid drug testing of small and heterogeneous clinical tumor biopsies. Moreover, the algorithm was able to distinguish cytotoxic vs. cytostatic drug effects and drug-resistant clones that will give rise to later relapse. This groundbreaking capability will pave the way for MOS to be used in the clinic to inform therapeutic decisions.

Dr. Shen and his team continue to refine and improve upon the MOS technology and to spotlight its versatility, not only as a physiological model for screening potential personalized treatments, but for disease studies and a variety of other applications as well, said Ali Khademhosseini, Ph.D., TIBIs Director and CEO. It looks to be the wave of the future for precision medicine.

Authors are: Zhaohui Wang, Matteo Boretto2, Rosemary Millen, Naveen Natesh, Elena S. Reckzeh, Carolyn Hsu, Marcos Negrete, Haipei Yao, William Quayle, Brook E. Heaton, Alfred T. Harding, Else Driehuis, Joep Beumer, Grecia O. Rivera, Ravian L van Ineveld, Donald Gex, Jessica DeVilla, Daisong Wang, Jens Puschhof, Maarten H. Geurts, Shree Bose, Athena Yeung, Cait Hamele, Amber Smith, Eric Bankaitis, Kun Xiang, Shengli Ding, Daniel Nelson, Daniel Delubac, Anne Rios, Ralph Abi-Hachem1, David Jang, Bradley J. Goldstein, Carolyn Glass, Nicholas S. Heaton, David Hsu, Hans Clevers, Xiling Shen.

This work was supported by funding from the National Institutes of Health (R35GM122465, U01CA217514, U01CA214300) and the Duke Woo Center for Big Data and Precision Health.

PRESS CONTACT

Stewart Han, shan@terasaki.org, +1 818-836-4393

Terasaki Institute for Biomedical Innovation

###

The Terasaki Institute for Biomedical Innovation (terasaki.org) is a non-profit research organization that invents and fosters practical solutions that restore or enhance the health of individuals. Research at the Terasaki Institute leverages scientific advancements that enable an understanding of what makes each person unique, from the macroscale of human tissues down to the microscale of genes, to create technological solutions for some of the most pressing medical problems of our time. We use innovative technology platforms to study human disease on the level of individual patients by incorporating advanced computational and tissue-engineering methods. Findings yielded by these studies are translated by our research teams into tailored diagnostic and therapeutic approaches encompassing personalized materials, cells and implants with unique potential and broad applicability to a variety of diseases, disorders, and injuries.

The Institute is made possible through an endowment from the late Dr. Paul I Terasaki, a pioneer in the field of organ transplant technology.

Stem Cell Reports

Experimental study

Not applicable

Rapid Tissue Prototyping with MicroOrganospheres

18-Aug-2022

Drs. Hans Clevers, David Hsu, and Xiling Shen are co-founders of Xilis, Inc, which aims to commercialize the MOS technology for clinical precision oncology. Dr. Clevers has been a member of Roches Corporate Executive Committee since March 18, 2022. His full disclosure is given at https://www.uu.nl/staff/JCClevers/. Drs. Zhaohui Wang and Shengli Ding recently took a leave from Duke to join Xilis.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Next generation patient avatars: Expanding the possibilities with MicroOrganospheres - EurekAlert

The Warren Alpert Foundation funding becomes the most significant award to support genetic counseling education nationwide

PHILADELPHIA Penn Medicine has been awarded a $9.5 million grant from the Warren Alpert Foundation to continue its efforts to increase diversity in genetic counseling, a field that, despite impressive leaps forward in genetic knowledge, lacks a diverse workforce. The Alliance to Increase Diversity in Genetic Counseling grant will support 40 underrepresented students in five genetic counseling programs in the Northeastern U.S. over five years to expand all dimensions of diversity. PI Kathleen Valverde, PhD, LCGC, the Director of the Master of Science in Genetic Counseling Program at the Perelman School of Medicine at the University of Pennsylvania, will lead this effort, joined by a consortium of participating Genetic Counseling masters programs from Boston University, Rutgers University, Sarah Lawrence College, and the University of Maryland School of Medicine. Ten students will be selected yearly, two from each program, to receive full tuition support and a cost of living stipend. Click here for more information on the Alliance to Increase Diversity Scholarships at the University of Pennsylvania.

Continued here:
Masters Program in Genetic Counseling - Perelman School of Medicine at ...

Join dozens ofStanford Medicine studentswho receive up to three years of funding and valuable leadership skills asKnight-Hennessy Scholars(KHS).

KHS admits up to 100 select applicants each year from across Stanfords seven graduate schools, and delivers engaging experiences that prepare them to be visionary, courageous, and collaborative leaders ready to address complex global challenges. As a scholar, you join a multidisciplinary and multicultural cohort, participate in up to three years of leadership programming, and receive full funding for up to three years of your graduate studies at Stanford.

Candidates of any country may apply. KHS applicants must have earned their first undergraduate degree within the last seven years, and must apply to both a Stanford graduate program and to KHS.

If you aspire to be a leader in your field, we invite you to apply. The KHS application deadline is October 12, 2022. Learn more aboutKHS admission.

Knight-Hennessy Scholars application deadline: 1:00pm pacific time, October 12, 2022

MS Human Genetics and Genetic Counseling application deadline: December 6, 2022

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Admissions | Master's Program in Human Genetics & Genetic Counseling ...