New chat with George Church on CRISPR’ing people, Zika, weapons, & more

George ChurchI talked last year about human genetic modification by CRISPR with George Church a year ago. Now we’ve followed up with a long chat on this topic going into much more detail and with questions on recent developments.

Each question is listed numerically and then there is a back and forth on that question with George and me before going on to the next question.

Frameworks for managing human genetic modification

1. Paul: What do you think of my ABCD plan for handling human germline genetic modification? Would you add or remove anything from it or change it? What would your plan be?

George: *1* Your plan seems similar to mine – possibly less strict, since yours only affects embryos, while I would also include restrictions on adults and children. Indeed, I feel that all aspects of the plan are already fully operational.  For all research involving human subjects, we must get:  Approval from IRB, Bioethics training (and pass a test),  Clarity: NIH requires free public access via Pubmed Central and we Don’t apply therapies to the general population without clinical trial data showing safety and efficacy.

Paul: Most scientists I’ve talked to don’t feel they’ve had much bioethics training and nearly none have had this level of involved discussions of human gene editing. Pubmed Central is great, but it takes months for pubs to appear there, this field is moving so fast and paywalls are up for many months in most cases. The other issue is that many countries including some doing quite a lot of CRISPR work have less of the ABC than we do here in the US, but I’m not sure what if anything could be done about that.

George: By “Most scientists” you hopefully don’t mean those approved for directing human subjects research, since they/we need to pass a fairly difficult training/testing protocol first. I’m not convinced that the ethics of gene editing are fundamentally different from the ethics of testing other medicines which are covered in those currently required tests. A bit faster than Pubmed Central is Biorxiv, but my point is that clarity is already mandated.   Do you have a specific country in mind with evidence of lax ABC?

Bioethics issues: get out of the way or a constructive role?

2. Paul: My letter “B” is bioethics consultation. How do you see that and what do you think of Steven Pinker’s “Get out of the way” idea for bioethics?

George: *2*  I was with Steve when he said this at the Atlanta BEINGS meeting 8-Apr-2015.  My feeling is that this was intentionally hypothetical.  Steve did not mention a specific person actually blocking research in any way beyond the normal mechanisms required by FDAs and IRBs and hence no reason to get out of the way.  Indeed, nearly all of us at that meeting were acting as bioethicists, and from my viewpoint, helping, not hurting, progress. 

Paul: I’ve also talked with Steve by email and maybe it was my reading between the lines, but I felt like he was trying to provoke more discussion, which is a good thing, but both in his essay and in my interview with him on my blog he was more absolute than most on stepping on the gas. It seems to me finding the right balance/speed to move forward on this kind of research is trickier than has sometimes been portrayed out there.

George: “Stepping on the gas”, in practice, means higher funding for more and better clinical trials. This should result in higher levels of safety.   Even with more gas you still need to satisfy the FDA.

A moratorium?

3. Paul: Is it prudent to use the word “moratorium” now on clinical use of CRISPR in humans or do you agree with the NAS human gene editing meeting in their closing statement in the sense that they consciously chose not to use the “M” word? As we’ve talked, even if there was a moratorium how would it be enforced and what could the penalties be? If it isn’t doable, what should we do?

George: *3*  I don’t see a problem with the word, but feel that it is redundant, since there is always a moratorium on using unapproved therapies.  For example, even though it is approved in Europe,  we cannot use Glybera gene therapy in the US — and there is no guarantee that we ever will.  It is worth noting that people use drugs illegally in the USA, but with significant legal consequences, when caught.

Paul: So if someone were to do germline human modification without FDA approval here in the US, should they be penalized and if so how?

George: If anyone distributes unapproved drugs in the US, they face the FDA Office of Criminal Investigations (OCI) and felony imprisonment. My impression is that the infraction has to also involve medical harm and/or fraud to get their attention.

A law on human modification coming?

Paul 4: Could Congress pass a law on human gene editing? If they did, how might that be harmful? I can imagine it overreaching an impeding even non-clinically focused CRISPR research.

George: *4* This seems very unlikely.  Even at the height of the G.W. Bush human embryonic stem cell restrictions (2001-2009), US laws only restricted use of government money, not private funds.  Indeed, Harvard and the state of California increased their hESC efforts by over $3 billion.  Since gene editing of sperm could actually reduce abortions, near future legislation might favor it, rather than discourage it (see *11*)

Paul: But what about that rider on the FY2016 federal budget that said the FDA could not even consider any requests related to human embryo modification? Do you think most efforts in this area would be privately funded?

George: About 75% of all clinical trials are paid for by companies (not the government) – so, yes, most sperm editing efforts will be privately funded — just like other therapies.

What could go wrong with CRISPR’ing people?

5. Paul: If someone were to use CRISPR in the near future to try to make a genetically modified person, what could go wrong? I can imagine off-target effects. There could be unexpected consequences even with perfect targeting. Other considerations?

George: *5* Gene editing is already used to make GM-persons (curing Leukemia and HIV-AIDS).  What could go wrong is that editing enzymes could hit off-target sites in a tumor suppressor gene, like TP53. The rate of such event for the current best practices seems to be undetectable (much less frequent than spontaneous mutations).  If by GM-persons, we limit our meaning to heritable DNA changes, then the most likely use would be changing deadly DNA variants into their common healthy versions.  This should be far safer than testing new drugs, which impact complex human systems in unknown ways. 

Paul: It seems like the experimental flow with a path toward germline human genetic modification eventually gets more complicated than with ordinary drug approval processes because at some stage one is going to literally have to produce a new human being to test if this will really be safe and effective in humans. This is unique in that the product of the experiment is a human being. If the experiment doesn’t go well, what does that mean for the person who was created? I suppose one could argue it is not so different than the risks of normal reproduction which aren’t that low, but the extra step of gene editing makes it feel different.

George: Many (and ideally all) therapies need to be tested for safety with respect to impact on germline or pregnancy. For each of these, we “literally have to produce a new human being to test if this will really be safe”. For example, thalidomide was aimed at anxiety, insomnia, gastritis, tension and nausea – and inadequately pregnancy-tested. Anti-cancer agents can affect the germline.   Gene therapy isn’t “unique” in this regard.

CRISPR as a basis for weapons & talking with national security?

6. Paul: Do you think Clapper was over the top on raising national security concerns about gene editing-based WMDs a couple weeks back? Even if that was over the top, could someone make a CRISPR weapon and do some harm even if not “mass destruction”.

George: *6* Not over-the-top.  His framing was “proliferation” and “dual use”.  Whenever you see a new technology which is very powerful and very inexpensive, then you really should raise a red flag as soon as possible.  My team made some of the first such warnings about CRISPR gene drives in 2014 (both accidental and intentional problems).  I don’t think it desirable to spell out the worst case scenarios, but a mild example of dual use could be gene drives  used to exponentially spread herbicide sensitivity DNA into invasive US weeds (white hat) or spread resistance (black hat). 

Paul: Have you been consulted with by the US government on these kinds of security issues? If you had, would you be allowed to tell me? Whether you have or not, what would you tell them?

Also, when I interviewed Harmit Malik on these topics, he pointed out the concern that the guide RNAs in gene drives, once out in the wild, could mutate and lead to targeting of new genomic domains and he also mentioned the possibility of horizontal transfer. Are you concerned about these too?

George: Yes, I am concerned about these and many other novel technologies. That is why a considerable amount of my time is dedicated to safety engineering and communication of risks. Yes, I have discussed this with many branches of the US government. A mutant gRNA would not create a gene drive because it would not be flanked by the correct homology regions. Horizontal transfer should be undetectably low for similar reasons. Physically contained lab “field” trials with and without artificially increased interspecies contact will be valuable components of rigorous testing.

Gene drive and possible gene spills

7. Paul: Are you more concerned about accidental release (what I called a “gene spill” on my blog) of a nuclease-powered gene drive out into the wild? Is it realistic to think a reverse gene drive could take care of that? I’m skeptical about such a clean up attempt.

George: *7* Yes.  We should be skeptical about any new technology until tested.   We have recently published experimental tests of gene drive reversal (DiCarlo JE, Chavez A, Dietz SL, Esvelt KM, Church GM Safeguarding CRISPR-Cas9 gene drives in yeast. Nat Biotechnol. 2015), which  showed very good efficiency.  We expect to do many more tests in many species.  Being prepared for both bioerror and bioterror seems prudent.

Paul: Regarding possible bioerror, which I also think is the more pressing concern at the moment at least, have there been or are there planned any meetings to hash out best practice guidelines for keeping gene drive organisms from escaping?

George: Yes meetings are planned, for example in Oahu IUCN Forum (Sep-2016). Some of this is also being done via internet and journals (e.g.  Safeguarding gene drive experiments in the laboratory. Science 2015).

Targeting Zika, extincting all mosquitoes?

8. Paul: Also regarding gene drives, some have said it is time to wipe out Zika transmitting mosquitos or even all mosquitos on Earth. Thoughts?

George: *8* GM-mosquitoes are already approved and fully deployed in some countries to push down mosquito populations, for example, using the “sterile males” approach.  Unfortunately the mosquito population bounces back (due to strong darwinian selection working against the strategy).  My team has advocated “stable gene drives”, which make the vector (mosquito or rodent) resistant to the pathogen (Zika, Malaria, Lyme, Dengue) — that way having darwinian selection on our side (or at least neutral).  Before wiping out any species, a solid EPA assessment of impact would be required, as with other potential environmental releases.

Paul: With no disrespect to the EPA, are they up to the task of this assessment? I guess they have assessed GM plants for years, but this technology is so new and evolving. It seems like a tough task for anyone since it is unprecedented in what it would do.

George: Not just GM plants, but also GM salmon, mosquitoes, microbes, etc. and not just EPA, but USDA and FDA collaborating.   Some of these projects date back to 1985 and represent many years of research and dialog.  

Possible benefits of human genetic modification?

9. Paul: Realistically, what do you think are the most likely benefits of human genetic modification in the next 5 years? 10-20 years?

George: *9* Initially, mainly correcting disease-bearing genes into healthy versions (see *11*).  Secondly, eliminating viral infections in adult gene therapies (HBV, HCV, HIV).  If those prove safe and effective, then  those anti-viral therapies  might be repurposed for prevention.  Next in line are a few therapies that already look promising for delaying or partially overcoming cognitive decline due to Alzheimer’s disease or other aging processes.  Some of these could be repurposed for younger, healthier people.

Paul: How would genetic modification work for tackling neurological disorders like Alzheimer’s? Germline or gene therapy? Specific target alleles to go after?

George: PGD-IVF and prenatal screening are used to prevent adult onset diseases (HD and BRCA1). Genetic counseling or modification could similarly be used to prevent Alzheimer’s (APP, PSEN1, PSEN2). (Plus dozens of well-characterized genes impacting early onset intellectual disabilities). Gene therapy trials for Alzheimer’s include NGF, NEU1, NGFR and miR-29b. In addition, simple genetic modifications in mice can significantly enhance performance on cognitive tasks, involving genes like FOXP2, PDE4B, GRIN2B. Clearly, synthetic biology is not limited by disappointing GWAS studies on cognition. Many additional genetic modifications (at all stages of development and aging) impacting cognitive enhancement and prevention of cognitive decline could move into this gene therapy pipeline in the near future.

How accurate does it need to be?

10. Paul: With these benefits in mind, we’ve also talked about how accurate CRISPR type approaches would have to be for us to be OK pulling the trigger to try germline modifications to try to make positive outcomes. I’m not sure how accurate it would have to be. What do you think? How do we even measure this accurately

George: *10* Gene editing off-target error rates are already far below background.  In contrast, flying in a jet or taking chemotherapy is far above normal mutational background.  We measure such toxicity issues in clinical trials — as is already happening (see *5* above). 

Paul: Does that mean you are comfortable with the current error rate as being tolerable?

George: Yes the current off-target rates are much better than tolerable (given current software, Cas9 improvements and empirical testing).

Targeting germ cells instead of embryos

11. Paul: We’ve all heard a lot of talk about “CRISPR’ing human embryos”, but wouldn’t it make more sense to gene edit human germ cells such as spermatogonial and oogonial stem cells or even primordial germ cells? Then you could screen potentially millions of those for the best ones in terms of accurate gene editing.

George: *11*  Yes. I pointed out the potential advantages of sperm over embryos in my 1-Dec-2015 presentation at the NAS gene editing meeting and my 25-Feb-2016 piece in the Washington Post. The main reason for sperm editing maybe providing non-abortion options for getting healthy babies when both mother and father are unaffected carriers of very serious genetic diseases like Tay-Sachs.  But you should not need to screen “millions” of spermatogonial stem cell clones, since on & off target errors are so minimal, you probably only need to screen five clones.  Indeed, we demonstrated this in Yang L, Grishin D, Zhang CZ, Wang G, Homsy J, Cai X, Zhao Y, Fan JB, Seidman C, Seidman J, Pu W, Church G Targeted and genome-wide sequencing reveal single nucleotide variations impacting specificity of Cas9 in human stem cells. Nature Comm. 2014.

Paul: Should we do further analysis though such as functional studies of the targeted cells? Could the cells be immunogenic due to the transient presence of Cas9, a bacterial protein? What about having a perfect edit with no off target effects but an unintended consequence such as hitting a transcriptional regulatory elements for a different gene? In other words, are there other risks to consider that don’t make it onto most people’s radar screens beyond off-target effects?

Do you think this could end up in 5-10 years being primarily implemented via existing fertility clinics?

George: Yes; functional studies should be part of clinical trials. The Cas9 protein would be degraded (and hence non-immunogenic) well before the clones are used. Off-target regulatory effects seem even less likely than off-target cutting, and relatively easy RNA analyses can be done on the clones to test this. Yes; probably implemented via existing fertility clinics.

Mitochondrial transfer/3-person IVF

12. Paul: Can you please weigh in on mitochondrial transfer/3-person IVF? Some claim it isn’t a form of human genetic modification even though there are dozens of mitochondrial genes.

George: *12* Mitochondrial gene transfer is germline gene therapy.  You could argue that it isn’t “modification” from the norm,  just a return to a healthy genome.  But if so, then the same could be said of gene editing of sperm from a disease version to the healthy DNA version.  

Paul: I agree. I guess the “norm” could be an issue though. What is the “norm” and are other genetic states “worse” or “better” than the norm?

George: For hundreds of deadly diseases the norm will be the non-deadly allele and these will probably be the main foci of clinical trials. The point is that germline vs soma is not a sensible dividing line.   Deadly vs normal alleles -or- safe vs unsafe therapies are more medically relevant discriminators.

Transhumanism and CRISPR

13. Paul: We’ve talked before about transhumanism and I asked you if you considered yourself a transhumanist. You said “yes”, but I may not have included all the subtleties that would have provided needed context. Can you please expound on that?  As we’ve emailed, you’ve also talked about how people are already in some senses transhumans. What do you mean?

George: *13* Yes. My 10-Mar-2015 email, mentioned my framing, surprisingly omitted from your blog and book. 

My definition of “transhuman” is someone whose culture is not comprehensible to ancestral humans (or indigenous peoples today).  Ancestral human archetypes would have great trouble understanding why we celebrate the recent gravity wave evidence supporting the 100 year old theory of general relativity.  They would scratch their heads why we have atomic clocks and GPS satellites so we can find our way home.  We have expanded our vision from a narrow optical band to the full spectrum from radio to gamma.  We can move faster than any other living species, indeed we can reach escape velocity from earth and then survive in the very cold vacuum of space.  If those characteristics (and hundreds more) don’t constitute transhumanism, then what would?  If you feel that the judge of transhumanism should not be fully ancient humans, but recent humans, then how do we ever reach transhuman? We may always be capable of comprehending the next technological increment.   If we do accept that we are transhuman already (with most of us asking for more), it doesn’t make sense to single one person (me) out in your book.

Paul: The reasons I singled you out in my book is that you are my favorite geneticist and a very influential person. To me at least, the fact that you are so interested in transhumanism is very significant. For better or worse, you are not an average Joe.

I mentioned this before in our discussion, but if we lost all our technology and libraries of information of various kinds, then I’m not sure that we intrinsically really are transhumans. For me the transhuman potential would need to be coded into us to really transcend our past selves in a more permanent way. Our ideas and technologies are potentially transient, aren’t they?

I can give a few examples of what I mean. Take bones. Today we can put in a titanium pin and get someone with a serious displaced fracture pretty much back to normal. In past centuries they would have died or been functionally imperiled. We might soon even be able to use stem cells to regrow the bone. But the moment that person dies, even if we consider them a transhuman, that state is gone. One could say it was a transient transhuman state. However, if you make a new human being with a germline gene edit in a certain gene that confers a unique bone architecture, now you’ve made a heritable change to the species. I’m not saying we should do this, but rather illustrating a difference.

George: The scenario of “if we lost all our technology” seems arcane, unlikely and not relevant to decisions at hand. Furthermore, many technologies last much longer than mutations. Sticking to your bone case, mutations in LRP5 can give humans effectively unbreakable bones, but these mutations come and go over the course of centuries. In contrast, technologies like combustion, knives, wheels and agriculture are effectively permanent over many millennia. DNA is not necessarily exceptional in this regard relative to other heritable components of our species.

2nd human embryo CRISPR paper.

14. Paul: Overall, what do you think of the new, now 2nd paper on CRISPR’ing of human embryos from the Fan group? It seems to have identified quite a few technical hurdles along the way as they did their studies. Indels where they wanted precise edits. Chimerism. And more. Are these kinds of issues going to be avoided by newer technological advances? It seems likely that we’ll see more of these papers where there is kind of a “so-so” technological outcome; do you think such work is valuable and advances the field, or there’s not much point to it?

George: *14* None of these are new issues. The first use of Cas9 in human stem cells (genetically and developmentally more normal than the triploid cells) demonstrated precise edits. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, Norville J, Church GM (2013) RNA-guided human genome engineering via Cas9 Science. And the chimerism is solvable, as described in *11* above. Also, as I’ve noted in *11*, modifying gametes to save embryos seems preferable to modifying embryos directly and hence putting them at risk.  

More from @TEDxVienna including photos and videos

A few weeks ago I spent a bit of time in Vienna participating in TEDxVienna. You can see two previous posts on my experience here and here.

My own video is not up yet on TED, but a few have popped up so far here. One of my favorites is the talk “What if we could become transhumans?” by Oskar Aszmann. See above. My own talk also touched briefly on transhumanism but from the very different angle of genetics, eugenics, and human genetic modification.

Volkstheater

Before our rehearsals we got a tour from one of the organizers including the view above from the back of the amazing Volkstheater. Believe me it felt different there than on the stage.

St. Stevens

The inside of St. Stephen’s Cathedral (above) was awe-inspiring. There’s something about stain-glass windows and candle-lighting that is really powerful.

Claim of risky DIY gene therapy linked to unlicensed stem cell clinic

Elizabeth ParrishIn a strange, but fascinating tale recounted by Antonio Regalado in an article over at MIT Tech Review, we hear the first claim of a do-it-yourself (DIY) gene therapy.

The owner of a small biotech called BioViva, Elizabeth “Liz” Parrish, reportedly traveled from her home in Seattle to get an unapproved, experimental gene therapy in another country.

The article pointed to a Reddit AMA that Parrish recently did where she discussed these events in the context of her interest in anti-aging efforts.

Regalado is fairly blunt about his view of the anti-aging crowd, describing it this way:

“The field of anti-aging research is known for attracting a mix of serious scientists, vitamin entrepreneurs, futurists, and cranks peddling various paths to immortality, including brain freezing.”

In the introduction to the AMA, Parrish is described as, “”the woman who wants to genetically engineer you.” You can read more about her here on her LinkedIn profile.

Below is a video of Parrish discussing anti-aging therapy. She’s clearly very articulate and bright. In the talk she claims that the doctor that she works with at BioViva received an anti-heart disease gene therapy five years ago and is doing well. It’s an extraordinary claim.

She also talks about stem cells and cures for a variety of serious and even fatal diseases such as ALS.

Apparently Parrish’s DIY “therapy” involved two components.

One effort targeted muscle through introduction (presumably through injections of virus?) of the follastatin gene into her muscle. The rationale seems to be that it would inhibit myostatin and give her big muscles. The second intervention reportedly was an IV of “viruses that express telomerase”.

The second one sounds particularly risky given the association between elevated telomerase and cancer. Many things can go wrong with gene therapy and when you combine that with DIY administration it gets even scarier.

Who knows the possible consequences of either of these gene therapies? Even tightly-regulated, experimental gene therapies in the past given as parts of controlled clinical trials have led to deaths. I hope that doesn’t happen here, but if true this situation sounds radical and possibly dangerous.

Still BioViva has had some impressive scientists on board. One, George Martin of the UW, has terminated his link to the company after these recent events. Harvard geneticist George Church, a transhumanist and at times a proponent of human genetic modification, apparently remains on board with BioViva.

By getting an unapproved and potentially dangerous gene therapy abroad, Regalado reports that Parrish was intentionally circumventing the FDA:

“Parrish said in an interview she chose to bypass the U.S. Food and Drug Administration by trying the procedure overseas. The FDA requires costly trials, and aging itself is not generally recognized as a disease that can be addressed by drugs. “What we did is we moved forward to try to treat biological aging,” Parrish says. “We are attempting to reverse aging at a biological level.”

This sidestepping of the FDA was not viewed positively by Church, but he indicated he was inclined to believe that the gene therapy intervention was real. He also has at other times recently been enthusiastic about the concept of a telomerase intervention in people as an approach to aging:

“Church, the Harvard professor, says he thinks targeted DNA changes could in fact extend the normal human life span, which has a maximum length of about 120 years. Earlier this month, at a meeting of the National Academy of Sciences organized to weigh policy on genetic interventions, Church proposed telomerase as one bearing serious consideration. “I think we are very close. I think the world is close, so long as we don’t have a setback,” he says. “The extension of life span is quite dramatic in model organisms … it would be amazing in humans.”

Again, to me the cancer connection with telomerase makes this a dangerous shot in the dark.

This tale gets more puzzling as Regalado points out the involvement of Jason Williams, who is more well-known in the stem cell world for his dubious stem cell clinic (Precision StemCell) that had been located here in the US. He has since moved that abroad after a situation with the FDA. Apparently Williams is also the co-owner of BioViva and he indicated to Regalado that Parrish’s DIY gene therapy took place in Colombia, but not at his clinic.

Parrish seems to espouse a very libertarian view of biomedicine and bioethics:

“We as a company have our own ethics,” she says, referring to what she calls the need for inexpensive gene therapy treatments. “I am certainly not going to ask someone’s permission to potentially create new industries and cures.”

This sounds reminiscent of transhumanism and disruptive technological innovation, but sure seems extremely risky.

It also could set a dangerous precedent for DIY interventions or encourage others to follow this uncertain path. Is this a one-time thing or the start of a larger trend in the world of genetic interventions?

Steven Pinker interview: case against bioethocrats & CRISPR germline ban

CRISPR-Cas9 gene editing technology is red-hot right now.

It has great power for research in the lab and there are hypothetical transformative clinical applications of CRISPR too. The latter efforts could include experimental attempts at reversal of disease-causing mutations in one-cell embryos with the hope that they then grow into full-fledged, healthy human beings. Hypothetically CRISPR could also be used for pursuing human enhancement via germline genetic modification.

As a tool CRISPR is exciting and my own lab is using it for genetic studies, but from a technical perspective it’s not perfect. It can introduce a range of types of errors into the genome, with largely unknown biological consequences. To date, the first and only report of CRISPR-based modification of human embryos was arguably most notable for the problems encountered including genetic errors. However, suboptimal CRISPR methods were used so better design would almost certainly reduce risks of errors.

CRISPR raises a number of questions and has sparked many discussions. How should we handle a cutting edge biotechnology of this kind as a community of scientists? What if anything should be the appropriate role of others in such considerations including bioethicists? Should there be a temporary moratorium on clinical use of CRISPR? I tackled some of these issues in my own past piece Practical Plan for Managing Human Germline Genetic Modification. Others advocate for a more liberal perspective on the road to possible clinical use of CRISPR, focusing on the potential for great benefits.

Overall, this all might be summed up as follows: how do we balance the gas pedal and the brakes on CRISPR’s use in humans to aim for the greatest overall net benefit?

Steven PinkerProfessor Steven Pinker of Harvard has been one of the most outspoken advocates for more gas and less brakes here. Both in writing and in talks he has expressed the view that we should move forward without substantial impediments to CRISPR-Cas9. For instance, Pinker’s “get out of the way” editorial last week in The Boston Globe on CRISPR was very critical of bioethics and advocated an expeditious path forward for the research without constraints. It sparked wide-ranging discussions and even some anger from bioethicists. Update: see also this brief reply to Pinker’s interview from noted bioethicist, Art Caplan.

A few days ago I reached out to Dr. Pinker to do an interview to learn more of the specifics about his views with a goal toward increasing dialogue. For instance, I wondered if he really felt that strongly about the harms caused by bioethics that were suggested in his editorial. I want to thank him for taking the time to provide such detailed answers that make the full depth of his views on these issues far clearer here than in the past.

Knoepfler. 1. Related to your talk at BEINGS and your more recent editorial, what do you see as the appropriate role for bioethics and bioethicists in the life sciences? “Get out of the way” seems rather absolute. Can you help us understand the nuances there in your view of bioethics if any?

Pinker: There’s a difference between ethics, on the one hand, and “bioethics” and “bioethicists,” on the other. Of course everything a scientist does—everything a human being does—ought to be ethically guided. But bioethics has become a professional guild that all too often impedes sound ethical concerns rather than advancing them. Many moral philosophers—the scholars who specialize in evaluating the soundness of ethical arguments—believe that mainstream bioethics commonly trades in confused claims based on emotion and woolly thinking (see these articles by Julian Savulescu, Sally Satel, and me for examples).

Take the very foundation of ethics. You’d think it would be an obvious ethical principle that life is better than death, health is better than disease, and vigor is better than disability. But, astonishingly, so-called bioethicists have repeatedly denied these truisms, either explicitly (in the case of the country’s former bioethicist-in-chief, Leon Kass, who argued that the desire to extend life is a sign of shallowness and immaturity), or implicitly, by fetishizing sweeping rubrics such as dignity, equity, social justice, sacredness, privacy, and consent at the expense of the health and lives of actual people.

It’s not just that many bioethicists practice bad moral philosophy. It’s that they are entangled in a conflict of interest. Institutionalized bioethics has become an academic and bureaucratic industry, and they need to rationalize their existence. You hardly need a bioethicist to tell you that it’s wrong to inject typhus into twins or to withhold antibiotics from syphilis patients. But to come up with an abstruse argument as to why a parent should be prohibited from saving the life of her infant by donating a part of her liver—for that you need a “bioethicist.”

Regarding my advice to “get out of the way,” the nuances were stated, albeit tersely, in the article. The first is that a truly ethical bioethics must weigh the benefits of any restriction on research against the harm that will be caused to the vast number of people who would benefit if the research proceeded expeditiously. Savulescu puts it starkly: “To delay by 1 year the development of a treatment that cures a lethal disease that kills 100,000 people per year is to be responsible for the deaths of those 100,000 people, even if you never see them.”

The second is that a truly ethical bioethics should justify any restrictions on research with rigorous, defensible arguments about benefit and harm, not with moralistic grandstanding, science fiction dystopias, perverse analogies to Nazis and nuclear weapons, esoteric theories pulled out of the air, or freak-show scenarios like armies of cloned Hitlers, people selling their eyeballs on eBay, or warehouses of zombies to supply people with spare organs—all of which I’ve heard in these debates.

And as I wrote, no one questions the need to protect patients and research subjects from exploitation or harm. If there are flaws in the existing safeguards, as, for example, Alice Dreger argues, the safeguards should be fine-tuned or re-engineered. This is not the same as giving more power to the bioethocrats. A great deal of bioethical argumentation has nothing to do with protecting people. It rather cooks up reasons why consenting adults should be prohibited from doing things that help them or others while harming no one—a prominent example being recipient-solicited or incentivized organ and tissue donation. And establishment bioethics has caused preventable harm. Most infamous is the case of Jesse Gelsinger, the young man who died in a Phase-1 trial of gene therapy in 1999. Common sense would say that the experimental therapy should have been tested for safety on infants with a severe form of the disease who would have died anyway. But Arthur Caplan, the country’s most famous bioethicist, argued that the parents of such infants would be so consumed with grief that they could not truly give consent—the kind of paternalistic argument that is all too common in this field—and that an 18-year-old with a mild form of the disease, who technically could give consent, should be enrolled instead. A strained interpretation of the magic word “consent” was allowed to trump expected harm and benefit, and the result was tragedy.

Today mainstream bioethics gets in the way on a massive scale. The most obvious example is Institutional Review Boards. They are blatant abridgments of free speech, convenient weapons for fanatics to wield against people whose opinions they don’t like, and high-volume red-tape dispensers which bog down research while being unnecessary or even harmful to the protection of patients and research subjects. (See the Illinois White Paper and American Association of University Professors reports on IRB mission creep, David Hyman’s “The Pathologies of Institutional Review Boards,” and the new books The Ethics Police by Robert Klitzman and The Censor’s Hand by Carl Schneider). Regulations on confidentiality and consent to use data and tissues have also gone way overboard. The future of medicine hinges on the use of massive, open-access datasets to find signals in the noise. If every byte has to be multiply certified for consent and privacy, or even destroyed after a few years, no matter how inconsequential to the person who contributed it, then huge numbers of future patients will suffer or will fail to be helped by our faulty knowledge of the real effects of treatments.

There is, to be sure, an important role for bioethics. Satel puts it well: bioethicists at their best are “scholars who study the intellectual and social history of value controversies in medicine and biotechnology. They can teach us about the technical and cultural antecedents of modern debates and show us how to engage in disciplined moral inquiry.  They are skilled at drawing conceptual maps of the dilemma at hand while enumerating various ways to resolve it.”

Knoepfler. 2. Forgetting bioethicists entirely for the moment, prominent scientists such as Jennifer Doudna, David Baltimore, and others have publicly called in unambiguous terms for at least a temporary moratorium on clinical applications of human germline editing technology. Do you disagree or agree? Why?

Pinker: Disagree. The specific harms they warn against, such as inducing cancer, mutations, or birth defects in the unborn child are already ruled out by a plethora of existing regulations and norms. Obviously we shouldn’t mess around with embryos in ways that have a significant probability of producing a sick or deformed child with no compensating benefit. But why do we need a new, across-the-board ban on an entire method to rule out what’s already ruled out on the uncontroversial grounds of protecting individuals against foreseeable harm? The authors seem to be acquiescing to the yuck-factor that surrounds the very idea of germline modification, if for no other reason than to draw a firewall around their own research programs, which are restricted to the genetic modification of somatic cells. But scientists should work to dismantle irrational taboos, not indulge them.

First, the idea that there is some sacrosanct entity called “the human germline,” such that deliberately manipulating it would violate this sanctity, or restrict the freedom of future generations, or alter the species in unprecedented and frightening ways, is biological nonsense. No two people, not even monozygotic twins, have the same germline. Each of us introduces dozens of random mutations into our germlines, often multiplied by voluntary choices such as exposing ourselves to mutagens like tobacco smoke or fathering a child in middle age. And we affect the genetic makeup of our offspring, and the species, every time we choose to have unprotected sex with one partner rather than another. So even if it did come to pass that some people edited out disease genes, or (far less likely—see below) edited in enhancement genes, it would be a droplet in the maelstrom of naturally churning genomes.

Second, a ban or moratorium would only reinforce the pernicious aura of dread that surrounds genomic modifications. This is the dread that incites across-the-board opposition to genetically modified organisms and that underpins the bogus moral arguments against cytoplasmic donation for mitochondrial disease (the so-called three-parent babies—another case in which so-called bioethical concerns increase rather than decrease death and suffering). And the spurious ideal of germline sacredness could compromise the treatment of disease in other ways. Though lots of things went wrong in the Gelsinger case, one complication was the decision to administer massive doses of the viral vector directly to his liver, with the risk of lethal inflammation, rather than systemically, out of the fear that (God forbid!) it might introduce the needed gene into his sperm-forming cells. That’s probably not what killed Gelsinger, but it did kill a monkey in a safety trial, and this germlinophobia could certainly endanger gene-therapy patients in the future.

Third, germline editing could have direct benefits in a number of scenarios: to parents with disease genes who don’t produce enough viable embryos for preimplantation genetic diagnosis (especially when more than one such gene is involved, which multiplies the number of necessary embryos); to parents who both are homozygous for some recessive disease gene (not far-fetched given how often people meet each other through support groups); if future data were to show that PGD babies have compromised longevity or health; and in other scenarios that perhaps we can’t imagine. For these reasons Savulescu, with Chris Gyngell, and Henry Miller with Drew Kershen argue that research on germline editing is not only morally permissible but morally imperative.

Knoepfler. 3. You appear relatively confident in future benefits of new biotechnology such as CRISPR to millions of people, but you seem very skeptical of the risk predictions that you described as “speculative harms”. What makes you so confident of benefit and at the same time so skeptical of risks? If us humans struggle generally at accurately predicting outcomes of biomedical science, why should there be a more accurate expectation of benefits as opposed to risks?

Pinker: No, this is wrong. Though it’s certain that the biomedical research enterprise as a whole will deliver benefits to billions of people, we can have no such confidence in particular technologies. That’s why we need a diversified research portfolio, without arbitrary bans. If you ban something, the probability that people will benefit is zero. If you don’t ban it, the probability is greater than zero.

As for the potential harms, they are far too nebulous to justify a ban or moratorium. Far from being confident in the power of gene editing, I’m on the record as being skeptical that we’ll ever see genetic enhancement of babies—the outcome that the prohibitionists and moratoristas dread and that many bioethicists blithely assume is inevitable. (For example, in 1999 Caplan announced that before the end of this century “We will see many children made by the artificial creation of embryos…This prediction is 100 percent certain.”) The prophesy of designer babies ought to be a relic of the early 1990s, when people thought there was “A Gene For” this or that talent. We now know that heritable psychological traits such as intelligence and personality are the product of hundreds or thousands of genes, each with a tiny effect, many of which may have harmful effects as well, such as an increased risk of neurological disease or cancer. With each enhancement gene providing a nugatory benefit and a non-negligible risk, and with the editing process itself imposing risks, it’s unlikely that today’s morbidly risk-averse helicopter parents will take a chance at enhancing a child—they won’t even feed their babies genetically modified applesauce! And that’s assuming that such a procedure ever got to the point of clearing conventional safety hurdles, which is far from likely. Add these risks to the fantastic expense and tribulation of IVF compared to good old-fashioned sex, and one should conclude that widespread genetic enhancement is too unlikely a possibility to worry about. And that’s assuming we should worry at all. There is, in addition, the argument (from Savulescu, the transhumanists, and others) that if enhancement were ever feasible it would be a good thing, not a bad thing—or at least a matter of individual freedom rather than government coercion.

Now, the story is different for editing out disease genes. There are more ways that a complex system can break down than that it can work better, and it’s easier to fix a defect than engineer in an improvement. Also, the benefits are very different for preventing death and disease (huge) than for implementing an enhancement (minor). So the possibility that germ-line editing might prevent disease in the future is well worth exploring.

Knoepfler. 4. Congress recently held a public hearing on human germline modification and is considering a legal provision to block editing of human embryos. What do you think of having such a hearing and the possibility of a restrictive legal provision? You said to bioethics, “get out of the way”. Should we scientists say the same thing to lawmakers? Why?

Knoepfler. 5. There is likely to be a NAS meeting sometime late this year on human germline modification by such technology as CRISPR-Cas9 and mitochondrial transfer (3-person IVF) in the spirit of the 1975 Asilomar meeting. Do you think this new meeting will achieve positive outcomes such as a white paper that appropriately has a vision for the future? What if the consensus is for a moratorium? Could you support that?

Pinker: I’ll answer these together. I think that scientists should reiterate the principle that no experiment should be permitted which imposes an unreasonable risk of an illness or birth defect on an individual. But no, I don’t think that scientists should support a ban or moratorium on germline genetic editing, for the reasons I set out in my answers to questions 2 and 3. Though the Asilomar recommendations have long been a source of self-congratulation among scientists, they were opposed by a number of geneticists at the time, who correctly argued that they were an overreaction which would needlessly encumber and delay important research. And the journalist Victor McElheny reminds us that the recommendations sowed a panic which came perilously close to shutting down some of the nation’s major laboratories, a danger he argues we are now in danger of repeating.

That having been said, I recognize that the political arena follows different rules than scientific and intellectual discourse. The scientists who lead major research institutions and deal with politicians and other public figures have to master the arts of compromise, tact, euphemism, and strategic deal-cutting. That’s how democracy works, and I’m grateful to the scientific leaders who carve out a space in which the rest of us can flourish. There are things they may believe but can’t say. But it’s important that someone says them, and that’s how I see my role in these debates.

Global transhumanist leader Natasha Vita-More on human germline modification

Natasha Vita-More - 2015In my continuing series of conversations with thought leaders related to heritable human modification, today’s post is an interview with Natasha Vita-More, a pioneer in the transhumanist movement and Chairman of the Board of Directors of Humanity+ (H+), the global transhumanist organization.

Where do you see transhumanism today? Has it changed over the years? What are the primary areas of focus today?

NVM: Transhumanism is no longer a subculture and an emerging academic discipline.  It has become a worldview that represents the currents in global society. These currents reflect the sciences, technologies, and innovations that are changing the way people do things—their health, lifestyle, communication and self-awareness, and adapting.Transhumanism_h+_2.svg

Looking back over the years, transhumanism introduced the first strong social interest in the benefits and possible risks of emerging and accelerating technologies.  The scientific research on human physiology and cognition, developments in biotechnology, along with who expanded on the notion of Moore’s Law formed the basis on which many of these critical ideas were based. The technological Singularity formed a related but different trajectory for deeper contemplation of humanity’s future, and alerted focused research on artificial intelligence, which fostered AGI (artificial general intelligence), and the new connections between fields that developed forming the loci for generating ideas for delivering novelty. The trends toward entrepreneurial practices, being an innovator, starting a company, making a change in the world brought about this current culture that aims to educate and inspire others to think about what is needed today to help us arrive into the future, safely. The focus changed from being far future visionary toward sustaining life long enough to get there. The means that adapting to the challenges of change is necessary to evolve.

Transhuman Visions 2-14
The primary focus is twofold. First, to progress forward, it’s necessary to have a thoughtful start. Unravel the confiscated knowledge and make it available and accurate as possible. The information that transmitted through the journalistic media, postmodernists wrestling with a new philosophical worldview, and info centers like Wikipedia (which is more of a bible of edited stories than a formative recording of facts) that chalkboard, erase and rewrite data are all mishaps in the branding of transhumanism. Second, to be forward, inclusivity and diversity are essential. This means that transhumanism exists in a world of different values and can respect others but to hold its own in the larger arena of policy making, laws and legislation. This reflects the basis for the Proactionary Principle, Morphological Freedom, and the Regenerative Generation.

Do you see genetic self-editing as an important part of transhumanism?

NVM: This is a loaded question. On the one hand DIY and QS are stables in the generation of innovators who see the body as a makerspace. On the other hand, messing with genes can have terrible consequences. Why would a person want to mess with their genes unless the practice was viable, ethical, and safe? But then sexual reproduction is a type of genetic self-editing not governed by legislation, the FDA, or AMA. But it is not 100% viable, ethical or safe. A person can be impregnated by force, or a person may transmit abnormalities in the sperm or egg causing a genetic disorder. In a society of self-responsibility of one’s body, and where access to medical and scientific information is accessible, it could become a field or business as a massively accelerated self-help trend. When looked at this way, techno-genetic self-editing may eventually pass through regulatory systems when it proves to be viable, safe, and beneficial, and a natural way to protect one’s sustainability.

What about human germline editing to produce healthier children, such as via CRISPR-Cas9 technology? Does that have a potential positive role for transhumanism and humanity? 

NVM: Most people want their children to be healthy, both mentally and physically. If a child has a horrific disease, to not remove the gene is simply wrong. It is far more immoral to allow a person – of any age – to exist in pain or suffering than to apply medical technologies to assist in their riddance of despair.

Would you be supportive of the use of such technology for enhancement, meaning not just for the correction of say a mutation that causes a disease, but also for making enhancements of potentially desirable traits such as intelligence, slow aging, strong bones, better muscles, etc.?

NVM: Yes, certainly, provided it is safe. Cancers ought to be caught and eradicated early on. But let’s consider what pharmacology and neuropharmacology offers today: for bone loss, currently the enhancements include calcium and vitamin D, and for more enhancements needs, Fosamax and Actonel. For muscle loss, current interventions include anaerobic exercise, and for more aggressively growth hormone, testosterone, and HRT. Enhancing intelligence is met with nootropics for an intelligence boost, but also the computer, smart phone, etc. do increase human intelligence because, even though they are external device, they interconnect with cognitive functions (memory, logic, calculation). The hypercognition probability will form a type of metabrain, whether it is an internal or external appendage to the brain.

Some people have made comparisons between transhumanism and eugenics: how do you feel about that kind of comparison? Is it valid? Is there a beneficial role for “positive eugenics” in the world today?

NVM: There is no comparison between transhumanism and the coercive manipulation of human beings. By its very nature, and certainly identified at its core, transhumanism values human rights. Human rights include individual freedom and the right to enhancement and the right never to be coerced to enhance.  This is human enhancement for healthy outcomes, based on the freedom of choice.

I think the word eugenics has too much of a vulgar taste in the mouths of humanity to make it positive. Historically, the horrific abuses to human kind at the hands of criminal minds are reprehensible to humanness. These abuses are inflicted by criminals who perform abusive acts – from cutting off a woman’s clitoris, to enslaving others with violent and egregious acts against their psychology and physiology. One might call this eugenics, but it really isn’t. It is a term allocated to the Germans under the influence of Hitler and who performed terrible, criminal acts against those they devalued.

Where do you foresee transhumanism being in the coming 5-10 years? How about in 25 years? Will there be transformative advances?

NVM: In the coming five to ten years, there will be outreach to inform the public about the challenges we all face. I like to think of it as the electronic grassroots of people realizing that they need to have more knowledge of what the late 20th century term NBIC means. Where is nanotechnology headed, and what is meant by nanomedicine; how can biotechnology protect and sustain human life; how can we protect our identities from black hat hackers and where is cognitive science headed? (Literally!) During this time frame people will become more self-aware of being healthy and active, and facing economic challenges as the baby boomer generation lives longer and find a need to be included in the social climate, rather than retire and be forgotten. Design plays an important leadership role because it sets the pace for usability and functionality of any product or process within all sectors.

In the next 25 years, many grand challenges will be tackled, with smart use of nanorobots to clean up the environment and to form protective molecular systems. The idea of a white cloud swarm could have important environmental attributes, such as forming a wall to protect a location from external dangers.  Expansive AI can integrate stale systems from task-based to solution-finding. A core issue is the protection of personal identity from black hats, and the growing need for forensic security. An area to concentrate on is the practice of “change fitness”, as we may all become athletes of life in exercising an ability to adapt to change.

Transhuman Politics is an area where we need visionary work. It may be a passing trend, but it could offer new insights to actually dealing with adversity.  Recently I was in France where I felt set up as being of a political persuasion rather than what I am — an independent, so I can look at this a bit objectively. I remember being elected on a transhumanist platform in 1992, in Los Angeles County, with a technology platform at a time of large anti-technology staging by Green Peace.  There were too many hard lies encircling witlessness.  Today the risk has become more human centric; either the human caused it or it will adversely affect the humanity. This ought not bog us down. To encourage progress, technology is crucial if grand challenges are to be tackled.  From the core values of transhumanism, others can apply their knowledge and experience to address the policies, laws, rules, legislation, of socio-economic-political conundrums.  And while there is certainly risk in the economic structure, if people gain new information bearing skills, societies can overcome obstacles.  The aim is to be informed.  Not easy, but well worth the effort.