Nature mixed signals on 3-person IVF: deep risks, but forge ahead

3-parent babyNature recently published a very thorough, insightful piece on the major risks that would come with the use of so-called 3-person IVF (aka mitochondrial transfer or 3-parent baby method).

In the UK 3-person IVF has, as of earlier this year, the government’s blessing to proceed despite the many serious unresolved risks that Nature‘s own piece so nicely outlines. Some scientists including myself have spoken out publicly about these risks, which include potentially disastrous developmental problems for the children produced via this method. However, others including a panel formed by HFEA, think the risks are small. The Nature piece on risk quoted the HFEA panel this way, “most respondents presenting evidence to the panel viewed these issues as “at best minor or non-existent”. Still, this particular Nature piece is quite convincing on there really being major, unresolved risks. It also highlights how much the field doesn’t know about mitochondria.

On the same day as this Nature piece on the risks, the journal also oddly enough published a cheery editorial that didn’t even mention risk and instead slapped HFEA and the UK on the back for forging ahead with this human experimentation. The editorial concluded:

“The United Kingdom has made an advisable step forward that serves as a useful invitation for all to follow.”

So what are we to think, Nature? Are there many serious risks to 3-person IVF? Or not so much?

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.

At mid-year, how are my top 20 stem cell predictions for 2015 doing?

Stem Cell PredictionsEach year towards the end of December I make predictions for the coming year as I did for 2015. In the past I usually make a top 10 prediction list, but for this year I made 20 predictions. Admittedly some of them may have been more hopes than predictions.

At mid-year today on June 30th, how am I doing? See below. Note that of course for some the jury is still out.

BTW, stay tuned for more on an upcoming update on the Japan IPSC macular degeneration trial where there seems to have been a (hopefully minor) hitch.

  • FDA ‘breakthrough’ on stem cells. FDA grants an investigational stem cell biological drug therapy the breakthrough status designation. Status: so far no luck, but still hoping.
  • Adult & pluripotent stem cell advances both impress. More encouraging publications and news on the clinical and translational fronts for both pluripotent and adult stem cell drug development including MSCs. Status: Definitely correct.
  • Doc training in stem cells. More new academic-related training programs for doctors to be true stem cell and regenerative medicine specialists. Status: so far no luck, but still hoping.
  • Big pharma’s big interest in stem cells grows further. Big pharma’s interest in stem cells & regenerative medicine continues to grow including at least one major development that might be takeover of a stem cell biotech or something else. That are some small stem cell biotechs that seem ripe as takeover targets. Status: Mixed bag. Both some positive and some negative signs on this.
  • RTT spread. At least one more state (and probably more) pass Right To Try (RTT) laws setting up a collision course between state and federal laws on investigational drugs including stem cell products. Status: Definitely correct. Tons of states moving on RTT.
  • Pro sports gets a bit more serious about dubious stem cell “treatments”. A pro sport players association or league acknowledges growing and difficult stem cell issues for players. Status: Mixed bag. 
  • More high-profile stem cell paper problems. At least one and probably more major stem cell paper problems pop up and could include retractions. Status: Yes, unfortunately (just see Retraction Watch on stem cells)
  • The UK Parliament OKs 3-parent baby tech. The parliament approves 3-parent/mitochondrial transfer technology, but more steps are required before it is practiced in humans. Status: Correct
  • Stem cell clinic chains Cell Surgical Network and Stem.md continue to grow for at least the first half of 2015 and probably beyond. They operationally challenge recent FDA draft guidances on adipose and minimal manipulation. Status: Correct
  • STAP-related news on the American front. We learn something on the US side of the story of the retracted STAP cell Nature papers. Status: Not yet, but stay tuned.
  • Muddier stem cell waters. More mixing of “legit” stem cell companies and researchers with the non-compliant side of the tracks. Status: Unfortunately correct
  • More stem cell paper debates and developments on PubPeer. A volatile situation continues with notable twists and turns. Status: Yep.
  • IPSC RPE safety. The IPSC-based RPE trial for wet AMD in Japan continues in 2015 without a reported safety hitch. Status: Probably Wrong (again stay tuned, but don’t freak out).
  • A stem cell biotech finds itself in a hairy situation. What a tangle. Status: stay tuned.
  • At least one patient is harmed or files suit for a dubious stem cell clinic treatment. This is a sad prediction, but unfortunately I think it is likely. Status: publicly not yet.
  • VSEL hell. There will be even more bad news for these Sasquatch of stem cells after the Weissman lab paper that seemed to refute these “very small embryonic-like” stem cells in 2013. What does this mean for NeoStem ($NBS) now known as Caladrius? Status: Nothing public yet, but I still expect it to be a bad year for VSELs. For Caladrius, I’m thinking the impact is minimal since their focus seems elsewhere under new leadership.
  • Celltex is going for an IND. This is an interesting development. Status: not publicly.
  • GOP on stem cells. Republications make some noise on stem cells or personhood. Status: not yet, but they are on CRISPR as my old soccer coach would say when I was a kid “like a duck on a june bug”.
  • FDA back in the game of taking action on dubious stem cell clinics. After a long quiet period in 2014, the FDA takes some action on dubious stem cell clinics. Status: depressingly, not yet.
  • Stem cell-based organs. The red-hot trend of bioengineering organs and tissues in part using stem cells as a material continues to develop. Status: Yes, organs and organoids are one of the hottest trends of 2015.

Top 10 Insider Trends on Stem Cells to Look Out for at ISSCR 2015 Stockholm

isscr meetingThe annual ISSCR meeting has started in Stockholm.

This is always a great annual meeting both for the science and for connecting with people including new friends and colleagues as well as old friends.

Another element to the meeting is the insider conversations in the halls, restaurants, and bars that tell a behind the scenes story of the stem cell field.

Below are my top 10 things to look for that might be discussed over a beer or coffee this year. Also be sure to check out the wonderful guide to Stockholm from Heather Main and if you are there at the meeting enter our stem cell contests to win up to $100.

  • Clinics make an appearance? It’s a long shot, but I keep wondering if some of the stem cell clinic folks will show up at ISSCR some day to try to legitimize themselves even if they don’t speak, etc. Maybe they’ll sneak in with some posters or even just attend to make some connections. Unlikely, but if it happened could prove very interesting.
  • I’ll be curious if the Hanna-Silva feud of a sorts continues persist over ground state pluripotency, MBD3 and NuRD.
  • Does anyone still believe in VSELs?  A scandal is still smoldering there.
  • Anybody know what happened to Vacanti and the assumed to exist Brigham & Women’s/Harvard investigation over STAP cells? Last year in Vancouver at ISSCR STAP cells were one of the hottest topics.
  • Will Mitalipov continue to assert that NT-hESC are better than IPSC after the more recent paper (on which he was an author seemed to show otherwise)? More broadly will the SCNT/human therapeutic cloning folks continue to claim a clear path to the bedside?
  • Any news on Masayo Takahashi’s IPSC trial? More preliminary data?. I’m excited to see how that goes.
  • I keep hoping also that more biotechs will present at ISSCR and be given plenary talks.
  • Is ethics/policy given sufficient attention at the meeting?
  • Will CRISPR-Cas9 editing of stem cells be the talk of the meeting? The explosive trend of this amazing gene editing technology in science overall has really gripped everyone’s attention.
  • How many reports of clinical trial data will be given? Sometimes in the past ISSCR meetings have had a sizable tilt towards basic science. Could that be changing?

Big push for 3-parent technology in UK: some thoughts from the other side

3-parent babyA new piece came out yesterday on the Wellcome Trust Blog, strongly promoting approval of so-called “3-Parent IVF” or Mitochondrial Transfer technology by the UK Parliament.

As I written in the past (here and here), my view is that this would be a mistake at this time.

There is room for respectful disagreement on this issue between scientists, although I realize I’m up against some very prominent scientists including Drs. Peter Braude and Robin Lovell-Badge, whose past response to my open letter to the UK Parliament was one that I published on my blog here.

I believe in presenting both sides and I respect Drs. Braude and Lovell-Badge greatly.

The new Wellcome Trust blog piece includes a letter signed by a host of additional top scientists and other prominent figures encouraging parliamentary approval of 3-parent technology (see the letter at the bottom of this post).

This letter is signed by 5 Nobel Laureates and even some UK royalty.mito

Do I really want to be on the other side from those folks too?

Not really, but I need to call it like I see it and this is an important issue.

I seem to be one of the few scientists including stem cell scientists who will publicly say that I believe we need to learn a lot more about this technology before it is used on humans.

There is no doubt that mitochondrial diseases are truly terrible and need to be addressed, but if the potential outcomes from the technology are still vague, there are safety concerns, and it raises profound ethical issues such as changing the human genome heritably as is the case here, then my view is that a careful approach is both practical and logical. We cannot at this time have a reasonable expectation that this technology would be safe and effective. That may change in coming years with new knowledge. I hope so.

As strange as it may sound, although mitochondria have been studied for around 150 years, they remain in many ways still a new frontier for science with many mysteries. We are only now, for example, starting to understand how the mitochondrial genome works. There was just recently a very unexpected discovery that the mitochondrial genome produces thousands of potentially powerful non-coding RNAs with largely unknown functions. Nobody has any clue how these RNAs might behave in the context of mitochondrial transfer.

What else we will learn about mitochondria in coming years that is unexpected? I’d venture to say many mitochondrial surprises are still to come and there may well be things that we wish we knew in advance before we did human mitochondrial transfer. Science only has a very shallow depth of knowledge about mitochondria and new powerful genomics technologies are poised to change that quickly. I favor waiting until we learn more before we transfer mitochondria.

Still, since there are so many big name folks on the other side including many I greatly respect, could I be wrong?

Maybe.

Am I making a mistake publicly taking the other side?

Perhaps.

To be clear, I have no “iron in the fire” as the expression goes on this issue myself. I don’t work on this area of science or a competing area. It makes no practical difference to me whether the UK goes forward with mitochondrial transfer. If anything, my speaking out could be negative to me as I am taking what seems to be an unpopular, public stance.

The UK House of Commons will debate this issue this coming Tuesday, February 3rd.

Here’s the letter pushing for approval of this technology.

3-person technology letter