A Monkey Circles in a Cage

Posted by Elliot Hosman, Biopolitical Times on January 29th, 2016

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Monkeys with Autism?

“…first ever nonhuman primates to show autism-like symptoms in the lab.”

On January 25, news broke widely in the press on research published in Nature by a team in Shanghai, who spent six years creating two generations of macaque monkeys engineered to have duplications of the MECP2 gene in their brains—a gene that researchers have associated with Rett Syndrome, a condition on the severe end of the human autism spectrum.

Trans-cranial Magnetic StimulationThe researchers listed a battery of behavioral tests which they claimed as evidence that the transgenic monkeys were now genetically predisposed to autism-associated behaviors. In a press briefing organized by Nature, Zilong Qiu, a leader of research at the Institute of Neuroscience at the Chinese Academy of Sciences, stated plans to leverage their research into human clinical trials down the line, with the aim of developing somatic gene therapies or non-invasive interventions like trans-cranial magnetic stimulation [Wiki] to correct autism in humans. Qiu stated the researchers are currently trying to identify the brain circuitry responsible for what they believe is the monkeys' changed, autism-like behavior; after that, they plan to use CRISPR-Cas9 gene editing to manipulate the MECP2 duplications in the transgenic monkeys they created.

With “autism,” “transgenic,” and “monkey” in the headlines, it’s not surprising that a flurry of media coverage might flatten the social and ethical implications of what’s at stake with using animals models to study stigmatized human behavioral conditions. One article was promoted on Twitter asFirst Monkeys with Autism are Sickly Loners Who Pace Their Cages.” Comments on that article included: “I have a child with autism and even I find what you are doing to these monkies [sic] repulsive. This is a sad commentary on science and our society.” …“I have a daughter with autism, and I find this to be very disturbing!!!” … “I'm autistic, but I don't need to be cured, thank you very much.”

The Limits of Animal Models in Studying Human Behavior

While unvalidated claims that vaccines cause autism are ongoing, scientists have been motivated for some time to clarify genetic bases for autism spectrum disorders. Some estimate that hundreds of genes are involved, many assert that environmental factors may also be at play, and many others assert that the majority of “disorders” classified as autism (and targeted by market-driven drug trials) are just points on the spectrum of human neurodiversity that we ought to be de-stigmatize and de-medicalize.

Most articles on the transgenic monkeys cited scientists who agree that cheaper, quicker mouse models have severe limitations in studying human behavior. Yet a number of reporters, or the scientists they quoted, pushed back on the claims of the study. David Cyranoski in Nature quoted stem cell and autism researcher Alysson Muotri, who stated that symptoms in mice and monkey animal models for autism are often “less severe than ‘what we actually observe in human patients… It remains to be seen if the model can actually generate novel insights into the human condition.’” James Cusack, research director at Autistica, told Ian Sample in the Guardian that “people with autism vary in a number of ways, and autism itself is linked to a number of other conditions. With this in mind, developing a single animal model of autism may be difficult to achieve.” A number of reporters also cited MECP2 pioneer Dr. Huda Zoghbi’s critiques of the study, including: (1) the monkeys did not exhibit behaviors associated with MECP2 duplication in humans like seizures and severe cognitive problems; (2) the monkeys’ circling behavior in their cages is a symptom not exhibited in human children with MECP2 duplications (perhaps the cage is relevant); and (3) the monkeys only carried MECP2 duplications in their neurons, not throughout the brain as in humans with Rett Syndrome.

The Ethics of Biomedical Research on Animals

Virginia Hughes in BuzzFeed discusses the pulse of clinical research moving from mice toward sentient non-human primates, linking to the recent debut of transgenic monkeys with a 2008 US study on the genetics of Huntington’s disease. The first transgenic monkeys made with CRISPR-Cas9 were reported by researchers in China in 2014. Hughes notes that research with non-human primates is “ethically fraught”; indeed the ethical pushback to genetic experimentation on monkeys and other animals is wide-ranging in recent news:

In just the last few months, this evidence shows a growing swath of concerns regarding animal research ethics that the biomedical sector will encounter as it moves forward with monetizing CRISPR gene editing and placing clinical applications in the research and development pipeline.

Previously on Biopolitical Times:

Image via Flickr/Vince O'Sullivan

Who's Looking to Profit from Human Germline Changes?

Posted by Pete Shanks on January 28th, 2016

Intrexon logo

The National Academies summit on human germline gene editing has dominated discussion over the last few months, with talk about international agreements and a voluntary moratorium or formal ban. But perhaps those of us concerned about the prospect have been looking in the wrong direction. Consider this scenario:

A multi-billionaire becomes fascinated by synthetic biology. He starts with a fairly small company, and decides to turn it into a big one without using venture capital. His goal is to make it "the Google of the life sciences." Among the acquisitions and partnerships he makes are:

  • a company developing personalized cell and gene therapies using iPS cells
  • an animal cloning company (both the agricultural and pet markets)
  • a biopharmaceutical company focused on cancer immunotherapies
  • a drug development and delivery company
  • a company that makes genetically modified fish (even before selling them was legal)
  • a company that makes sterile mosquitoes in order to effect permanent germline changes
  • a company that makes genetically modified apples
  • a company pushing hard into multiple IVF markets around the world, with
    • products not currently legal in the U.S., and
    • research into human egg precursors with the explicit intention of producing hundreds of eggs and possibly embryos — and the ambition of editing them

In short, lots of private money, deep connections with the pharmaceutical industry, a major focus on synthetic biology, a willingness to jump borders for legal convenience, a deep interest in reproductive technologies, and the clear intention to work on "enhancing" embryos.

That could turn into a nightmare. But it's real, and it's happening now.

The billionaire is Randal Kirk, the main company Intrexon, which cannily snagged the URL The iPS company is Fibrocell; the cloning one is Viagen (part of Trans Ova Genetics); the (disappointing so far) biopharmaceutical is Ziopharm; the drug company is Halozyme; the fish are AquAdvantage salmon made by AquaBounty; Oxitec makes the sterile mosquitoes; the Arctic® Apple was developed by Okanagan; and the IVF company is the extremely controversial OvaScience.

Kirk, a lawyer by training, made his first fortune ($65 million) with a medical supplies company; his first big one with New River Pharmaceuticals (he cleared $1.2 billion); his second with Clinical Data (roughly $600 million); and his third when he took Intrexon public in 2013 (his shares have been valued at $1.5 billion). He avoids outside venture capital, and held onto over 60% of Intrexon; the success of its IPO may have been largely because of his existing reputation.

Clearly Kirk bought Intrexon as a way into synthetic biology. Its founder, molecular geneticist Thomas Reed, positioned what was originally called Genomatix as a gene-tools or DNA-parts venture, but Kirk had much broader ambitions (yes, the Google quote was his, though he said it before Google became the Google of the life sciences). In a 2011 profile, Forbes also reported Kirk's prediction that:

in a decade it [Intrexon] could become "the largest, most significant company" in its burgeoning field.

He could be right.

Of course, he also might not. Indeed, Viagen was a spin-off from Genetic Savings and Clone (GSC), a pet cloning company that was set up by the billionaire John Sperling. GSC was finally abandoned, partly for technical and ethical reasons and above all because it was not commercially viable.

Intrexon and OvaScience

Last April, MIT Technology Review noted that OvaScience intended to "correct [harmful genetic] mutations before we generate your child," and Motley Fool pointed out the potential synergies between OvaScience and Intrexon, focused on a joint venture called OvaXon, described on the Intrexon website thus:

The joint venture looks to create new applications for improving human and animal health. Under the joint venture, OvaScience's EggPC platform will be combined with Intrexon's genome engineering capabilities with the goal of offering an innovative approach for the prevention of inherited diseases in humans, such as mitochondrial and other genetic disorders.

The technology behind OvaScience is scientifically controversial, ultimately based on the disputed discovery of "egg precursor cells" that "have the potential to develop into mature eggs, thereby replenishing a woman’s egg supply." Its main product at present is Augment, which "uses the energy-producing mitochondria from your own egg precursor (EggPC℠) cells … to supplement the existing mitochondria in your eggs" and thus supposedly improve fertility.

One of the founders of OvaScience told a stock analyst last spring that using CRISPR in germline engineering was not on the current agenda ("they have enough headaches at this point") but they do admit to being aware of the potential to use it that way.

The FDA will not allow Augment to be sold in the U.S. without clinical trials. However, it is sold in Canada, where the first baby was born after that treatment in May, 2015; and also in Japan, Turkey and Dubai. A British IVF clinic is applying for permission to use the procedure "in a pilot trial involving about 20 women."

Permission may not be granted in the UK — Robin Lovell-Badge, for one, is extremely skeptical — but the attempt illustrates the difficulty of establishing, let alone enforcing, international standards. The company is trying to pressure the FDA by creating consumer demand here with promotional stories from abroad.

Intrexon and its subsidiaries have other experience with transnational evasion techniques: AquaBounty was an American company, founded in Maynard, MA, and incorporated in Delaware, that set up in Canada to create eggs that would be grown in Panama. It nearly went bust until Kirk bought in.

Kirk is arguably "Biotech's Best Investor." He's clearly a technophile and definitely thinks that synthetic biology is the future — he's called his partner Reed "the Henry Ford of DNA" — but he does not seem to be primarily an ideologue; he wants to make another boatload of money.

So what's to stop Kirk and his companies and allies, or people like them, from developing a germline "enhancement" technology that they could introduce in, say, Dubai and promote everywhere else?

[This post was edited on January 30th to include Oxitec, previously omitted by mistake.]

Previously on Biopolitical Times:

Genetic Issues at the London Sperm Bank

Posted by George Estreich, Biopolitical Times guest contributor on January 22nd, 2016

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On December 29th, 2015, the Guardian reported that the London Sperm Bank is being investigated for discriminating against people with disabilities. The bank had turned away a man with dyslexia; it had published a 2010 pamphlet with a long list of disqualifying “neurological diseases,” including dyslexia, autism, ADHD, and other conditions.

Vanessa Smith—described as a “quality manager at the JD Healthcare Group,” the bank’s parent organization—defended the bank. Backpedaling without budging an inch, she said that the pamphlet had been withdrawn and policies would be reviewed. Still, little seems likely to change. According to Smith, “We are looking for someone who is medically clear of infectious diseases and genetic issues that may possibly be passed on to any resulting child.” She also claimed, “We definitely don’t work in eugenics.” She may mean something like, “In the popular mind, ‘eugenics’ is associated with Nazis, an association we wish to avoid.” But to shape future children, based on a policy that describes human variation as disease, is by definition eugenic. The bank’s currency is genes, and it wants good ones.

Smith’s grouping of “infectious diseases” with “genetic issues” is significant. Both are disqualifiers: in the view of the London Sperm Bank, they make the sperm unsuitable to produce a future human being. In the Guardian article, people with dyslexia were quoted, questioning the Bank’s criteria. My interest is less in the specific items on the list, or in the need for one—of course a prospective mother would prefer to have a child free of, say, hepatitis-C—than in the neutral, euphemistic vagueness of the phrase genetic issues, and the way it tends to pathologize human variation. (When I think of our rapidly increasing, fine-grained knowledge of human genetic variation, and the pressures that turn said variations into Issues, I imagine the pans of a giant balance. On one side is the gigantic and growing pile of genomic data, and on the other side is an equally gigantic but correspondingly undifferentiated idea, a blobby sense of abnormality stuffed into a neutral-sounding word, like issues. Even as we generate specificity, we generate vagueness, ideas and words capacious enough to suggest all that is different from an undefined norm, and therefore undesirable.)

Specifics imply caring. To lump together a vast array of conditions as “genetic issues” suggests an unconcern about the radical differences between said conditions, and a lack of interest in exploring the question. (Of course, the ability to predict and select makes precisely those explorations necessary.) Conversely, the pamphlet is obsessively specific about Different Brains, even to the point of redundancy: forbidden are ADD and ADHD, autism and Asperger’s (yes, a special Not Welcome Mat is spread out for you, high-functioning Different Person), and both “mental retardation” and Down syndrome. Since men with Down syndrome are thought to be sterile, the prohibition seems—well, let’s just say it’s on the cautious side.

Disease and disability are different but overlapping categories. There is no tidy division between them. But the (evolving) criteria of the London Sperm Bank pathologize pretty much everything not nailed down. Autism is not a disease. Neither is dyslexia. Neither are unambiguously genetic, in the way that Tay-Sachs or Down syndrome is. Cerebral palsy can occur without genetic influence at all. But since these conditions may have a significant genetic component, they’re on the list. This is the one-drop rule for the new millennium: any hint of a disorder that may or may not be genetic is, in this scenario, sufficient to disqualify its bearer. The London Sperm Bank’s approach to human difference can be thought of in terms of Russian nesting dolls: inside Difference is Medicalization, which opens to reveal Geneticization.

We are always thinking/not thinking about disability, it is always just beneath the surface of our days and discussions, and I am interested in the places where our ideas break into the open. Discussions of future humans provide one place: they are virtual arenas of the normal and abnormal, where our assumptions bubble up to the surface. Because we seem to be discussing only the prospect of dyslexia or mental illness, and not specific people with those conditions, no actual person appears to be directly harmed. We are only discussing an A vs. B scenario, one where A (a future human without dyslexia) appears clearly preferable, the better choice. All other things being equal, that is.

This is flawed for several reasons, the first being that all things are never equal; the second being that we are talking about present people with dyslexia when we imply dyslexia is serious enough to disqualify a future person; and the third being that actual people with different brains are being discriminated against in the present: in the minor way of not being allowed to donate to a specific sperm bank, and in the major way of being publicly described as lesser humans, as unwelcome.

George Estreich received his M.F.A. in poetry from Cornell University. His first book, a collection of poems entitled Textbook Illustrations of the Human Body, won the Gorsline Prize from Cloudbank Books. His memoir about raising a daughter with Down syndrome, The Shape of the Eye, was published in SMU Press’ Medical Humanities Series. Praised by Abraham Verghese as “a poignant, beautifully written, and intensely moving memoir,” The Shape of the Eye was awarded the 2012 Oregon Book Award in Creative Nonfiction. Estreich lives in Oregon with his family.

Previously on Biopolitical Times:

Image via Pixabay

Why Is Editas Going Public?

Posted by Pete Shanks on January 14th, 2016

Editas logo

Editas, the gene-editing company founded by several of the scientists who developed CRISPR technology, announced on January 4th that it had filed preliminary paperwork for a public offering of stock. The filing with the Securities and Exchange Commission is extremely long, but lacks certain vital details, For instance, some clearly unanswered questions are:

  • How much cash does Editas hope to raise? There is a placeholder number of $100 million, but that is very likely to change dramatically.
  • When will this take place? "As soon as practicable after this Registration Statement is declared effective."
  • Will anyone be cashing in? "A significant portion of our total outstanding shares is restricted from immediate resale but may be sold into the market in the near future."

The Economist response seems acute:

As difficult sales pitches go, this one is hard to beat. This biotech company has burned through $75m in the past few years and has not yet started clinical work on a drug candidate. It says it will be many years, "if ever", before it has something ready to commercialise. If this were not enough, not only is there a thorny patent thicket to manage but the firm must fight and win a case seeking to overturn its own intellectual-property claims on the ground that it was not the first to invent them.

The prospectus does include some new information, including the gossipy history that the company was originally incorporated as Gengine. (Gene-engine? Could we have been spared the whole "editing" metaphor? Probably not.) There is certainly more detail about its product plans and, if you can read the tables correctly, current shareholders, the largest of which, per Xconomy's summary, are all venture capital funds:

16.6%   Flagship Ventures
15.6%   Third Rock Ventures
15.6%   Polaris Venture Partners
  9%      Bng0 (a Bill Gates-affiliated fund)
  5.7%   Viking Global
  5.7%   Fidelity
  5.7%   Deerfield
  4.8%   CEO Katrine Bosley

The prospectus confirms that Editas hopes to begin clinical trials on a therapy for Leber congenital amaurosis in 2017. That disease, which affects 2–3 per 100,000 newborns, is listed by NIH as being associated with at least 14 genes. Mutations in CEP290 (the Editas target, also known as LCA10) account for 15–22% of cases.

Being able to claim that the blind shall see is of course a great selling point, but even if the proposed treatment works, no price has been set for it. (Spark Therapeutics, which may be a competitor, has in the pipeline at least one gene therapy product for LCA blindness that seems likely to cost $500,000 per eye.)  Presumably this is more of a proof of concept for Editas than a big moneymaker.

Editas is not the only gene-editing firm considering raising money on the stock market. Intellia, one of the companies founded by Jennifer Doudna, co-author of the first published paper on the technology, has been rumored to be "IPO-ready." CRISPR Therapeutics, founded by Doudna's co-author Emmanuelle Charpentier, is at least considering one, according to CEO Rodger Novak, who noted wryly that

Coming late to this party is not very smart.

Meanwhile, the patent wars are coming to a head. In headline terms, that's a fight between Feng Zhang of Editas on one side, and Doudna (and Charpentier) on the other. Doudna was also a co-founder of Editas, along with Zhang, George Church and others, but withdrew when the patent dispute arose. The Patent Office has officially declared an "interference" and Doudna seems to be a slight favorite at present. (UC Berkeley is favored over the Broad Institute and MIT.) Both sides have stated that the technology will be freely available to researchers, but commercial licenses could be very, very lucrative. When this all ends is unclear.

The business of business is, of course, business, and far be it for those not expert in such matters to criticize decisions about going public. But Editas is said to have at least two years' cash on hand, and the current investors might even snap up the shares on offer.

So why now? Is this all about striking while the publicity is hot?

Previously on Biopolitical Times:

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