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Are All Pluripotent Stem Cells Equal?

Posted by Pete Shanks on November 12th, 2014


Research cloning of humans has always been controversial, because the technology (if ever perfected) would require women’s eggs — many, many eggs if it led to therapies — and would certainly make human reproductive cloning technically more feasible. There were therefore sighs of relief when Shinya Yamanaka discovered how to reprogram readily available somatic cells to become pluripotent, for which he won a Nobel Prize.

Induced pluripotent stem cells (iPSCs) were such an exciting development that many people thought that there was no longer any point in pursuing research cloning, or generating pluripotent embryonic stem cells via nuclear transfer (NT-ESCs). After all, it hadn’t been done after years of trying. But not everyone agreed.

Last year, a team at Oregon State led by Shoukhrat Mitalipov did report success in generating NT-ESCs, and in 2014 two other teams duplicated the result: one led by Dieter Egli’s team at the New York Stem Cell Foundation, the other a collaboration between the Korean Cha Institute and Advanced Cell Technology.

The stakes were raised further when a consortium (including Mitalipov’s team) published a paper in Nature in July that claimed that NT-ESCs were clearly better than iPSCs. Comparing both with stem cells derived from standard IVF embryos, this paper asserted that the iPSCs had flaws, whereas:

human somatic cells can be faithfully reprogrammed to pluripotency by SCNT [somatic cell nuclear transfer] and are therefore ideal for cell replacement therapies.

Not so fast.

A new study led by Dieter Egli’s team (but again including Mitalipov) was just published in Cellcomparing NT-ESCs and iPSCs:

The two cell types showed similar genome-wide gene expression and DNA methylation profiles. … The occurrence of these genetic and epigenetic defects in both NT-ESCs and iPSCs suggests that they are inherent to reprogramming, regardless of derivation approach.

This is particularly noteworthy, coming as it does from people who have been promoting and working on SCNT for many years.

For more detailed analysis, see the Stem Cell Blog of UC Davis professor Paul Knoepfler. He makes the strong point that, given the ethical and practical problems with cloning, NT-ESCs really would have to be significantly better than iPSCs to be worth pursuing — and the new research suggests that they are not.

Nevertheless, all the scientists involved advocate pursuing all lines of research, specifically including nuclear transfer, even though they oppose using it for human reproduction. Which provides further support for the longstanding argument that, at a minimum, the United States needs a firm, specific, national law banning human reproductive cloning.

Previously on Biopolitical Times:





Open-Source DNA

Posted by Jessica Cussins on October 31st, 2014


Prometheus Brings Fire by Heinrich Friedrich Füger

Untitled Document

About a year ago, Steven Brenner posed this question in Nature,

How long will it be until an idealistic and technically literate researcher deliberately releases genome and trait information publicly in the name of open science?

We now seem to be well on our way.

For just $5 and your acknowledgement of the fact that DNA variations offer limited information (so you really ought to discuss the findings with a doctor or genetic counselor), an online venture called Promethease will provide you with the full explanation of your 23andMe health data in just 15 minutes, FDA be damned.

Promethease acknowledges that “For now, consumers have to fend for themselves in a thicket of scientific information—and make their own decisions about risks.” Apparently, people are happy to do so; the site averages 50-500 reports each day. But the trend to gain access to genetic data isn’t merely coming from “consumers” curious about their own data; it’s also coming from researchers and companies looking to greatly expand their databases to find statistically relevant genetic variants.

Many trait-affecting alleles can only be identified by analyzing huge amounts of data, because each one has a tiny effect. For instance, some 697 variants have been identified that are linked to height, but they are only thought to represent an estimated "16% of the genetic contributors to height.” Other researchers are trying to find genes affecting intelligence (one-twentieth the influence found with height), as well as rare mutations leading to or preventing diseases (hopefully to fare better.)

For example, the Haplotype Reference Consortium was unveiled in San Diego last week at the annual meeting of the American Society of Human Genetics. The consortium includes data collected by 23 other research collaborations and has identified 50 million genetic variants in two years.

While anyone can make use of their haplotype reference panel to expand upon their own data, the Exome Aggregation Consortium, unveiled on the same day, goes even further. This resource has made the entire exome sequencing data of 61,486 unrelated individuals, from “a variety of large-scale sequencing projects,” available to anyone “for the benefit of the wider biomedical community.”

Harvard biologist and prolific blogger Daniel MacArthur’s tweet about the announcement received over 100 “retweets” and was “favorited” nearly as many times. In the comments, people referred to the consortium as a “beautiful resource” that is “simply a game changer.”

Another effort, the Personal Genome Project (PGP) has been leading the charge to develop an open source database of genetic information for years, though their model is on the far end of the spectrum. Every participant not only volunteers their genetic data to the entire world, but their date of birth, gender, weight, height, blood type, race, list of health conditions, medications, allergies, zip code, other family members enrolled, answers to surveys, and even whether they can carry a tune. The fact that one’s full name is omitted is really only a formality, since anyone who wanted to know could easily find it out.

Another critical player in this trend is the Global Alliance. In just over a year, the alliance has expanded to include more than 170 organizational members in a “public-private partnership” representing over 25 nations. Their stated goal is to “unlock the great potential of genomic data,” by sharing all of their data and making “comparisons across millions of human genome sequences.”

Importantly, the trend to “free the data” is a significant antidote to Myriad’s “trade secrets,” but huge challenges remain.

The Personal Genome Project does a pretty good job of outlining the risks involved with sharing your genetic data with the world in its consent form. These include the acknowledgement that you are foregoing privacy, and the acceptance that this means your data could be used as a barrier for you or your family to obtain employment, insurance or financial services; to implicate you or your family in criminal activity; or even to make synthetic DNA based on your genome and plant it at a crime scene to frame you or your family.

But while those who send their sequence to the PGP explicitly consent to these risks, the merging of research databases presents a critically different reality. According to New York Times writer Gina Kolata, “There are no common procedures for assuring that patients consent to sharing their information.” The initiatives have simply moved forward anyway. While some people are pleased to share all of their personal and health information, obviously not everyone is privileged enough to afford that luxury.

Furthermore, with all the talk about “the greater good,” it can be easy to overlook the fact that this information is poised to become really big business. When all of these noble efforts to promote open-access lead to the creation of drugs, tests, and treatments – these findings will be patented, and the wealth that flows from them is unlikely to be quite so “open.”

Previously on Biopolitical Times:





What Good is a Scientific Meeting If You Dismiss the Science?

Posted by Jessica Cussins on October 29th, 2014


Untitled Document

I want to be wrong about this.

Based on the evidence hearing held by the UK Parliament’s Science and Technology Committee last week, it is apparent that there is ample enthusiasm among many in Parliament for changing the UK law against human germline modification to allow what’s called “mitochondrial donation” into fertility clinics. The technique would combine genetic material from two women and one man into a single embryo.

Perhaps naively, I am still shocked by the hubris of some proponents of this technique. I really thought that mounting evidence of the risks to resulting children would encourage more people to question the advisability of this path.

But if the upcoming Parliamentary vote isn’t informed by a more realistic approach, it seems likely that women will be offered this technique by their fertility specialists as early as next year, making the UK the only nation in the world to explicitly allow a form of human inheritable genetic modification. Importantly, this would not be attempted as a closely controlled clinical trial, but in the open market of the fertility industry (with guidance from the HFEA, but no required follow-up).

I sincerely hope that any children born via this technique do not have to pay the price for our desires and curiosity. To reiterate, I really want to be wrong about this. But unlike many at this “evidence hearing,” I cannot so easily dismiss the evidence.

Dr. Edward Morrow, an evolutionary biologist at the University of Sussex, was the sole panelist out of nine to raise a single concern about the state of the science. Dr. Morrow is hardly alone in his concerns; numerous scientists, fertility specialists (pg. 36), and public health advocates have questioned the safety and efficacy of these techniques. But Morrow’s fellow panelists were remarkably unmoved.

Every concern that was raised – either from Morrow or as a question from others in the room – was dismissed as a “theoretical concern.” This worked rhetorically to marginalize those urging caution, and to make the proponents the keepers of the “practical reality” of the matter. But the possible benefits of this technique are no less theoretical than the possible risks.

In fact, if you stack the evidence side by side, the chance that “mitochondrial donation” will actually lead to a healthy child seems like the greater leap of imagination.

Since the hearing at which he was effectively sidelined, Morrow has taken the trouble to enumerate some of the evidence for us. He has compiled numerous papers that highlight problems that can occur from mito-nuclear mismatch here. He has also provided a link to a new meta-analysis in the Journal of Evolutionary Biology that reviews 66 publications showing evidence of significant effects on a variety of traits from the interaction of the nucleus and the cytoplasm (which includes the mitochondria). What this all suggests is that if even a single one of the complex interactions that occur continuously between the nucleus and mitochondria are disrupted by “mitochondrial donation,” it could lead to a range of adverse outcomes in a resulting child.

At the hearing, Morrow’s claims were dismissed as being irrelevant to humans because they took place in inbred animal tests. But as Morrow pointed out, that is only the case in one of the studies reported above. Furthermore, there is all of the following additional evidence of possible health risks for resulting children, though they got no real attention at the meeting:

  • When pronuclear transfer was attempted in macaques, researchers couldn’t get a single embryo to implant; moreover, human embryos have been shown to be more sensitive to manipulations than macaque embryos
  • Even a tiny amount of carryover mutated mitochondria can lead to disease if preferentially replicated
  • Epigenetic harm can be caused by the removal and reinsertion of a nucleus from one egg or embryo into another
  • The reagents used could pose risks of toxicity to any resulting child

In addition to dismissing all this evidence, proponents relied on another move: they repeatedly downplayed the novelty of what is at stake.

Doug Turnbull, Director of the Wellcome Trust Centre for Mitochondrial Research, said that mismatches between nucleus and mitochondria can be compared to what happens naturally after multiple generations of not breeding with our cousins. Similarly, he insisted that the fact that there is no greater rate of disease among mixed-race babies tells us that this technique will be safe.

This kind of argument often pops up when new technologies are being promoted… Don’t worry! We’ve been doing (basically) this for forever! But at least in this case, the reassurance just isn’t based in reality. There is obviously a desire to placate a nervous public, but mixing DNA from three people into a single embryo is not the same as having a child with someone from a different ethnicity than you, and frankly, the notion that it could be is insensitive and insulting.

The patronizing effort to appease an “irrational,” “fearful” public extended to the HFEA’s Orwellian redefinition of genetic modification to specifically exclude mitochondrial manipulation techniques. The growing body of evidence that mitochondria impact traits means that despite the insistence of UK Chief Medical Officer Dame Sally Davies, this re-definition is neither “based on science” nor “reasonable.”  Morrow has a great post on this point here.

One participant at last week’s hearing asked about the fact that the UK would be going against international law if it moves ahead with this, pointing to international treaties stating that germline modification is incompatible with human dignity. Conservative MP Jane Ellison’s response avoided the question altogether. Rather than admitting to any concern about the UK becoming an outlier, she stressed that she is “extremely proud” that Britain is a “pathfinder” and “innovator” in this respect, and happily referred multiple times to the country’s “well-respected regulatory regime.”

The effort to change UK law in order to permit this biologically extreme procedure has been in the works for more than six years. There have certainly been a lot of documents, meetings and consultations. But I can’t help but wonder the same thing as Morrow:

Advances in genomic medicine are thrilling. I look forward to improved gene therapy treatments for consenting individuals who are currently suffering from diseases. But the deliberate creation of a new human being through an experimental technique that puts the most fundamental mechanisms of human biology at jeopardy is an entirely different calculus. Who will be responsible if this doesn’t work out?

Untitled Document Previously on Biopolitical Times:





Why We Should Teach the History of Eugenics

Posted by Jonathan Chernoguz on October 28th, 2014


Source: Miles Cole

This month, New York University and University College London have both launched initiatives to focus on the history of eugenics. Students and faculty at UCL hosted an event to encourage their institution to face up to its complicity in constructing unjust racial hierarchy through its support of Francis Galton’s research on eugenics. At NYU, a new exhibit, “Haunted Files: The Eugenics Record Office,” opened at the university’s Asian/Pacific/American Institute.   

At both universities, these initiatives acknowledge that advances in modern genetic technologies make education about the history of eugenics increasingly important.   

Galton’s legacy at UCL is extensive. It began 110 years ago this month, when he contributed funds to establish a position there for a “research fellow” in “National Eugenics,” which he defined as “the study of the agencies under social control that may improve or impair the racial qualities of future generations either physically or mentally.”   

The NYU exhibit brings to life the physical offices and paper archives of Cold Spring Harbor Laboratory on Long Island, the center of the eugenics movement in the United States between 1910 and 1939. According to The New York Times, the exhibit’s curators relied heavily on Cold Spring Harbor’s online Image Archive on the American Eugenics Movement:

David Micklos, executive director of the laboratory’s DNA Learning Center, applied for a government grant to scan files from the office and display them in an online archive, which opened in 2000. “It was a hidden part of American scientific history — people didn’t like to talk about it,” said Mr. Micklos, who added that he was inspired by ethical concerns surrounding the Human Genome Project.

Other educational projects have also aimed to bring to light the history of twentieth-century eugenics. An ambitious online effort called Living Archives on Eugenics in Western Canada, “directly engages communities in developing accessible resources to bring to light the history of eugenics in Canada.” Two public events have been co-organized by the Center for Genetics and Society – Future Past: Disability, Eugenics, and Brave New Worlds in 2013 and Eugenics in California: A Legacy of the Past? in 2012. The motivations behind these efforts included concerns about misuses of new and emerging genetic technologies.

Many educational institutions still avoid discussing the history of eugenics, and many are reluctant to confront their own complicity in the abuses it facilitated. But studying eugenics in the twentieth century is important not just as a matter of learning history, but as part of what we need to know in order to thoughtfully consider the responsible uses of genetic technologies today. 






 


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