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.  

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.

Nita Farahany Interview on Human Germline Modification: Defining A Road Forward

Nita FarahanyThe topic of heritable human genetic modification has been heating up recently. Prominent scientists, ethicists, and legal scholars have being weighing in, and there is a range of attitudes. Some favor a complete, moratorium including even lab work, while on the other end of the spectrum there are those who have a more liberal perspective. Many of us fall in the middle somewhere.

I have been interested in having conversations with people with diverse views and posting them on this blog. You can see past interviews with Jennifer Doudna here and George Church here.

Duke Professor Nita Farahany, J.D., Ph.D has been one of the more prominent, public proponents of some forms of human germline modification. She has been in a number of debates arguing on the “pro-human modification side”, including just to cite one debate this one where she argued against prohibitions on genetically modified babies. I also recommend watching the video below where she debated Marcy Darnovsky of CG&S  and advocated for allowing human genetic modification. The way the debate framed it was, “Should we design our babies?” and Farahany argued the “yes” side. She has mainly focused on three-person IVF rather than nuclear editing such as by CRISPR-Cas9, but the latter has become increasingly feasible on a technical level and important as an area of discussion.

I reached out to Professor Farahany, who is also a member of the prestigious Presidential Commission for the Study of Bioethical Issues, to have a conversation about human germline modification. I found many of her answers to be intriguing and surprising.

PK: You’ve been characterized in various debates, to put it simply, as being on the side arguing the “pro-designer baby” case. Is that correct? And why?

NF: No. I’m in favor of mitochondrial transfer, but not nuclear gene editing at this time. We haven’t reached a point in the technology where nuclear gene editing could be done with an expectation of safety and efficacy. Still, the bright line between somatic and germline modification – it’s not tenable. Could I be convinced on nuclear modification in the future if there’s more information? Possibly. I’m not opposed to germline modification ever happening.

PK: What has made you more supportive of mitochondrial transfer compared to nuclear gene editing?

NF: The UK has taken the appropriate approach on mitochondrial transfer. They held meetings and hearings. They involved the public. The HFEA provided information. They engaged the Nuffield Bioethics Commission. Their process was thoughtful and considered. They made the right choice at the end of the day. I’d like us (in the U.S.) to follow that lead. We need to reconsider. I’m concerned that the alternative is people facing mitochondrial disorders turning to risky medical tourism.

PK: What specifically makes you feel differently about mitochondrial transfer versus CRISPR of nuclear genes?

NF: CRISPR is newer. And editing of nuclear genes raises greater ethical concerns. That being said, I don’t draw a bright line around it. The difference is where the technology is today. A place I could imagine nuclear gene editing being appropriate is if we know that there is a particular single polymorphism that creates an unhealthy condition and that with CRISPR technology we could replace the unhealthy portion with a healthy portion. We aren’t introducing any new traits in that case. I could imagine that could be a place for gene editing and if we also had adequate safety and efficacy information, I could possibly support that.

PK: Is mitochondrial transfer a form of heritable genetic modification? Some have argued it isn’t.

NF: Yes, it is germline genetic modification. The controversy has had less to do with the technology than to crossing the line to germline modification.

PK: A few months ago the first human embryo editing paper was published. One can fault the specific form of CRISPR methods they used, but they still found numerous problems such as off-target effects and mosaicism. What was your reaction to that paper?

NF: I’m unsurprised about the effects and that’s part of why it is too soon. We need to really understand the technology better. I’m in favor of using it in animal models. Then we could consider human work later based on what is found.

PK: Does the non-viable embryo aspect of that study make it less problematic?

NF: I wouldn’t be doing human embryo work at all today even in vitro in the lab. What would be reason to use human? There hasn’t been adequate democrat deliberation. Making the leap to humans is problematic. At this point we need to focus on animal studies. Even in nonviable human embryos there are ethical concerns.

PK: Let’s say we get to a point where we know CRISPR is safe in humans. Even if it is safe and effective, are there still other ethical issues?

NF: I personally would probably be in favor of it, but my opinion is not the basis of deciding as a whole whether we as a society do it. It’s already happening elsewhere. It’s figuring out how to enable progress.

PK: Some have raised the issue that the future genetically modified children cannot consent to being edited. Is that a valid issue?

NF: We can’t consent future children to be born to begin with. Children also don’t consent to parenting strategies. The idea that children cannot consent to gene editing is a bit of a red herring. It’s less about consent and more about the impact on that child and on the human population more generally.

PK: What about using genetics technology for prediction of offspring traits? I read that you and your husband had used the 23andMe genetic predictive tool for future offspring. What was that experience like?

NF: We thought it was interesting. It was very limited though. They predict traits such as lactose intolerance, eye color, wet earwax, and things like that. We now have a 6-month old daughter and we did compare the 23andMe predictions to what she is really like. If we could have had it be much more predictive we would have liked that. As it was, it was just more a novelty and fun.

PK: Lee Silver’s GenePeeks and other groups are already offering gamete screening kinds of tools in part based on predictive genetics. What’s your reaction?

NF: There are some ethical concerns there, but compared to gene editing it is relatively less problematic. If you are able to select between embryos and find the one that is the healthiest, that is appropriate. It’s about selection for health versus editing.

PK: How about the selection that is already happening of certain kinds of embryos based on genetic information? For example, what’s your view of PGD for embryo sex selection?

NF: I’m not troubled by sex selection in this country. In other countries it can be more problematic. For example, if there’s a one-child policy or gender imbalances in a society, sex selection can be much more of an issue. I think sex selection can be valuable and if, for example, a couple wouldn’t get pregnant with a child of a certain gender, but they will have another child of the other gender with the help of sex selection then that is positive.

PK: What about for PGD for trait selection?

NF: We already do this. We look for embryos without a heart condition or for ones without other conditions such as Tay-Sachs. What you probably mean is trait selection for things like eye color?

PK: Yes, that’s more the kind of trait selection I was meaning.

NF: Am I concerned about it? It’s a little weird. I have a hard time imaging I would care about my future child’s eye color. But if it really matters for someone, then I don’t find it problematic. If there are five embryos that are all healthy and one has brown eyes and the parents wants to choose that one, I don’t see that being a problem.

PK: But what if it goes further to say height, body mass, musculature, facial features, and such?

NF: Even if people do that (e.g. select for certain features), we won’t end up with eugenics. When people are given choices, they tend to choose to have children who look like them but a little better. Do we already have high expectations of our children? I think so.

PK: You mentioned eugenics. Does gene editing raise the risk of eugenics?

NF: We don’t have a pretty history of eugenics. It’s an appropriate concern to have in mind when we start talking about gene editing. Genetics is not so simplistic as we once thought. The ability to have an “effective eugenics” policy is much less likely than previously thought. I don’t think heritable human genetic modification will reawaken genetic determinism. It may reawaken a desire to improve the heath and prospering of future generations. Still we have to make sure it happens in a way that doesn’t create a society that favors determinism.

PK: What about not just selecting for certain traits, but actively using genetic modification for specific trait enhancement? Not just for genetic disease prevention, but for human “enhancement”?

NF: We are nowhere close to that being okay. But if we can show it is safe and efficacious…if we as a society are okay with editing, am I going to be the one to draw the line there? We’ll have to see. It also depends on the type of traits. Consider traits in the existing population versus totally different traits. For instance, if we can correct a person’s vision to 20-20 vision that is positive and different than say giving them UV vision or something else that is entirely outside the range of the normal human population.

PK: Looking to the future, there is slated to be an upcoming NAS meeting on germline human modification. Will that be sufficient to engage the public on this issue?

NF: What does democratic deliberation look like? A NAS meeting doesn’t engage a broad public audience. The NAS meeting will be positive, but more is needed. This issue (germline genetic modification) touches on pro-life, pro-choice, and people have concerns on “designer babies”. There are many issues here. What does society look like when we starting germline editing, traits start being edited, etc.? This justifies the need for a broader public audience.

What Would Spock Say About Grouchy ‘Practical Ethics’ Piece on Human Genetic Modification?

Kirk SpockOver at Practical Ethics they are calling for an almost Spock-like, emotion-free, and logical approach to the topic of heritable human genetic modification.

Sounds good in principle, right?

Well, unfortunately it fails in execution in their essay.

The authors of “Editing the germline – a time for reason, not emotion” seem to include Chris Gyngell, Tom Douglas, and Julian Savulescu.

It is notable that this Practical Ethics piece itself has an unmistakable bias toward allowing human germline modification to proceed unfettered by what they view as unnecessary and harmful constraints. The authors’ tone seems downright crotchety with those on the other side.

They take issue more specifically with both the recent Nature and Science perspectives pieces on this topic, and generally want to downplay potential negatives to human germline modification.

For example, their most strongly worded statements in the essay attack and minimize concerns over human genetic modification. They cast human germline genetic modification in the light of something that only has an upside and is really not that big a deal in terms of risks. Some examples of their one-sided verbiage include:

“While these statements appeal to broad concerns about germline editing, they do not provide clear reasons to resist or restrict it. Many technologies have unpredictable effects on future generations but this does not mean they are either dangerous or morally unacceptable. Who can predict the effect of information technologies like the internet or smart phones on future generations?

…One might object that such technologies don’t operate at the genetic level, like CRISPR, and are not passed heritably down to the next generation. But this is a deep mistake – environmental interventions, such as modified social interaction, have epigenetic effects, modify brain development and can be passed on to the next generation.

…Similarly many new technologies are non-therapeutic but this rarely warrants a moratorium on their use. While many medical technologies are only approved for use in a therapeutic setting, the mere fact that a technology could be used non-therapeutically does not justify placing broad restrictions on it. Lasik eye surgery can be used non-therapeutically, but this doesn’t justify restrictions on its therapeutic uses.

….A key fact noticeably absent from both the Nature and Science commentaries is that many other human activities cause modifications to the human germline.

So experimentally de novo creating designer babies with gene edits that the resulting genetically modified people could then pass along to future generations forever with unknown consequences is really not so different than say getting your vision corrected, stepping outside to smoke a cigarette, changing ones friends or allowing new generations to use the Internet?

I don’t think so.

In addition, this Practical Ethics piece uses a regrettable device of denigrating those who are concerned about human germline engineering. They are cast as too “emotional” or having other problems. For example, the authors conclude the piece with this rather sharply worded paragraph only focusing on potential upsides and not downsides of this emerging human modification technology and insulting those with whom they disagree:

“Gene editing is a revolutionary technology, which potentially offers the next generation an enormous range of benefits. It is important that bad arguments, empty rhetoric and personal interests do not cloud rational thinking and deny the next generation the enormous benefits on offer. It is a time for reason, not emotion.”

So, to paraphrase, if one looks at this human germline editing issue with reason and without personal bias, one must then necessarily agree with them? And if one disagrees with them then you must be some kind of a wackadoodle swayed by emotion and irrational thinking?

It’s sort of like saying, “I’m the logical, obviously correct Spock and you, if you disagree with me on human genetic engineering, are the reckless, overly emotional human, Kirk.”

My own views on how to approach human germline genetic modification can be read here. Also note the ISSCR policy statement too.

Genetically Modified Humans Now Inevitable?

human egg editDiscussion of concerns over heritable human genetic modification has spiked in 2015.

This dialogue is a good thing, but is it in a sense too late?

Are genetically modified (GM) people a foregone conclusion?

Rumors are swirling that upwards of four papers reporting production of GM human embryos are in various stages of review at high-profile journals, sparking a sense of urgency for some kind of steps to deal with this new reality. Could these papers report germline correction of the CTFR mutation in cystic fibrosis or of a BRCA1 mutation? Were these GM human embryos used to make embryonic stem cell lines or are they cryopreserved?

The prime concern now is that GM human embryos could in principle be rather simply turned into GM humans at any one of thousands of IVF clinics around the world with a surrogate mother. That simple technological step of going from GM human embryo to GM human being of course invokes incredibly complicated, thorny legal, bioethical and societal issues.

So stakeholders have been weighing in recently on anticipating how to deal with this evolving situation.

Lanphier, et al. in Nature recently made the case in a piece called “Don’t edit the human germline” that GM human embryos should not be produced. Baltimore, et al. argued in Science for increased dialogue, but stopped short of proposing any kind of moratorium. ISSCR called for a moratorium on attempts at clinical applications of human nuclear germline modification.

My own take on this has been a more practical, specific approach that I call the ABCD plan that draws a bright line between allowable in vitro work (under very specific, mandatory rules, training, transparency, and oversight) and in vivo applications.

As this positive dialogue has proceeded, there is a troubling backstory. The sense I’ve gotten from some of those in the know is that there are researchers already intent upon going ahead to make GM human beings. Some believe it is not a question of if, but rather when and under what circumstances.

Interestingly, while there has been talk that from a legal and regulatory perspective that such an endeavor would “not be allowed” currently, I’m not so sure.

For example, here in the US if a GM baby was made, what could anyone do after the fact? Would the FDA really take some kind of punitive action and wouldn’t it be too little too late anyway? What about in China? I’ve heard people say there are regulations against making GM humans in China, but would they be effective?

If it is not too late to stop the production of GM people at this time, are there things we could be doing now besides increased dialogue to chart a safer path forward? If so, my sense is that time is short.