Category Archives: Human Genetics

August 7, 2017 These population trees with embedded gene trees show how mutations can generate nucleotide site patterns. The four branch tips of each gene tree represent genetic samples from four populations: modern Africans, modern Eurasians, Neanderthals, and Denisovans. In the left tree, the mutation (shown in blue) is shared by the Eurasian, Neanderthal and Denisovan genomes. In the right tree, the mutation (shown in red) is shared by the Eurasian and Neanderthal genomes. Credit: Alan Rogers, University of Utah

Hundreds of thousands of years ago, the ancestors of modern humans diverged from an archaic lineage that gave rise to Neanderthals and Denisovans. Yet the evolutionary relationships between these groups remain unclear.

A University of Utah-led team developed a new method for analyzing DNA sequence data to reconstruct the early history of the archaic human populations. They revealed an evolutionary story that contradicts conventional wisdom about modern humans, Neanderthals and Denisovans.

The study found that the Neanderthal-Denisovan lineage nearly went extinct after separating from modern humans. Just 300 generations later, Neanderthals and Denisovans diverged from each other around 744,000 years ago. Then, the global Neanderthal population grew to tens of thousands of individuals living in fragmented, isolated populations scattered across Eurasia.

"This hypothesis is against conventional wisdom, but it makes more sense than the conventional wisdom." said Alan Rogers, professor in the Department of Anthropology and lead author of the study that will publish online on August 7, 2017 in the Proceedings of the National Academy of Sciences.

A different evolutionary story

With only limited samples of fossil fragments, anthropologists assemble the history of human evolution using genetics and statistics.

Previous estimates of the Neanderthal population size are very smallaround 1,000 individuals. However, a 2015 study showed that these estimates underrepresent the number of individuals if the Neanderthal population was subdivided into isolated, regional groups. The Utah team suggests that this explains the discrepancy between previous estimates and their own much larger estimate of Neanderthal population size.

"Looking at the data that shows how related everything was, the model was not predicting the gene patterns that we were seeing," said Ryan Bohlender, post-doctoral fellow at the M. D. Anderson Cancer Center at the University of Texas, and co-author of the study. "We needed a different model and, therefore, a different evolutionary story."

The team developed an improved statistical method, called legofit, that accounts for multiple populations in the gene pool. They estimated the percentage of Neanderthal genes flowing into modern Eurasian populations, the date at which archaic populations diverged from each other, and their population sizes.

A family history in DNA

The human genome has about 3.5 billion nucleotide sites. Over time, genes at certain sites can mutate. If a parent passes down that mutation to their kids, who pass it to their kids, and so on, that mutation acts as a family seal stamped onto the DNA.

Scientists use these mutations to piece together evolutionary history hundreds of thousands of years in the past. By searching for shared gene mutations along the nucleotide sites of various human populations, scientists can estimate when groups diverged, and the sizes of populations contributing to the gene pool.

"You're trying to find a fingerprint of these ancient humans in other populations. It's a small percentage of the genome, but it's there," said Rogers.

They compared the genomes of four human populations: Modern Eurasians, modern Africans, Neanderthals and Denisovans. The modern samples came from Phase I of the 1000-Genomes project and the archaic samples came from the Max Planck Institute for Evolutionary Anthropology. The Utah team analyzed a few million nucleotide sites that shared a gene mutation in two or three human groups, and established 10 distinct nucleotide site patterns.

Against conventional wisdom

The new method confirmed previous estimates that modern Eurasians share about 2 percent of Neanderthal DNA. However, other findings questioned established theories.

Their analysis revealed that 20 percent of nucleotide sites exhibited a mutation only shared by Neanderthals and Denisovans, a genetic timestamp marking the time before the archaic groups diverged. The team calculated that Neanderthals and Denisovans separated about 744,000 years ago, much earlier than any other estimation of the split.

"If Neanderthals and Denisovans had separated later, then there ought to be more sites at which the mutation is present in the two archaic samples, but is absent from modern samples," said Rogers.

The analysis also questioned whether the Neanderthal population had only 1,000 individuals. There is some evidence for this; Neanderthal DNA contains mutations that usually occur in small populations with little genetic diversity.

However, Neanderthal remains found in various locations are genetically different from each other. This supports the study's finding that regional Neanderthals were likely small bands of individuals, which explains the harmful mutations, while the global population was quite large.

"The idea is that there are these small, geographically isolated populations, like islands, that sometimes interact, but it's a pain to move from island to island. So, they tend to stay with their own populations," said Bohlender.

Their analysis revealed that the Neanderthals grew to tens of thousands of individuals living in fragmented, isolated populations.

"There's a rich Neanderthal fossil record. There are lots of Neanderthal sites," said Rogers. "It's hard to imagine that there would be so many of them if there were only 1,000 individuals in the whole world."

Rogers is excited to apply the new method in other contexts.

"To some degree, this is a proof of concept that the method can work. That's exciting," said Rogers. "We have remarkable ability to estimate things with high precision, much farther back in the past than anyone has realized."

Explore further: DNA of early Neanderthal gives timeline for new modern human-related dispersal from Africa

More information: Alan R. Rogers el al., "Early history of Neanderthals and Denisovans," PNAS (2017). http://www.pnas.org/cgi/doi/10.1073/pnas.1706426114

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New look at archaic DNA rewrites human evolution story - Phys.Org

Israeli scientists have developed the first haploid human stem cells, a discovery that will change our understanding of human genetics and medical research.

Already being used to predict whether people are resistant to chemotherapy drugs, the finding earned Igo Sagi, a PhD student at the Hebrew University of Jerusalem, the 2017 Kaye Innovation Award.

The long-sought haploid

Most of the cells in our body are diploid, which means they carry two sets of chromosomes (the structure in which DNA is contained) one chromosome from each parent. Haploid cells, in contrast, contain only a single set of chromosomes.

Scientists have long been trying to develop haploid stem cells. It is an important area of research, as embryonic stem cells are able to grow into any cell in the human body; this makes them extremely useful for treatment of diseases.

Haploid cells in particular are a powerful discovery, as they allow for a much better understanding of the human genetic makeup. For example, in diploid cells, it is difficult to identify the effects of mutations in one chromosome because the other copy is normal and provides a backup. Haploid cells dont have this limitation.

SEE ALSO: Five Israeli Biotech Companies Using Stem Cells To Change The Face Of Medicine

Up until now, scientists have only succeeded in creating haploid embryonic stem cells in animals such as mice, rats, and monkeys. The research conducted by Igo Sagi was the first time anyone was able to successfully isolate and maintain human haploid embryonic stem cells. These haploid stem cells were able to turn into many other cell types, such as brain, heart, and pancreas, while still retaining a single set of chromosomes.

The benefits are immense. Professor Nissim Benvenisty, who worked with Sagi on the research, explained: It will aid our understanding of human development for example, why we reproduce sexually instead of from a single parent. It will make genetic screening easier and more precise, by allowing the examination of single sets of chromosomes. And it is already enabling the study of resistance to chemotherapy drugs, with implications for cancer therapy.

SEE ALSO: Biological Breakthrough: Researchers Succeed In Creating Human Egg and Sperm Cells In Lab

Haploid Human Embryonic Stem Cells

Diagnosis of Chemotherapy Resistance

Based on this research, Yissum, the Technology Transfer arm of the Hebrew University, launched the company NewStem. The company is currently developing a diagnostic kit that can predict resistance to chemotherapy drugs. The large library of human haploid stem cells they are amassing will allow them to provide therapeutic and reproductive products, as well as personalized medication.

The haploid stem cells were developing have the potential to change the face of medical research as they hold a pivotal role in regenerative medicine, disease therapy and cancer research, revealed CEO of NewStem, Ayelet Dilion-Mashiah.

The research was conducted by Igo Sagi, a doctoral student at the Hebrew University of Jerusalem, along with Professor Nissim Benvenisty, Director of the Azrieli Center for Stem Cells and Genetic Research at the Hebrew University. The Kaye Innovation Awards at the Hebrew University of Jerusalem have been awarded annually since 1994 with the goal of encouraging academics to develop innovative methods and inventions with good commercial potential.

Photo:Azrieli Center for Stem Cells and Genetic Research at Hebrew University

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Israeli Scientists Develop First Haploid Human Stem Cells - NoCamels - Israeli Innovation News (press release) (blog)

The secret to healing what ails you lies within your own DNA. (photo credit:DREAMSTIME)

The biological basis of a severe and mysterious neurological disorder in children that is caused by a single error in one gene has been described for the first time by a multinational team led by researchers from Jerusalem.

Just published in the American Journal of Human Genetics, the study was headed by Prof. Orly Elpeleg of the pediatrics department at the Hebrew University of Jerusalems Faculty of Medicine and director of the genetics department at Hadassah- University Medical Center.

Elpeleg credits the discovery to deep sequencing technology that Hadassah and Hebrew U. were among the first to introduce into clinical practice in Israel and in the world.

The team found that affected childrens cells are flooded with ribosomal RNA and are poisoned by it. It was the first time an excess of ribosomal RNA has been linked to a disease in human regression and neurodegeneration.

The disease does not yet have a name.

At first, affected children lead normal lives and seem identical to their age-matched peers.

However, beginning at age three to six, they show neurological deterioration gradually losing motor, cognitive and speech functions. Although the condition progresses slowly, most patients are completely dependent sometime between 15 to 20 years of age.

Working with colleagues from the Pennsylvania State University College of Medicine and a multinational research team, the Israeli-led team have now identified and studied seven children from Canada, France, Israel, Russia and the US who suffer from the disorder.

The researchers found in all patients the same spontaneously occurring, non-inherited genetic change in a gene, named UBTF, responsible for ribosomal RNA formation.

It is because of this small change that patients cells are flooded with ribosomal RNA.

Ribosomes are responsible for the translation and production of cell proteins. They are made up of ribosomal proteins and of ribosomal RNA in a precise ratio.

The researchers found an identical error in the same gene in all the patients tested, representing a difference of one letter among the roughly three billion that make up human DNA.

By finding the identical change in children with the identical clinical disease, the researchers determined the altered gene was indeed the cause of the disease.

Elpeleg initially encountered the disease in a young girl who came to Hadassah.

Five years ago, I saw a patient who was healthy until the age of three and then experienced a disturbance in her walking and motor function, speech and cognition. Around that time, we had introduced the deep-sequencing technology for clinical use at Hadassah, which enabled us to read all the coding genetic material of a person within a couple of days, in order to identify genetic defects.

Since 2010, Hadassah has assembled the largest genetic mapping database in Israel with around 2,400 patients.

Searching for similar genetic defects in this database, we found a nine-year-old boy who had been treated at Hadassah and now lives in Russia. The boy had been healthy until the age of five and then displayed neurological deterioration just like the girl I had diagnosed, said Elpeleg.

Dr. Simon Edvardson, a pediatric neurologist at Hadassah, flew to Russia, examined the boy, took genetic samples from him and his parents and confirmed that his illness was identical to that of the Israeli girl. We then knew we had identified a new disease that was not recognized in the medical literature, said Elpeleg.

Comparing their data in a program called Gene Matcher, the researchers found several more children around the world who shared an identical genetic defect and the same course of disease.

To understand the mechanism of the newly identified disease, the researchers collaborated with Dr. George-Lucian Moldovan at Pennsylvania State University College of Medicine who confirmed the disease mechanism in the childrens cells, there is an excess RNA of the ribosome, which probably causes brain cells to be flooded and poisoned.

While there is currently no cure for genetic diseases of this kind, the identification of the exact mutation may allow for the planning of therapies designed to silence the mutant gene.

Science may not be able to repair the gene, but now that our findings are published, it may be possible to make early identification of the disease and in the future find ways to prevent such a serious deterioration, Elpeleg said.

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Israeli team finds biological basis for rare neurological kids' disease ... - The Jerusalem Post

BETHESDA, Md., Aug. 4, 2017 /PRNewswire-USNewswire/ --Madhuri Hegde, PhD, FACMG of PerkinElmer, Inc. in Waltham, MA has been elected to the ACMG Foundation for Genetic and Genomic Medicine Board of Directors, the supporting educational foundation of the American College of Medical Genetics and Genomics. The ACMG Foundation is a national nonprofit foundation dedicated to facilitating the integration of genetics and genomics into medical practice. The board members are active participants in serving as advocates for the Foundation and for advancing its policies and programs. Dr. Hegde has been elected to a 2-year renewable term starting immediately.

Dr. Hegde joined PerkinElmer in 2016 as Vice President and Chief Scientific Officer, Global Genetics Laboratory Services. She also is an Adjunct Professor of Human Genetics in the Department of Human Genetics at Emory University. Previously, Dr. Hegde was Executive Director and Chief Scientific Officer at Emory Genetics Laboratory in Atlanta, GA and Professor of Human Genetics and Pediatrics at Emory University and Assistant Professor, Department of Human Genetics and Senior Director at Baylor College of Medicine in Houston, TX.

Dr. Hegde has served on a number of Scientific Advisory Boards for patient advocacy groups including Parent Project Muscular Dystrophy, Congenital Muscular Dystrophy and Neuromuscular Disease Foundation. She was a Board member of the Association for Molecular Pathology and received the Outstanding Faculty Award from MD Anderson Cancer Center. She earned her PhD in Applied Biology from the University of Auckland in Auckland, New Zealand and completed her Postdoctoral Fellowship in Molecular Genetics at Baylor College of Medicine in Houston, TX. She also holds a Master of Science in Microbiology from the University of Mumbai in India. She has authored more than 100 peer-reviewed publications and has given more than 100 keynote and invited presentations at major national and internal conferences.

"We are delighted that Dr. Hegde has been elected to the ACMG Foundation Board of Directors. She has vast experience in genetic and genomic testing and is a longtime member of the College and supporter of both the College and the Foundation," said Bruce R. Korf, MD, PhD, FACMG, president of the ACMG Foundation.

The complete list of the ACMG Foundation board of directors is at http://www.acmgfoundation.org.

About the ACMG Foundation for Genetic and Genomic Medicine

The ACMG Foundation for Genetic and Genomic Medicine, a 501(c)(3) nonprofit organization, is a community of supporters and contributors who understand the importance of medical genetics and genomics in healthcare. Established in 1992, the ACMG Foundation for Genetic and Genomic Medicine supports the American College of Medical Genetics and Genomics' mission to "translate genes into health" by raising funds to help train the next generation of medical geneticists, to sponsor the development of practice guidelines, to promote information about medical genetics, and much more.

To learn more about the important mission and projects of the ACMG Foundation for Genetic and Genomic Medicine and how you too can support the work of the Foundation, please visit http://www.acmgfoundation.org or contact us at rel="nofollow">acmgf@acmgfoundation.org or 301-718-2014.

Contact Kathy Beal, MBA ACMG Media Relations, rel="nofollow">kbeal@acmg.net

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Madhuri Hegde, PhD is Elected to the Board of the ACMG Foundation for Genetic and Genomic Medicine - Markets Insider

Researchers have successfully edited the genes of viable human embryos to repair mutations that cause a dangerous heart condition. The team published their controversial research in the journal Nature.

The versatile gene-editing technique known as CRISPR-Cas9 is no stranger to headlines. Scientists have already used it to breed tiny pigs, detect disease, and even embed GIFs in bacteria. As our understanding of the process grows more advanced and sophisticated, many researchers have wondered how it could be applied to human beings.

For the new study, an international team of researchers fertilized healthy human eggs with sperm from men with a disease called hypertrophic cardiomyopathy, a condition that can lead to sudden death in young people. The mutation responsible for the disease affects a gene called MYBPC3. Its a dominant mutation, which means that an embryo only needs one bad copy of the gene to develop the disease.

Or, considered another way, this means that scientists could theoretically remove the disease by fixing that one bad copy.

Eighteen hours after fertilizing the eggs, the researchers went back in and used CRISPR-Cas9 to snip out mutated MYBPC3 genes in some of the embryos and replace them with healthy copies. Three days later, they checked back in to see how their subjectswhich were, at this point, still microscopic balls of cellshad fared.

The treatment seemed successful. Compared to subjects in the control group, a significant number of edited embryos appeared mutation- and disease-free. The researchers also found no evidence that their intervention had led to any unwanted new mutations, although it is possible that the mutations were there and overlooked.

Our ability to edit human genes is improving by the day. But, many ethicists argue, just because we can do it doesnt mean that we should. The United States currently prohibits germline editing of human embryos by government-funded researchers. But theres no law against such experimentation in privately funded projects like this one.

The same day the new study was published, an international committee of genetics experts issued a consensus statement advising against editing any embryo intended for implantation (pregnancy and birth).

"While germline genome editing could theoretically be used to prevent a child being born with a genetic disease, its potential use also raises a multitude of scientific, ethical, and policy questions, Derek T. Scholes of the American Society of Human Genetics said in a statement. These questions cannot all be answered by scientists alone, but also need to be debated by society."

Ethicists and sociologists are concerned by the slippery slope of trying to build a better human. Many people with chronic illness and disability live happy, complete lives and report that theyre limited more by discrimination than by any medical issues.

Disability studies expert Lennard Davis of the University of Illinois says we cant separate scientific decisions from our societys history of violence against, and oppression of, disabled and sick people.

A lot of this terrific science and technology has to take into account that the assumption of what life is like for people who are different is based on prejudice against disability, he told Nature in 2016.

Rosemary Garland-Thomson is co-director of the Disability Studies Initiative at Emory University. Speaking to Nature, she said we are at a cultural and ethical precipice: At our peril, we are right now trying to decide what ways of being in the world ought to be eliminated.

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Scientists Remove Disease-Causing Mutations from Human Embryos - Mental Floss

DNA research is shining new light on the Biblical Canaanite civilization, which existed thousands of years ago in the Middle East.

The ancient civilization, which created the first alphabet and is mentioned frequently in the Bible, has long fascinated historians. LiveScience reports that, because the Canaanites kept their records on papyrus, rather than clay, relatively little is known about them.

Now, however, scientists have found a genetic trail back to the Canaanites ancient world.

By sequencing the genomes of five Canaanites that lived 4,000 years ago with genomes from 99 people living in modern day Lebanon, researchers identified a strong genetic link to the mysterious civilization.

The results surprised the scientists, whose work was supported by UK biomedical research charity The Wellcome Trust.

In light of the enormously complex history of this region in the last few millennia, it was quite surprising that over 90 percent of the genetic ancestry of present-day Lebanese was derived from the Canaanites, said Chris Tyler-Smith, senior group leader at The Wellcome Trust Sanger Institute, in a statement.

In addition to the ancient Canaanite DNA, the analysis of genomes from the modern day Lebanese people also showed a small proportion of Eurasian ancestry that may have come from conquests by Assyrians, Persians or Macedonians, according to the experts.

The researchers also discovered that the ancient Canaanites were a mixture of local people, who settled in farming villages during the Neolithic period, and eastern migrants who arrived about 5,000 years ago. Using ancient DNA we show for the first time who were (genetically) the ancient Canaanites, how they were related to other ancient populations and what was their fate, explained Marc Haber, a genetic data expert at The Wellcome Trust Sanger Institute, in an email to Fox News. Our work shows the power of genetics in filling gaps in human history when the historical records are absent or scarce.

Haber added that the results complement Biblical accounts of the Canaanites. While the Israelites are commanded to utterly destroy the Canaanites in Deuteronomy 20:16-18, Judges 1 describes the survival of a number of Canaanite communities.

Canaanites once lived in what we now recognize as Israel, the Palestinian territories, Lebanon, Syria and Jordan. The remains of the five ancient Canaanites studied as part of the DNA research were recovered in the modern-day Lebanese city of Sidon.

The research was published in the American Journal of Human Genetics on July 27.

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Scientists find genetic 'trail' to mysterious Biblical civilization - New York Post

Medical genetic disorders affect about one person in 25. Genetic engineering and DNA sequencing invented in the 1970s led to a revolution in genetics. Photograph: AP

The work on the repair of a gene in human eggs, reported in the journal Nature, is an important scientific achievement. It made use of Crispr (clustered regularly interspaced short palindromic repeats) technology to make a single specific change in the three billion units of the human genome. The work is indeed a stunning application of Crispr, with some elegant and surprising results and the publicity is good for my science but it is not likely to change the way reproductive medical genetics is practised and it raises no new ethical problems.

The claims made for the work, amplified by the media, will raise expectations in families carrying genes with severe medical effects and has already excited the critics who fear that geneticists are busy undermining our society. So let us first look at what has been achieved in the science, and then tease out some of the implications.

Medical genetic disorders cause a great deal of suffering and affect about one person in 25. Genetic engineering and DNA sequencing invented in the 1970s led to a revolution in genetics. Mutant genes causing many genetic disorders have been identified. Advances in human embryology led to in-vitro fertilisation (IVF) in 1978, leading to the birth of more than five million children and untold happiness in their families. The question arose whether IVF could be useful in dealing with medical genetic cases.

By the early 1990s geneticists could detect mutant genes in single cells taken from IVF embryos without harming the embryos. This led to the gradual introduction of preimplantation genetic diagnosis (PGD). Today parents who are concerned that they may conceive a child with a significant genetic disorder can produce embryos by IVF, these may be tested for the genetic defect and one or more unaffected embryos can then be implanted.

PGD requires a specific probe for each genetic mutation. Some mutations are common, such as F508 in cystic fibrosis, but for many families the mutations have to be analysed and specific probes prepared and tested. As many people know, IVF is itself complex PGD adds another level of complexity, meaning that the number of successful clinical cases dealt with worldwide to date is still only a few thousand. PGD is in its infancy.

So what will be the clinical impact of the new method on PGD? In their experiments, biologist Shoukhrat Mitalipov and his fellow researchers treated 58 embryos in which about 50 per cent carried the normal and half the mutant gene. After treatment they found that 42 (or 72 per cent) carried two normal genes. The mutant gene had been repaired in an estimated 13 out of 29 embryos. Crucially, not all embryos were repaired, nor was it possible to say that Crispr did not cause other unintended, off-target damage to other genes. The embryos were not implanted.

The authors suggest that repair by Crispr will increase the efficiency of PGD. In fact it will have almost no practical effect on PGD services, for two reasons. First, not all of the defective genes are repaired, so after Crispr the embryos still have to be screened by standard PGD to avoid implanting mutant genes. Second, repairing is much more complicated than the current method, which is already complicated. Two Swedish commentators who work in the field note dryly: Embryo genetic testing [PGD] during IVF remains the standard way to prevent the transmission of inherited diseases in human embryos.

In contrast to its use in reproductive medical genetics, use of Crispr in repairing genes in body tissues is a really promising approach to treating genetic disorders after birth, but that is another story.

What do we really need to do in developing PGD? The technical priority is to make IVF itself more efficient. Then we need to refine the current methods of PGD and apply them routinely to a much wider range of genetic mutations. The social priority is to provide PGD on national health services to all couples faced with a high chance of conceiving a child with a major genetic disorder.

Now what about the ethics? Since PGD, which is a medical procedure, is well accepted in international medicine there is nothing new on that front. If in the past, like the Catholic Church, you opposed IVF (and PGD), or the wishes of parents to avoid having children with genetic disorders, this work will not change opinions, and should not increase your concerns.

It is possible that the Crispr techniques of changing genes will be used for non-medical purposes in reproduction, for example to alter genetic qualities which have nothing to do with health. In the UK, such use is regulated by the Human Fertilisation and Embryology Authority, and might be made illegal (as for example is the non-medical use of PGD for sex selection). But it may be more difficult to make all applications illegal for example, parents might wish to have a child with blue instead of brown eyes, and if so is foolishness something we should make illegal?

One thing is clear. It is long past time that we put into effect the recommendations of the Irish Commission on Assisted Human Reproduction of 2005 dealing with these issues, which are not new, and are well known to the Government. IVF is not regulated in Ireland, nor is PGD, making it difficult for pioneers in the field such as Dr John Waterstone of Cork Fertility to provide a service that is badly needed in Ireland.

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Impact of gene editing breakthrough will be muted - Irish Times

A day after a blockbuster report that researchers had edited harmful genetic mutations out of human embryos in an Oregon lab, an international group of genetics experts urged scientists against taking the next step.

A panel of the American Society of Human Genetics, joined by representatives from 10 organizations scattered across the globe, recommended against genome editing that culminates in human pregnancy. Their views were published Thursday in the American Journal of Human Genetics.

In the United States, the Food & Drug Administration forbids any medical use of gene editing that would affect future generations, and the agency strictly regulates experimental use of the technology in labs. But around the world, scientists sometimes circumvent restrictions like these by conducting clinical work in countries that have no such strictures.

People who want to gain access to these techniques can find people willing to perform them in venues where they are able to do so, said Jeffrey Kahn, director of the Berman Center for Bioethics at Johns Hopkins University. That underscores the importance of international discussion of what norms we will follow.

Indeed, some of the groups signing on to the new consensus statement acknowledged that they inhabit parts of the world in which medical and scientific regulatory bodies scarcely exist, or are not robust.

The panel said it supports publicly funded research of the sort performed at Oregon Health & Science University and reported Wednesday in the journal Nature. Such work could facilitate research on the possible future applications of gene editing, according to its position statement.

In the Nature study, researchers created human embryos with a mutation in the MYBPC3 gene that causes an often fatal condition called inherited hypertrophic cardiomyopathy. Then they edited the DNA of those embryos during the first five days of their development. At that point, the embryos were extensively analyzed and used to create stem cell lines that can be maintained indefinitely and used for further research.

But advancing to the next step allowing pregnancies to proceed with altered embryos will require further debate, the genetics specialists asserted.

They cited persistent uncertainties regarding the safety of gene-editing techniques. They also said the ethical implications of so-called germ-line editing, which would alter a patients genetic code in ways that would affect his or her offspring, remain insufficiently considered.

Panel members raised questions about who would have access to therapies made possible by manipulating the genome, and how existing inequities could be exacerbated. And they expressed concerns that the availability of germ-line editing could encourage experiments in eugenics the creation of people engineered for qualities such as intelligence, beauty or strength that would set them apart as superior.

Perhaps the most deeply felt concern is conceptual: the sense that in identifying some individuals and their traits as unfit, we experience a collective loss of our humanity, the group wrote.

The position statement comes on the heels of the Nature study reporting the first successful use in human embryos of a relatively new and increasingly popular gene-editing technique known as CRISPR-Cas9. That study offered some reassurance that unforeseen or off target effects of such therapies can be avoided with certain practices.

Study leader Shoukhrat Mitalipov, a biologist at the Oregon university, said that while there is a long road ahead, he hoped to employ these techniques in human clinical trials in the coming years.

The genetics groups consensus statement lays out some of the scientific and ethical debates that should come before any trial would attempt the incubation and birth of children whose faulty genes had been repaired while they were still embryos.

The group also voiced concerns about the potential impact of germ-line editing on families and societies in which they might become widely used.

Arguably, the ability to easily request interventions intended to reduce medical risks and costs could make parents less tolerant of perceived imperfections or differences within their families, panel members wrote. Clinical use of germline gene editing might not be in the best interest of the affected individual if it erodes parental instinct for unconditional acceptance.

melissa.healy@latimes.com

@LATMelissaHealy

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Here's where experts say we should draw the line on gene-editing experiments on human embryos - Los Angeles Times

August 4, 2017

A Stanford professor of genetics discusses the thinking behind a formal policy statement endorsing the idea that researchers continue editing genes in human germ cells.

A team of genetics experts has issued a policy statement recommending that research on editing human genes in eggs, sperm and early embryos continue, provided the work does not result in a human pregnancy.

Kelly Ormond, MS, professor of genetics at the Stanford School of Medicine, is one of three lead authors of the statement, which provides a framework for regulating the editing of human germ cells. Germ cells, a tiny subset of all the cells in the body, give rise to eggs and sperm. Edits to the genes of germ cells are passed on to offspring.

The statement, published today in the American Journal of Human Genetics, was jointly prepared by the American Society for Human Genetics and four other human genetics organizations, including the National Society of Genetic Counselors, and endorsed by another six, including societies in the United Kingdom, Canada, Australia, Africa and Asia.

Germline gene editing raises a host of technical and ethical questions that, for now, remain largely unanswered. The ASHG policy statement proposes that federal funding for germline genome editing research not be prohibited; that germline editing not be done in any human embryo that would develop inside a woman; and that future clinical germline genome editing in humans not proceed without a compelling medical rationale, evidence supporting clinical use, ethical justification, and a process incorporating input from the public, patients and their families, and other stakeholders.

Ormond recently discussed the issues that prompted the statement's creation with writer Jennie Dusheck.

Q: Why did you think it was important to issue a statement now?

Ormond: Much of the interest arose a couple of years ago when a group of researchers in China did a proof of principle study demonstrating that they could edit the genes of human embryos.

The embryos weren't viable [meaning they could not lead to a baby], but I think that paper worried people. Gene editing in human germ cells is not technically easy, and it's not likely to be a top choice for correcting genetic mutations. Still, it worried us that somebody was starting to do it.

We've been able to alter genes for many years now, but the new techniques, such as CRISPR/Cas9, that have come out in the past five years have made it a lot easier, and things are moving fast. It's now quite realistic to do human germline gene editing, and some people have been calling for a moratorium on such work.

Our organization, the American Society of Human Genetics, decided that it would be important to investigate the ethical issues and put out a statement regarding germline genome editing, and what we thought should happen in the near term moving forward.

As we got into the process, we realized that this had global impact because much of the work was happening outside of the United States. And we realized that if someone, anywhere in the world, were moving forward on germline genome editing, that it was going to influence things more broadly. So we reached out to many other countries and organizations to see if we could get global buy-in to the ideas we were thinking about.

Q: Are there regulations now in place that prevent researchers from editing human embryos that could result in a pregnancy and birth?

Ormond: Regulations vary from country to country, so research that is illegal in one country could be legal in another. That's part of the challenge and why we thought it was so important to have multiple countries involved in this statement.

Also, since 1995 the United States has had regulations against federal funding for research that creates or destroys human embryos. We worry that restricting federal funding on things like germline editing will drive the research underground so there's less regulation and less transparency. We felt it was really important to say that we support federal funding for this kind of research.

Q: Is germline editing in humans useful and valuable?

Ormond: Germline editing doesn't have many immediate uses. A lot of people argue that if you're trying to prevent genetic disease (as opposed to treating it), there are many other ways to do that. We have options like prenatal testing or IVF and pre-implantation genetic testing and then selecting only those embryos that aren't affected. For the vast majority of situations, those are feasible options for parents concerned about a genetic disease.

The number of situations where you couldn't use pre-implantation genetic diagnosis to avoid having an affected child are so few and far between. For example, if a parent was what we call a homozygote for a dominant condition such as BRCA1 or Huntington's disease, or if both members of the couple were affected with the same recessive condition, like cystic fibrosis or sickle cell anemia, it wouldn't be possible to have a biologically related child that didn't carry that gene, not unless germline editing were used.

Q: What makes germline editing controversial?

Ormond: There are families out there who see germline editing as a solution to some genetic conditions. For example, during a National Academy of Sciences meeting in December of 2015, a parent stood up and said, "I have a child who has a genetic condition. Please let this move forward; this is something that could help."

But I also work in disability studies, as it relates to genetic testing, and there are many individuals who feel strongly that genetic testing or changing genes in any way makes a negative statement about them and their worth. So this topic really edges into concerns about eugenics and about what can happen once we have the ability to change our genes.

Germline gene editing impacts not just the individual whose genes are edited, but their future offspring and future generations. We need to listen to all of those voices and try to set a path that takes all of them into account.

That's a huge debate right now. A lot of people say, "Let's not mess around with the germline. Let's only edit genes after a person is born with a medical condition." Treating an existing medical condition is different from changing someone's genes from the start, in the germline, when you don't know what else you're going to influence.

Q: There was a paper recently about gene editing that caused mutations in excessive numbers of nontargeted genes, so called "off-target effects." Did that result surprise you or change anything about what you were thinking?

Ormond: I think part of the problem is that this research is moving very fast. One of our biggest challenges was that you can't do a good ethical assessment of the risks and benefits of a treatment or technology if you don't know what those risks are, and they remain unclear.

We keep learning about potential risks, including off-target mutations and other unintended consequences. Before anyone ever tries to do germline gene editing in humans, it is very important that we do animal studies where the animals are followed through multiple generations, so that we can see what happens in the long term. There's just a lot that we don't know.

There are so many unknowns that we don't even know what guidelines to set. For example, what's an appropriate new mutation level in some of these technologies? What is the risk we're willing to take as we move forward into human studies? And I think those guidelines need to be set as we move forward into clinical trials, both in somatic cells [cells of the body, such as skin cells, neurons, blood cells] and in germline cells.

It's really hard because, of course, we're talking about, for the most part, bad diseases that significantly impact quality of life. So if you're talking about a really serious disease, maybe you're willing to take more risk there, and these new mutations aren't likely to be as bad as the genetic condition you already have. But we don't know, right?

We haven't had any public dialogue about any of this, and that's what we need to have. We need to find a way to educate the public and scientists about all of these issues so people can have informed discussions and really come together as this moves forward, so that were not in that reactive place when it potentially becomes a real choice.

And that goes back to your first question, which is why did we feel like we needed to have a statement now? We wanted to get those conversations going.

Explore further: 11 organizations urge cautious but proactive approach to gene editing

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Genetics expert discusses creating ground rules for human germline editing - Medical Xpress

Dr. Hegde joined PerkinElmer in 2016 as Vice President and Chief Scientific Officer, Global Genetics Laboratory Services. She also is an Adjunct Professor of Human Genetics in the Department of Human Genetics at Emory University. Previously, Dr. Hegde was Executive Director and Chief Scientific Officer at Emory Genetics Laboratory in Atlanta, GA and Professor of Human Genetics and Pediatrics at Emory University and Assistant Professor, Department of Human Genetics and Senior Director at Baylor College of Medicine in Houston, TX.

Dr. Hegde has served on a number of Scientific Advisory Boards for patient advocacy groups including Parent Project Muscular Dystrophy, Congenital Muscular Dystrophy and Neuromuscular Disease Foundation. She was a Board member of the Association for Molecular Pathology and received the Outstanding Faculty Award from MD Anderson Cancer Center. She earned her PhD in Applied Biology from the University of Auckland in Auckland, New Zealand and completed her Postdoctoral Fellowship in Molecular Genetics at Baylor College of Medicine in Houston, TX. She also holds a Master of Science in Microbiology from the University of Mumbai in India. She has authored more than 100 peer-reviewed publications and has given more than 100 keynote and invited presentations at major national and internal conferences.

"We are delighted that Dr. Hegde has been elected to the ACMG Foundation Board of Directors. She has vast experience in genetic and genomic testing and is a longtime member of the College and supporter of both the College and the Foundation," said Bruce R. Korf, MD, PhD, FACMG, president of the ACMG Foundation.

The complete list of the ACMG Foundation board of directors is at http://www.acmgfoundation.org.

About the ACMG Foundation for Genetic and Genomic Medicine

The ACMG Foundation for Genetic and Genomic Medicine, a 501(c)(3) nonprofit organization, is a community of supporters and contributors who understand the importance of medical genetics and genomics in healthcare. Established in 1992, the ACMG Foundation for Genetic and Genomic Medicine supports the American College of Medical Genetics and Genomics' mission to "translate genes into health" by raising funds to help train the next generation of medical geneticists, to sponsor the development of practice guidelines, to promote information about medical genetics, and much more.

To learn more about the important mission and projects of the ACMG Foundation for Genetic and Genomic Medicine and how you too can support the work of the Foundation, please visit http://www.acmgfoundation.org or contact us at acmgf@acmgfoundation.org or 301-718-2014.

Contact Kathy Beal, MBA ACMG Media Relations, kbeal@acmg.net

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Madhuri Hegde, PhD is Elected to the Board of the ACMG Foundation for Genetic and Genomic Medicine - PR Newswire (press release)