Monthly Archives: August 2017

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.

More:
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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See the original post here:
Fearing stigmatization, patient's father seeks retraction of paper on rare genetic mutation - Retraction Watch (blog)