Category Archives: Human Genetics

Imagine the moment, youve just been told youre expecting twins. You are trying not to think about The Shining.

You are wondering why you, specifically, have somehow ended up doubly pregnant. Allow Techly to shed some light on the subject.

Now while that clip from the late 80s buddy comedy Twins isnt the most scientific thing youll see today, its always fun to see Arnie acting in the rare scenes when he isnt mowing down foot soldiers and it does raise a significant point. There is a large difference between identical (or monozygotic) twins and fraternal (dizygotic) twins, here demonstrated ably by DeVito and Schwarzenegger.

In the case of identical twins, as the medical term monozygotic may suggest, they occur when one zygote (essentially a fertilized egg) splits into two halves during early development, meaning both embryos have identical genetic information. Fraternal twins, on the other hand, develop from two separate zygotes and are therefore made up of differing, while similar, genetic information.

So, is there a genetic reason for the occurrence of twins? Could there be some genetic predisposition to carrying twins? Well according to this post on The Stanford Tech forum its kind of yes and no territory. To be more specific, the post states identical twins do not run in families and a history of fraternal twins only helps if it comes in on the mothers side. Furthermore, it says that a female fraternal twin is 2.5 times more likely to give birth to a further set of twins and that goes up to 3-4 times when the woman already has already given birth to a set of fraternal twins.

According to the Sciencemag site scientists from eight countries found two genes that increase a womans chance of having twins. A team of researchers in Amsterdam, where the Nederlands Twin Register which currently contains 75,000 cases, started in 1987 collated data from databases in the Nederlands, USA and good ol Australia.

The researchers, working on a sample of over 2000 births, examined the genetic information of the mothers to see if there was a common link between the mothers of fraternal twins. They eventually narrowed it down to two SNPs (essentially single stretches of DNA that signpost genetic differences between people) and subsequently reported in the American Journal of Human Genetics that having a copy of each of them will increase that persons chances of giving birth to fraternal twins by a huge 29%. The first SNP relates to the production of the follicle stimulating hormone (FSH), which, if the levels remain quite high while the ovaries mature, can lead to the production of more than one egg. The other SNP is a little more mysterious, SMAD3 has been noted to change how ovaries respond to FSH, at least in mice but in terms of its role in human fertilization, research is ongoing.

So there you have it, of course, a full genetic analysis is not necessarily available to everyone, so whether or not you are genetically predisposed to have your own DeVito/Schwarzenegger caper may have to remain a surprise for now. Having said that, youre family history can, of course, be a handy indicator when considering your own genetic make-up, so Auntie Jane should be able to give you some idea!

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Techly Explains: Are twins genetic? - Techly

From the opening scene, questions of identityboth existential and scientificprovide the shows narrative thrust.

BBC America

This article contains spoilers about the series finale of Orphan Black.

After five seasons of clone cabals, the BBC America/Space series Orphan Black has come to a mostly happy end. Yet an ellipsis follows wrapping of the show, hinting at bigger questions that transcend the characters storylines. Orphan Blacks conspiracies, camp, and Tatiana Maslanys riveting performances as a dozen different clones make it easy to overlook its prescience and profundity. From the opening scene in which Sarah Manning sees her clone kill herself by stepping in front of a train, questions of identityboth existential and scientificprovide the shows narrative thrust. Who created the clones? How? Why? How much control do their creators have over them? The shows final season provides answers while raising questions that transcend science fiction. What role should ethics play in science? Do scientific subjects have the right to self-determination?

If you stopped watching a few seasons back, heres a brief synopsis of how the mysteries wrap up. Neolution, an organization that seeks to control human evolution through genetic modification, began Project Leda, the cloning program, for two primary reasons: to see whether they could and to experiment with mutations that might allow people (i.e., themselves) to live longer. Neolution partnered with biotech companies such as Dyad, using its big pharma reach and deep pockets to harvest peoples genetic information and to conduct individual and germline (that is, genetic alterations passed down through generations) experiments, including infertility treatments that result in horrifying birth defects and body modification, such as tail-growing.

In the final season, we meet the man behind the curtain: P.T. Westmoreland, who claims to be 170 years old thanks to life-extension treatments such as parabiosis (transfusions of young blood). Westmoreland wants to harness the healing powers of the particular LIN28A gene mutation found in the fertile clones kids. (Real-world studies suggest that while LIN28A mutations are linked to cancer, its RNA-binding protein promotes self-renewal of embryotic stem cells.)

Westmorelandultimately discovered to be a fraud who assumed the original Westmorelands identity after he diedpersonifies one of the shows messages: that pseudoscience and megalomania can masquerade as science. Just because someone has a genetic sequencer and a lab coat doesnt mean hes legitimate, and just because someones a scientist doesnt mean hes ethical.

Orphan Black demonstrates Carl Sagans warning of a time when awesome technological powers are in the hands of a very few. Neolutionists do whatever they want, pausing only to consider whether theyre missing an opportunity to exploit. Their hubris is straight out of Victor Frankensteins playbook. Frankenstein wonders whether he ought to first reanimate something of simpler organisation than a human, but starting small means waiting for glory. Orphan Blacks evil scientists embody this belief: if theyre going to play God, then theyll control not just their own destinies, but the clones and, ultimately, all of humanitys. Any sacrifices along the way are for the greater goodreasoning that culminates in Westmorelands eugenics fantasy to genetically sterilize 99 percent of the population he doesnt enhance.

Orphan Black uses sci-fi tropes to explore real-world plausibility. Neolution shares similarities with transhumanism, the belief that humans should use science and technology to take control of their own evolution. While some transhumanists dabble in body modifications, such as microchip implants or night-vision eye drops, others seek to end suffering by curing human illness and aging. But even these goals can be seen as selfish, as access to disease-eradicating or life-extending technologies would be limited to the wealthy. Westmorelands goal to sell Neolution to the 1 percent seems frighteningly plausibletranshumanists, who statistically tend to be white, well-educated, and male, and their associated organizations raise and spend massive sums of money to help fulfill their goals. Critics raise many objections to transhumanism, including overpopulation and the socioeconomic divide between mortals and elite immortals, which some think might beget dystopia. Researchers are exploring ways to extend the human lifespan whether by genetic modification, reversing senescence (cellular deterioration with age), nanobots, or bio-printed tissues and organs, but in the world of Orphan Black we dont have to speculate about the consequences of such work.

The show depicts the scientists dehumanization of the clones from its first scene, when Beth, unable to cope with the realities of her cloned existence, commits suicide. When another clone, Cosima, tries to research her DNA, she gets a patent statement: This organism and derivative genetic material is restricted intellectual property. It doesnt matter that Cosima is sick or that shes in love. Shes not a person: Shes a trademarked product, as are the other clones.

Orphan Black warns us that money, power, and fear of death can corrupt both people and science.

The shows most tragic victim is Rachel, the evil clone. Shes the cautionary tale: Frankensteins monster, alone, angry, and cursed. The only one raised with the awareness of what she is, Rachel grows up assured of her own importance and motivated to expand it by doing Neolutions dirty work. Westmoreland signs a document giving Rachel sovereignty, but later she sees computer files in which shes still referred to by her patent number. Despite her leadership, cunning, and bravery, even those working with her never regard her as human. Her willingness to hurt her sisters and herself shows what happens to someone whose experience of nature and nurture is one and the same.

We, the viewers, also dehumanize Rachel by writing her off as one of them. When she lands on the side of her sisters, she does so not out of morality but out of vengeance. At the end, Westmoreland, the closest thing she has to a father, taunts her: its fitting you return to your cage. All lab rats do. But her childhood flashbacks suggest she doesnt want others to experience what she has. When Neolutionists take 9-year-old Kira from her home at gunpoint, Rachel initially supports the plan to load Kira with fertility drugs and then harvest her eggs to access her mutated gene. But when Kira gives Rachel a friendship bracelet (and perhaps her first friendship), Rachels haunted expression suggests that beneath her usually unflappable demeanor, shes still a frightened little girl. When Kira asks, Who hurt you? Rachel responds, They all did.

Whether motivated by retaliation, morality, or both, Rachel helps save Kira and takes down Neolution. Yet its unclear whats left for her as shell never be welcomed into Clone Club. Her last act is to provide a list of clones around the world so Cosima and former Dyad researcher Delphine can cure them. Rachel gives the clones control over their livesand in so doing, asserts control over her own.

Ultimately, Orphan Black is all about choice. Theres much in life we cant choose: our parents, the circumstances of our birth, our DNA. Its no surprise that a show that espouses girl power (the future is female is both spoken and seen on a T-shirt in the final two episodes) dwells on the importance of choice. The finale flashes back to Sarah in front of Planned Parenthood debating whether to have an abortion. Reckless, rough Sarah surprises herself (and Mrs. S, her foster mother) by deciding to keep the baby. Years before she learns how many decisions others have made about her body, she makes a decision for herself.

On Orphan Black, denial of choice is tantamount to imprisonment. That the clones have to earn autonomy underscores the need for ethics in science, especially when it comes to genetics. The shows message here is timely given the rise of gene-editing techniques such as CRISPR. Recently, the National Academy of Sciences gave germline gene editing the green light, just one year after academy scientists from around the world argued it would be irresponsible to proceed without further exploring the implications. Scientists in the United Kingdom and China have already begun human genetic engineering and American scientists recently genetically engineered a human embryo for the first time. The possibility of Project Leda isnt farfetched. Orphan Black warns us that money, power, and fear of death can corrupt both people and science. Once that happens, loss of humanityof both the scientists and the subjectsis inevitable.

In Carl Sagans dark vision of the future, people have lost the ability to set their own agendas or knowledgeably question those in authority. This describes the plight of the clones at the outset of Orphan Black, but as the series continues, they challenge this paradigm by approaching science and scientists with skepticism, ingenuity, and grit. The lab rats assert their humanity and refuse to run the maze. Freedom looks different to everyone, Sarah says in the finale. As she struggles to figure out what freedom will look like for hershould she get her GED? Sell the house? Get a job?its easy to see how overwhelming such options would be for someone whose value has always been wrapped in a double helix. But no matter what uncertainties their futures hold, the clones dismantle their cages and make their own choices, proving what weve known all alongtheir humanity.

This article is part of Future Tense, a collaboration among Arizona State University, New America, and Slate. Future Tense explores the ways emerging technologies affect society, policy, and culture. To read more, follow us on Twitter and sign up for our weekly newsletter.

Excerpt from:
Orphan Black Was Never About Cloning - Slate Magazine

The DNA of early human embryos carrying a sequence leading to hypertrophic cardiomyopathya potentially deadly heart defecthas been edited to ensure they would carry a healthy DNA sequence if brought to term. The Nature paper announcing this has reenergized a terrific national and international debate over whether permanent changes in DNA that can be passed from one generation to another should be made. Bioethicists are asking, Should we genetically engineer children? while some potential parents are almost certainly asking, When will this technique be available?

The Should questions bioethicists are asking are probably not relevant. The only question whose answer ultimately matters is: Can techniques like CRISP-R be used to genetically engineer children safely? Because a variety of forces guarantee that if they can be, they will be.

The key questions reliable practitioners must answer are: Can we prove it works? Then: Can it be used safely?. If yes on these questions, then we will see: Who is marketing this technique to potential parents? Finally, we will learn: Where was it done, who did it, and who paid for its use?

We are closer than ever before to using CRISP-R to replace dangerous DNA sequences with those that wont keep a baby from being healthy. Fortunately, this Nature paper leaves many questions Unanswered because the embryos were not allowed to come to term.

Most importantly, we still dont know Could the embryos have developed into viable babies? Just as in 2015 when researchers at Sun Yat-Sen University in China didnt implant engineered embryos into a womans womb, the scientists who published in Nature recently didnt feel ready (and didnt have permission) to try this potentially enormous step. As experiments proceed, this question will, at some point, be answered.

It will be answered because there is an enormous, proven market for techniques that can be used to ensure that a baby will be born without DNA sequences that can lead to genetically-mediated conditions; many of which are devastating as we have been tragically reminded of late.

Under the best circumstances, in-vitro fertilization leads to a live birth less than half of the time. As a result, whoever tries to see if an embryo that has had targeted DNA repaired using CRISP-R will doubtless prepare a lot of embryos for implanting in quite a few women. When those women are asked to carry these embryos to term we will not know about it. We will probably not find out if none of the embryos come to term successfully.

We *will* know about this procedure if even one baby comes to term and is born with the targeted genetic sequence corrected as intended. Until now, (and maybe even with our new knowledge), any baby brought to term after CRISP-R was used to edit and replace unhealthy DNA would have almost certainly had other DNA damaged in the editing process. This near-certainty and other concerns have held people back from trying to genetically engineer an embryo that they would then bring to term. They could not, until recently, have confidence that only the sequence being targeted has been affected. With this new Nature report, this, at least, is changing.

The results of these newly reported experiments are many steps closer to usability than the Chinese experiments reported in 2015. This is the nature of scientific experimentation, particularly when there is demand for the capability or knowledge being developed.

People try something. It either works or it doesnt. Sometimes when it doesnt work, we learn enough to adjust and try again. If it does work, it often doesnt function exactly the way we expected. Either way, people keep trying until either the technique is perfected or it ultimately proves to be unusable.

This Nature paper is an example of trying something and doing a better job than the first attempt. It does not represent a provably safe and reliable technique . Yet. If market driven research works as it often does, people will work hard to publish data (hopefully from reliable experimental work) suggesting they have a safe and effective technique. Doing so will let them tell some desperate set of wealthy prospective parents: We should be able to use this technique with an acceptable chance of giving you a healthy baby.

Princetons Lee Silver predicted parents desire for gene editing in his Remaking Eden, a book published in 1997. He argued this because people fear sickness or disability and feel strong personal, economic and social pressures to have healthy, beautiful children who should become healthy attractive adults.

People already spend a great deal on molecular techniques like pre-implantation genetic diagnosis (PGD). PGD is regularly used to reduce couples risk of having babies with known (or potential), chromosomal abnormalities and/or single gene mutations that can lead to thousands of DNA-mediated conditions.

As I showed in my Genetics dissertation published from Yale in 2004, different countries respond differently to controversial science like this. Similarly, different individuals responses are equally diverse. One poll indicates nearly half of Americans would use gene editing technology to prevent possible DNA-mediated conditions in their children. Policy makers who object to the technology therefore have a problem: if they succeed in blocking it somewhere, research and real world experience indicate other governments may well permit its use. If this happens, these techniques will be available to anyone wealthy and desperate enough to find providers with the marketingand hopefully scientificskill needed to sell people on trying them.

This gene editing controversy is a reminder that we are losing the capacity to effectively ask, Should we? As our knowledge of science grows, becomes more globalized, and is increasingly easy to acquire for people with different morals, needs and wants, we must soon be ready to ask, Can we? and ultimately, Will someone? Their answers will give us the best chance to ensure any babies that may come from any technique described as genetic engineering are born healthy, happy, and able to thrive.

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It's Time to Stop Asking Whether Human Genetic Engineering Should Happen and Start Planning to Manage it Safely - HuffPost

India The department of medical genetics at Kasturba Medical College, Manipal (a constituent college of Manipal University), led by Dr Girish Katta, has discovered a new genetic disease called multiple mitochondrial dysfunction syndrome. Defects in ISCA1 gene are the likely cause of the disease in four children from two families in the region.

The team comprising clinical geneticist Dr Anju Shukla studied two families with a severe neurological disease in infancy. All four affected children died early in childhood. DNA from the first family was analysed by exome sequencing. The bioinformatics analysis then identified a similarly affected family from the in-house database of exomes. All the four children showed a severe white matter disease of brain.

The iron-sulfur (Fe-S) cluster (ISC) biogenesis pathway is indispensable for many fundamental biological processes, and pathogenic variations in genes encoding several components of the Fe-S biogenesis machinery, such as NFU1, BOLA3, IBA57 and ISCA2, are already implicated in causing four types of multiple mitochondrial dysfunctions syndromes (MMDS). The two unrelated families, with two affected children each with early onset neurological deterioration, seizures, extensive white matter abnormalities, cortical migrational abnormalities, lactic acidosis and early demise were investigated. Exome sequencing identified a homozygous c.259G>A [p.(Glu87Lys)] variant in ISCA1 gene. This was due to a founder effect. The phenotype observed in all affected subjects with the ISCA1 pathogenic variant is similar to that previously described in all four types of multiple mitochondrial dysfunctions syndrome (MMDS).

The findings suggest association of a pathogenic variant in ISCA1 with another new type MMDS, added Dr Vinod Bhat, vice chancellor of Manipal University. The research work was funded by National Institutes of Health (NIH), USA.

The work is now published online in the highly reputed Journal of Human Genetics, published by Nature Publishing Group. A new bone disease short rib thoracic dysplasia type 16, which was identified by the same team, has already been catalogued in Online Mendelian Inheritance in Man (OMIM) following discovery of similar disease from United States of America.

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Team Manipal discovers a new mitochondrial genetic disease - QS WOW News (press release) (registration)

The father of a boy with a rare genetic mutation has accused a scientist of exploiting his child by proclaiming the defect a genetic syndrome and naming it after herself.

At an impasse with scientists investigating, publicizing, and interpreting his sons condition, the father seems willing to use any leverage he can muster to remove the syndrome entry in an online genetic disease database. Based solely on an email he obtained from the database director, the father became convinced that if the paper underpinning the entry were retracted, the syndrome would go down with it. So earlier this year, he withdrew his consent and asked the journal that published the paper for a retraction, based on improper patient consent. He has also threatened to lob accusations of research misconduct at the papers last author.

Marc Pieterse, of The Netherlands, is the father of Vincent, a teenager who has a mutation in the RPS23 gene that has only been found in one other person, so far. In March, an international team of researchers published a paper on Vincents RPS23 mutation in the American Journal of Human Genetics (AJHG), linking it to defective ribosomes, organelles involved in protein synthesis.

One of the scientists Pieterse engaged several years ago is Alyson MacInnes, a rare disease researcher at the University of Amsterdams Academic Medical Center. She is last author of the AJHG paper and the person whose name is now connected to an entry in the Online Mendelian Inheritance in Man (OMIM) database. MacInnes told Retraction Watch that, contrary to what Pieterse claims, she played no direct role in naming the syndrome; OMIM confirmed this account.

The OMIM entry for MacInnes Syndrome, which links the RPS23 mutation with a collection of features that resemble Vincents hearing loss, issues with the hands was created on March 29, weeks after the paper was published. Pieterse said he was shocked when he found it in April as he was browsing the database.

Pieterse told us he feels used and fears that the designation will stigmatize his sons mutation. A syndrome is a disease, he said. Now, he wants the database entry either changed he prefers the umbrella term ribosomopathy, which is used in the paper or taken down.

Believing MacInnes submitted Vincents condition for consideration, Pieterse demanded she find a way to remove it. When she didnt respond, he went directly to AJHG and OMIM to get the paper and syndrome entry removed.

So far, nothing has worked.

A campaign begins

The Pieterses found out about Vincents mutation after a long diagnostic odyssey that ultimately resorted to sequencing all the protein-coding regions of Vincents genome. In 2015, the Journal of the American Medical Association published a news feature on Vincents diagnosis, saying it heralded a new era of clinical genomics.

Marc is a former telecommunications engineer and entrepreneur who has shifted his focus to raising his four children. He told Retraction Watch that although hes not a scientist, in the years since receiving Vincents diagnosis he has committed himself to advocating for further study of the mutation and has even co-authored a paper on RPS23. Marc claims he played a role in connecting MacInnes, Baserga, and several other European scientists, who eventually published the AJHG paper together.

When Pieterse found the OMIM entry for MacInnes syndrome, he believed that MacInnes had created it to boost her career. He told us that after he found it, he tried asking her to take it down. However, their relationship had at that point already suffered a communication breakdown and he didnt hear back. This further upset him and he began a campaign to bring down the entry by any means possible.

But MacInnes told us she had nothing to do with either the OMIM entrys creation or its naming:

I did not submit this paper to OMIM or in any way initiate this entry as a syndrome. This was independently picked up by OMIM and registered as such; apparently such registrations are made upon their decision only.

OMIM director Ada Hamosh confirmed this to Retraction Watch:

Dr. Macinnes did not ask for this to be named after herself and did not bring it to our attention.

We are dealing with this gene-phenotype relationship exactly as we would any other. We did this because this is what we do.

Hamosh, a geneticist at Johns Hopkins University, told us that the term syndrome is for a constellation of features and that the naming was done in accordance with policies that have long been in place at OMIM:

Sometimes something has too many features to be described succinctly. In that case, the default way to name something is to use the first authors last name and last authors last name.

Indeed, Hamosh told us that at first the syndrome was called Paolini-MacInnes syndrome, after first author Nahuel Paolini, of the University of Amsterdam. However, Hamosh said OMIM later realized there were four co-first authors. OMIM never adds more than three names to a syndrome, so Hamosh simply named it after MacInnes:

Given how little we know about it, it makes more sense to name it eponymously than after some features I cant put my hands on, especially since we have a policy on not ever naming something after a gene.

Its stigmatizing

Part of Pieterses issue with dubbing the condition a new syndrome is the early and ongoing nature of RPS23 research, and he isnt alone. In an email to Hamosh, MacInnes co-author Susan Baserga, a professor at the Yale School of Medicine, said:

I was very surprised that you are so pressed to name the phenotype as a new syndrome, especially since the clinical findings are so non-specific. I find this very odd indeed, and worry that it muddles the medical and genetic literature instead of providing clarity. This is so new that I am not even sure that it is a syndrome, and worry that it is presumptuous at best and wrong at worst.

Baserga, who did not respond to our requests for comment, also suggested that OMIM simply call the condition a ribosomopathy, as the AJHG paper does. But Hamosh told Retraction Watch:

We never, ever, ever, name a disease after a gene.

Gene symbols are not stable. More fundamentally, many, many, many genes have more than one condition associated with them. It is not a good idea to put a gene name into a disease name. Thats why we wont call it RPS23 ribosomopathy. Its not personal, we wont do this for any gene.

Pieterse told us that neither Hamosh, nor anybody else from OMIM, has ever informed him that OMIM itself created the entry and that MacInnes Syndrome is the result of standard naming procedures.

Like MacInnes, Hamosh wont respond to his attempt at contact. But Pieterse has obtained an email chain, from late April, between those two scientists, as well as Baserga. In it, Hamosh wrote:

Are you planning to retract or correct the paper to indicate the apparent uncertainty regarding its conclusions? If so, we will remove the phenotype and reclassify the variants.

Niether MacInnes nor Baserga thought a retraction was necessary, but this exchange convinced Pieterse that a retraction would force OMIM to remove the entry. So he wrote MacInnes to inform her he was withdrawing his parental consent and asked AJHG to retract the paper. Pieterse told Retraction Watch that the consent form he submitted to the University of Freiburgs medical center, in Germany (cells used in the study were created there) was very broad and that he believed it would allow him get the paper pulled.

Readers may recall some of the cases weve covered in which patient consent issues have led to papers being retracted. Pieterses situation most closely resembles a story we covered in 2015, where the authors requested a retraction from the Journal of Medical Case Reports after a legal guardian withdrew permission after publication.

But his attempt to trigger retraction didnt work. AJHG editor David Nelson, of the Baylor College of Medicine, told Pieterse the journal had looked into the situation but found nothing improper. According to an email shared by Pieterse, Nelson wrote:

Because there was no reason to retract the article due to misrepresentation of scientific content, we investigated the issues around withdrawal of patient consent. We have been in communication with the [University of Amsterdam Academic Medical Center] Biobank Committee and Medical Ethics Committee and they have confirmed that withdrawal from the study is not relevant to the article and data that have been published already.

Given the serious implications of a retraction on the journal, the authors of the article, and the scientific record, we have therefore decided that the American Journal of Human Genetics will not retract the article.

In an email to Retraction Watch, Nelson expanded on what he told Pieterse:

Our understanding from the authors and their institutions who obtained and approved consent for this study is that it is possible for research subjects to withdraw their consent at any time and that samples and information should be destroyed upon withdrawal. However, published scientific articles deriving from the studies are not subject to the consent withdrawal and this was confirmed by individuals familiar with European Union Regulations relating to personal data.

Pieterse told us that knows a retraction would be counterproductive to his long-term goal, which is to see the research around Vincents mutation grow. But he still wants to see the OMIM entry come down:

At a certain moment, people are going to cite OMIM in genetics papers and its going to spread. If you want to correct something, you should correct it fast. Once the internet is soaked, you cannot do that.

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Fearing stigmatization, patient's father seeks retraction of paper on rare genetic mutation - Retraction Watch (blog)

CNSNews.com

Genetic Arms Race: A Threat to Human Dignity And National Security? CNSNews.com A new genetic technology is being called a weapon of mass destruction. I'll tell you why that may not be hyperbole. In late July, the MIT Technology Review published news many of us have been dreading: A team of scientists at Oregon Health and Sciences ... and more »

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Genetic Arms Race: A Threat to Human Dignity And National Security? - CNSNews.com

Baylor College of Medicine is one of six U.S. institutions to receive a grant through the National Human Genome Research Institutes Clinical Sequencing Evidence-Generating Research Consortium, or CSER2. The four-year grant, including $2.8 million for fiscal year 2017, co-funded by the National Cancer Institute, will support Baylors new KidsCanSeq program that will compare the results of large-scale genomic testing, such as whole exome sequencing, to targeted clinical tests in childhood cancer patients at five sites across the state that serve a highly diverse patient population, including Texas Childrens Cancer Center.

In addition to Texas Childrens Cancer Center, pediatric patients will be enrolled in KidsCanSeq at the Vannie E. Cook Childrens Cancer Clinic in McAllen, the Childrens Hospital of San Antonio, the University of Texas Health Science Center at San Antonio, and Cook Childrens Health Care System in Fort Worth.

KidsCanSeq follows the Baylor Advancing Sequencing in Childhood Cancer Care(BASIC3) study at Baylor and Texas Childrens Cancer Center, which developed the initial protocols for performing clinical genomic testing of pediatric cancer patients, reporting results and communicating those results to families and oncologists. BASIC3 was part of the NHGRI Clinical Sequencing Exploratory Research program, a precursor to CSER2.

Through BASIC3 we explored broad questions, such as whether we could conduct large-scale genomic testing in a clinical setting, what kind of results it would generate, and how to communicate the results to families and physicians. KidsCanSeq is focused more on generating specific data on what tests are better or worse than standard tests in pediatric cancer patients, said the studys principal investigator Dr. Sharon Plon, professor of pediatrics and of molecular and human genetics at Baylor and director of the Cancer Genetics Clinical and Research Programs at Texas Childrens Hospital.

BASIC3 was essentially a pilot study, and now that we have a better idea of how to implement broad-scale genetic testing in the clinic, we can focus this study more specifically on determining which patients would be most likely to benefit from it or for whom it would be most likely to impact care, said Dr. Will Parsons, co-principal investigator and associate professor of pediatrics at Baylor and Texas Childrens Cancer Center. For example, tumor sequencing of cancer types for which kids are almost always cured at the time of diagnosis is not likely to be as useful as for high-risk and relapsed cancers.

KidsCanSeq will strive to answer questions such as how effective is a germline and tumor panel of approximately 150 to 200 genes at picking up hereditary genetic factors and tumor-specific actionable information compared with larger scale tests, like whole exome sequencing, which evaluates thousands of genes. Specifically, the study will compare the targeted cancer panel to whole exome sequencing of a blood sample of all enrolled childhood cancer patients to find hereditary factors and to whole exome sequencing, transcriptome sequencing and copy number array of tumor samples for the subset of patients with high-risk or relapsed tumors to find mutations that might guide treatment. This comprehensive set of genomic tests will be performed by a unique collaboration between multiple diagnostic facilities with the involvement of Dr. Richard Gibbs, director of the Human Genome Sequencing Center, Drs. Christine Eng and Shashikant Kulkarni, professors of molecular and human genetics, all of Baylor, and Dr. Angshumoy Roy, assistant professor of pathology & immunology at Baylor and Texas Childrens Hospital.

The program, in which about 900 patients are expected to be enrolled over four years, also will include parent and doctor surveys to determine what they found most useful from the testing as well as the development of video and other educational materials in both English and Spanish. Understanding differences among families from different ethnic or racial backgrounds as well as in different healthcare settings, including large academic medical centers versus smaller clinical settings, also is a goal of KidsCanSeq.

Dr. Amy McGuire, Leon Jaworski Professor of Biomedical Ethics and director of the Center for Medical Ethics and Health Policy at Baylor, also is co-principal investigator of the study. She will investigate the ethics and utility of genomic testing for pediatric cancer patients.

It is important to study the clinical and psychosocial risks and benefits of any new technology in order to plan for its responsible use, McGuire said. We also want to make sure the infrastructure is in place so that oncologists in non-academic settings can understand, effectively communicate and appropriately manage the results of germline and tumor whole exome sequencing.

Specific aims of the KidsCanSeq study include:

Assess the clinical utility of large-scale genomic testing by measuring the frequency of diagnostic and/or actionable germline (blood) and tumor findings and the effect on treatment decisions Compare uptake by first-degree relatives for familial genetic testing and recommended cancer surveillance by race, ethnicity and clinical settings. Describe perceived utility of large scale testing by surveying and interviewing parents and participating pediatric oncologists. Work with pediatric cancer stakeholders, including advocates, BASIC3 study parents and national organizations, to create and evaluate the use of culturally sensitive educational materials, including videos in English and Spanish, improved integrated genomic test reports and counseling materials, and compare in-person versus telemedicine exome results disclosure. Provide data to guide future application of clinical genomics through three innovative pilot projects focused on health economics, decision support for cancer surveillance and whole genome sequencing.

Drs. Plon, Parsons and McGuire all are members of the NCI-designated Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine.

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Grant to compare large-scale genomic sequencing, standard clinical tests for childhood cancer patients - Baylor College of Medicine News (press...

The ACMG Foundation for Genetic and Genomic Medicine announced Aug. 4 that Indian American Madhuri Hegde of Waltham, Mass.-based PerkinElmer Inc. was elected to its board of directors.

"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 Dr. Bruce R. Korf, president of the ACMG Foundation, in a statement.

Hegde, who will serve a two-year renewable term, joined PerkinElmer in 2016 as vice president and chief scientific officer of global genetics laboratory services. She is also an adjunct professor of human genetics in Emory Universitys human genetics department.

Previously, Hegde served as the executive director and chief scientific officer at Emory Genetics Laboratory in Atlanta, Ga.; professor of human genetics and pediatrics at Emory University; and assistant professor at Baylor College of Medicines Department of Human Genetics in Houston, Texas.

Additionally, Hegde has served on a number of scientific advisory boards for patient advocacy groups including Parent Project Muscular Dystrophy, Congenital Muscular Dystrophy and the Neuromuscular Disease Foundation.

She earned her doctorate from the University of Auckland in Auckland, New Zealand, and completed her postdoctoral fellowship in molecular genetics at Baylor College of Medicine. She also holds a masters from the University of Mumbai in India.

The foundation, a national nonprofit dedicated to facilitating the integration of genetics and genomics into medical practice, is the supporting educational foundation of the American College of Medical Genetics and Genomics.

Board members are active participants in serving as advocates for the foundation and for advancing its policies and programs.

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Madhuri Hegde Elected to ACMG Foundation for Genetic, Genomic Medicine Board - India West

It appears, by all accounts, to be a momentous scientific achievement and possibly a turning point in human evolution. In a study released last week, scientists at Oregon Health and Science University confirmed they were able to modify genes in viable human embryos, proving the potential to permanently alter the makeup of a genetic line.

In this case, that meant replacing and repairing a mutated gene that causes a common and deadly heart disorder. But the possibilities heralded by gene-editing technology are endless, the scenarios as divided as they are bold. In some visions, it leads to a population of designer babies or consumer eugenics. Others imagine a utopia of scientific advancement where humans live free of disease, and devastating conditions are eradicated for the betterment of humanity. What direction the technology will take is the topic of much debate.

The big thing which is making the scientific and ethics community get excited, and on the other hand a little bit hot and bothered, is its a mechanism to change genes for multiple generations, says Dr. Alice Virani, a genetic counsellor and director of ethics at British Columbias Provincial Health Services Authority. There are two ways to look at it, the more realistic ramifications and the sci-fi, if-this-was-out-of-control ramifications.

Opinion: Gene editing is not about designer babies

The team at the Oregon universitys Center for Embryonic Cell and Gene Therapy used technology called CRISPR, or Clustered Regularly Interspaced Short Palindromic Repeats, to repair or edit the gene carrying the heart disorder, seemingly with greater success than previous attempts by scientists in China.

News of the research has been anxiously anticipated by many in the field, both for what it means for the potential eradication of a disease such as hypertrophic cardiomyopathy and for the fundamental questions it raises about human reproduction, health and society.

When the study was leaked days before its publication in the journal Nature, its lead scientist, Dr. Shoukhrat Mitalipov, attributed the release to likely a combination of hot words: CRISPR, gene-editing, and designer babies.

The study and its combination of hot words didnt disappoint.

The New York Times hailed the milestone in research, while The New York Post cried BABE NEW WORLD and described an amazing and slightly terrifying breakthrough. A headline on Vox declared simply, This Is Huge.

Even actor Ashton Kutcher tweeted enthusiastically about the scientific breakthrough, writing: Scientists successfully used CRISPR to fix a mutation that causes disease. This is why I wanted to be a geneticist!

The tweet ignited among his followers the same range of responses that are always so keenly tied to the issue of changing human genes, from hope that devastating conditions such as muscular dystrophy will be eradicated, to fear about the unknown consequences of playing God.

Dr. Timothy Caulfield, a Canada Research Chair in Health Law and Policy and professor at the University of Alberta, says the polarized and dramatic response he has seen in recent days reminds him of early reaction to stem-cell science, where, he says, It was either going to be cloned armies, or we were going to eradicate all disease.

In fact, neither has turned out to be the case, and so it may be with gene editing as well.

We need to be cautious not to hype the benefits and be cautious not to hype the ethical concerns, he says. There are real issues on both sides of the debate but lets make sure our discourse is evidence-formed.

He described the new research as a genuinely exciting area, and said the potential of CRISPR which is used not only in human genetics, but also has potentially revolutionary applications for agriculture, animals, plants and food has introduced both exciting possibilities and reasons for deep policy reflection.

Erika Kleiderman, a lawyer and academic whose work focuses on gene-editing technologies, stem-cell research and regenerative medicine at the Centre of Genomics and Policy at McGill University, says the Oregon teams research is exciting because it confirms the ability of CRISPR technology to repair genetic mutations, and establishes the basic safety of the technique in a research context. And while she said people often go straight to thinking about the potential for manipulating genes to create so-called designer babies, a concept that is cool but also quite frightening, the medical implications could be equally staggering, and are far more likely.

For example, something like Huntington disease, she says. Being able to prevent that or treat that one day, in my opinion, would be a fantastic leap for our scientific knowledge and medical advancement. That being said, people will raise the eugenics argument. Is that a possibility? Yes. Are we close to that? I dont think so.

Canada has strict laws around genetic modification and editing, and altering genes in a way that could be passed on to future generations is a criminal offence under the Assisted Human Reproduction Act, punishable with fines up to $500,000 or 10 years in prison.

But as the technology takes a large step forward, Ms. Kleiderman and Dr. Caulfield and are among a group of Canadian scientists and academics calling for less regulation around genetic science and research in Canada, not more.

Both were involved in the creation of an editorial published in the journal Regenerative Medicine in January calling for new consideration of the issues and ethics involved in gene editing, and a revision of Canadian legal policy.

A criminal ban is a suboptimal policy tool for science as it is inflexible, stifles public debate, and hinders responsiveness to the evolving nature of science and societal attitudes, the editorial read. It was signed by seven other experts and ethicists, and came out of a think tank on the future of human gene editing in Canada held at McGill last summer.

Dr. Caulfield says legal prohibition of certain genetic research doesnt make sense when we dont yet know or understand where the science is going, or what the benefits or harms could be. Instead, he says he believes in regulation in problematic areas, while allowing for studies and trials. He says that some of the slippery slope scenarios people fear such as using genetic modification for human enhancement and to achieve superficial traits such as height remain distant possibilities given the complexity of the science.

That is not to say there are not risks or issues to be addressed as the technology continues to evolve. Ms. Kleiderman says that includes consideration of the potential risk to future generations, the safety of the technology and other irrevocable, if unintended, consequences, although she says those risks are not unique to gene modification but true of all technologies.

When it comes to CRISPR, one of the areas it would be most beneficial is with the treatment of prevention of disease which I think most people would be in agreement with, she says. Of course, we need to be mindful of doing not-so-positive things with it, like going down the enhancement route.

She said other potential issues, such as the preservation of human diversity and individuality, the welfare of children born from this technology and the potential for creating new forms of inequality, discrimination or societal conflict, all require significant consideration and research.

There is time. Although the technology is moving quickly, there is still a long way before gene editing is used in clinical human trials. Even after that, Dr. Virani says for the foreseeable future the technology will most likely be used by a small group of people in specific scenarios related to the prevention of serious genetic disease.

Im not saying we shouldnt be concerned about those potential issues, but sometimes we make that leap too quickly, she said. We dont necessarily [think] that the most likely scenario is that couples will use this technology on a very limited basis if they know their child may potentially have a devastating genetic condition. Thats not something that suddenly everyone is going to start to do. I think theres sometimes that leap to, Oh, we can create designer babies, but I think were very much in the lessening-burden-of-disease phase rather than the designer-baby phase, though thats where peoples minds go.

Dr. Virani said one of her own concerns is the possibility of off-target effects, where changing a gene unexpectedly alters something else in the genome. Other concerns are more social reality than science fiction, including that the technology and the ability to prevent disease may only be available to those who can pay for it. Eradicating a horrible disease is one thing. Eradicating it only for families who can afford it is another.

So is it going to look like just the wealthy are going to be able to afford this type of technology? she asks. Thats very problematic in my eyes from an ethics point of view, and thinking about fairness in society. If only poor people get Huntington disease, then the lobby to support Huntington disease research is greatly diminished. Its kind of like a two-fold negative effect.

On Thursday, the American Journal of Human Genetics ran a policy statement signed by 11 organizations from around the world, including the Canadian Association of Genetic Counsellors, urging a cautious but pro-active approach as the science moves forward. The statement includes an agreement that gene editing should not yet be performed in embryos carried on to human pregnancy. (The embryos used in the Oregon research were created only for the research, and were not developed further.) It also outlines a number of criteria that should be met before clinical trials take place, and supports public funding for the research. The U.S. government does not allow federal funding for genetic research on embryos. The Oregon research was funded by the university.

We dont want it to go speeding ahead, said Kelly Ormond, the lead author of the policy statement and a genetics professor at Stanford University in California. We want people to be very transparent about whats happening and we want things to undergo good ethics review, and for society to actually be engaged in these dialogues now while this research is just starting to happen.

She said she believes its important to be pro-active in talking and thinking about the issues related to the technology, and starting a broader conversation of how gene editing should and will be used.

We can all agree that that world [of eugenics and designer babies] doesnt feel very comfortable, and I think most of us dont want to go there, she said. So we need to find ways to prevent that from happening.

Follow Jana G. Pruden on Twitter: @jana_pruden

Link:
Modification of genes in human embryos could mark turning point in human evolution - The Globe and Mail

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