- Pilar is going to talk about what is probably the biggest step in the last 25 years in biology.  And that is the development of a system which even a high school student could use to edit the genome.  It's really very simple.  And the interesting thing was it's the simplicity of this genome editing system that has rocketed it to the lay press, to the national academies, to organizations all over the world because it's not the first system for editing the genome.  This is actually the third system.  And when the others came online, nobody paid any attention to them even though the implications were the same.  But it's the simplicity of CRISPR Cas that I think has drawn so much attention to it.  And I don't think there's anyone better at this university, or most universities, than Pilar to talk about this because she has a PhD degree in microbiology and immunology, and with respect to talking about its implications, she has a JD degree from UC Berkeley.  And she has been on numerous government and other foundation committees, chairing committees on genome, genetics, etcetera.  It's hard to imagine anybody could come to this issue with more knowledge and background than Pilar Ossorio. 

 So, right now, she's the inaugural scholar in residence in bioethics at the Morgridge Institute for Research, and she's also a law school faculty member.  She's a professor of law and bioethics.  And so she's going to talk to us today about what is going on in an effort to try to get some control over CRISPR so that the bad actors don't get into the game and start using it for purposes that are going to leave people aghast.  Pilar.  - Thank you, Ron.   All right, so I'm assuming that most people in this room know a fair amount about CRISPR Cas9, but I know that we are also--  We're also being broadcast.  And so I'm going to show a really short YouTube video that was made at MIT that just sort of explains the technology and a little bit of the background of the technology.   - [Voiceover] Every cell in our body contains a copy of our genome.  Over 20,000 genes, three billion letters of DNA.  DNA consists of two strands twisted into a double helix and held together by a simple pairing rule. 

 A pairs with T, and G pairs with C.  Our genes shape who we are as individuals and as a species.  Genes also have profound effects on health, and thanks to advances in DNA sequencing, researchers have identified thousands of genes that affect our risk of disease.  To understand how genes work, researchers need ways to control them.  Changing genes in living cells is not easy, but recently a new method has been developed that promises to dramatically improve our ability to edit the DNA of any species, including humans.  The CRISPR method is based on a natural system used by bacteria to protect themselves from infection by viruses.  When the bacterium detects the presence of virus DNA, it produces two types of short RNA.  One of which contains a sequence that matches that of the invading virus.  These two RNAs form a complex with a protein called Cas9.  Cas9 is a nuclease, a type of enzyme that can cut DNA. 

 When the matching sequence, known as a guide RNA, finds its target within the viral genome, the Cas9 cuts the target DNA, disabling the virus.  Over the past few years, researchers studying this system realized that it could be engineered to cut not just viral DNA but any DNA sequence at a precisely chosen location by changing the guide RNA to match the target.  And this can be done not just in a test tube but also within the nucleus of a living cell.  Once inside the nucleus, the resulting complex will lock onto a short sequence known as the pan.  The Cas9 will unzip the DNA and match it to its target RNA.   If the match is complete, the Cas9 will use two tiny molecular scissors to cut the DNA.   When this happens, the cell tries to repair the cut, but the repair process is error prone, leading to mutations that can disable the gene, allowing researchers to understand its function.   These mutations are random, but sometimes researchers need to be more precise.  For example, by replacing a mutant gene with a healthy copy.  This can be done by adding another piece of DNA that carries the desired sequence. 

 Once the CRISPR system has made a cut, this DNA template can pair up with the cut ends, recombining and replacing the original sequence with the new version.   All this can be done in cultured cells, including stem cells that can give rise to many different cell types.  It can also be done in a fertilized egg, allowing the creation of transgenic animals with targeted mutations.   And unlike previous methods, CRISPR can be used to target many genes at once, a big advantage for studying complex human diseases that are caused not by a single mutation but by many genes acting together.  These methods are being improved rapidly and will have many applications in basic research, in drug development, in agriculture, and perhaps eventually for treating human patients with genetic disease.   - So that should give everybody just a basic background.  Put everybody on the same page with respect to the technology.  And I think, as Ron said, what's really different about this is that it's cheap, simple, highly efficient compared to previous methods of genome editing.  It can be used to insert, delete, or modify genes.  And, as mentioned in the video, in a single cell a number of different, up to, well, we have a recent paper on 60 changes made in one genome all at the same time. 

  And so there are a vast number already of applications for this technology.  In the last year there were over a thousand papers published using this technology.  So I'm just going to give you a couple of examples.  Here, George Church's group reported quite recently that they were able to remove all of the endogenous virus sequences out of pig genomes.  Why would someone want to do that? Well, there's a lot of interest in using pigs to grow organs for humans or using parts of pig organs in transplants for humans, and but if they have endogenous retroviruses, then we're concerned, we can't really transplant that material into humans because it might actually infect humans.  So what he did was he basically made transgenic pigs where he had removed all of the endogenous retrovirus, at least of one certain sort.  So it was 60 or 60 plus sites in the genome that he changed.   Thus making it at least one step closer to the possibility that we could use pigs to grow organs for humans.   Another thing that's happening and that raises many, many policy governance ethics questions that I'm really not going to be able to talk about today because I don't have unlimited time is using CRISPR Cas9 to develop gene drives.  So, a gene drive is when you encode the protein, the Cas9 protein, you encode the relevant guide RNA and any other gene that you want. 

 You put this as a module into the DNA of an organism.  If it's a diploid organism, then when it reproduces, the one copy of the-- So when it reproduces, any alleles that are not the desired allele you can change them.  You can edit them.  So, basically, you create one genome that is kind of like a perpetual gene editing machine.  That gene edits the diploid, the other copy of the allele that you're interested in.  And so, in that way, slowly but surely, a gene could spread throughout a population.  And so this is more than just kind of germ laying transmission of a gene.  And over a number of generations you could actually fix a particular allele in a population.  So it's proposed that one might do this, for instance, to cause mosquitoes to be resistant to malaria.  So mosquitoes are an intermediate host for malaria. 

 So if you could cause the relevant species of mosquito to be resistant to malaria, then you could also stop the transmission to humans.  Other things that people have proposed using this for would be something like gene editing pest species that have become resistant to pesticides so that they were no longer resistant to pesticides or so that they just couldn't reproduce very well, for instance.  So there are a lot of potential uses, but, of course, these potential uses would involve releasing gene edited organisms with these gene drives into the environment.  So that raises many, many questions of ethics, of governance, of how scientists can think about their social responsibility when their research and their products are going to potentially impact lots and lots of people.  I'm not really going to have any more time to talk about that today, but you should just know that this is out here and there are a number of papers written about it.  So, quite recently, there was also, at a conference, a report that a company is about to start using CRISPR Cas9 gene editing in research in humans and a somatic cell study in humans to try and cure a certain genetic kind of blindness.  So, not to be outdone, just a month or so after that report came out, it was recently reported on November 5th that healthcare providers had used CRISPR Cas9 to actually do a medical treatment on a child.  So there are a number of studies going on, a number of clinical trials using a kind of cell therapy, adoptive cell therapy, in which a person's own T cells are removed from their body, genetically engineered to help fight cancer, and then put back into their body.  A lot of this is chimeric antigen receptor, for those who care about it.  You make a chimeric antigen receptor, transect the T cell with that, put those T cells back in the person's body. 

 So, here they did essentially that but they used genome editing to do it.  And this is maybe the first or certainly one of the first instances in which it's been used as a therapy.  So, in many cases in which these studies are happening, the children have cancer, they have not responded to chemotherapy, and they don't have any other options.  So, this is being done in studies, but I don't know of any studies currently underway that are using CRISPR Cas9 to do the sort of genetic modification.  Here they just did it as emergency medicine.  Okay? So, who needs research anyway, right?  So, not to be outdone, so to speak, actually a little earlier this year, came a report from some researchers in China.  They had used human embryos that were very early stage and that had various kinds of chromosomal abnormalities that would render them unable to really go through a developmental process.  So these are extracorporeal human embryos.  Perhaps embryos from an assistant reproductive clinic.  But they were ones that had problems for various reasons, would not have been implanted into a human being. 

 So they used them to see whether gene editing would work in a human embryo.   And it did, but it was, in their experiment, not very efficient at all.  And by not very efficient, we mean that there were lots of off-target effects.  And so even though CRISPR Cas9 type of gene editing is supposed to be, and it is, far more efficient and more effectively targeted than other kinds of genome editing that we've done in the past, still there can be off-target effects where you make genetic changes in genes that you didn't intend to change.  And that was part of what they saw, a fairly high rate of that in the human embryos that they were studying.   This paper raised a huge international firestorm of criticism.   And there's been a lot of fallout from that.  A couple of different journal articles and reports.  This is one by a very, very august group of scientists, including a couple of Nobel Prize winners, people like Jennifer Doudna, who is considered to be one of the inventors, if you will, of CRISPR Cas9 technology.  And so they basically argue for a pause in the use of this technology for any kind of attempt at human reproduction. 

  And they're not the only ones.  So, in the UK, there is a sort of deliberative group that considers bioethical issues and puts out reports called the Hinxton Group.  And they also put out a report on this.  Their conclusion, "We do not believe "that sufficient knowledge "is available to consider the use of genome editing "for clinical reproductive purposes at this time." And so, again, what we saw in the treatment of the child was basically what we call innovative medicine, right? It's not done as part of a clinical trial.  It's not done for research purposes.  It's innovative medicine when you-- In these cases, okay, you have a born person and that person is dying, and you have no other option.  And so even something very risky might look like better than nothing in terms of what you would try.   But I would say that all of the groups of scientists and social scientists who have written about genome editing, in the wake of this Chinese paper, have said we need to take a pause, we need not to go forward at this time with any kind of genome editing on a human embryo, particularly not for reproductive purposes, right? Not for attempts at medicine in some sense.   And I think people differ as to whether research should go forward on human embryos.   So, I want to talk about some of the ethical issues that are raised by human genome editing. 

 I'm only going to have a chance to touch the surface.  There are many, and there are lots of discussions of this going on.  And then talk about approaches to governance.   So, thinking about ethics, really, people tend to make a kind of separation between somatic cell interventions that would affect only the existing person or individual and germ line or gamete cell interventions, the kind of interventions that would affect all future generations.  Okay? Or potentially could affect all future generations.   Of course, there are some ethical issues that transcend that boundary.  So I'm going to mention some of those first.  And, of course, we have a whole set of issues that are research ethics issues, right? And we have research ethics issues regardless of whether we were doing somatic or germ line.  In many countries in the world, there are very few opportunities or no opportunities to actually do research on human embryos.  In this country, you cannot do such research using federal funding. 

 So, most of what I'm going to say here really applies to somatic just because people really, at least credible researchers who are following the law, with federal funding would not be doing that research.   All right, so, of course, the overall question and one of the most important ones in a research protocol are whether the risks and uncertainties are justified in relation to the value of the knowledge that you would gain from the study, and potential for benefit, if any, to the research participant, right? And, of course, with this kind of brand new technology, there are risks and there are uncertainties and there are many just completely unknowns.  There are domains of massive ignorance.  So, some of the risks, as I mentioned earlier, have to do with off-target effects.  That is changing genes that you did not intend to change and you might not know that you've changed.  Another thing with somatic therapy might be mosaicism, right? That not all of the cells would necessarily be changed.  So if you're targeting a certain cell type in the body, maybe you're trying to target islet cells in a person's pancreas to help a person with diabetes produce insulin.  Whatever kind of cell type you are trying to target, not all of the cells will necessarily be changed.  And so some cells will be changed, some cells won't.  That is a kind of mosaic. 

 And the question is, what impact does that have on the person's functioning?  And to try and even assess what the risks are, of course we need preclinical data, right? And preclinical data is not going to give us all the information we need, but, you know, if we do a good job, it'll give us the best information we can get before we move forward.  One of the important questions that I'll talk about in a minute is, what kind of preclinical information should we have? How do we know when it's appropriate to move from animal models, tissue culture models, in vitro models into the first-in-human trials of a brand new technology?  Some of the questions that come up when you're doing first-in-human trials, one question would be dosing, right? So when you do a first-in-human drug trial, you often start out trying to understand the biochemistry of the drug using a subtherapeutic dose.  But, of course, if what you're doing here is transferring living cells that have been modified, then it's not clear that the concept of dosing-- It certainly can't be thought about the same way you thinking about a non-living, dosing with a non-living thing, right? Because whatever you put in, the cells are going to multiply, but you don't know necessarily how well they will multiply in the person.  And so the question is perhaps instead of thinking about dosing, we might think of some other criterion aside from dose, such as how can we reach a target number of cells? What should the target number of cells be for a certain inoculant? Those kinds of questions that have to be thought out.   There's also the question of what happens if something goes wrong.  What happens if you modify genes and you get some off-target effects and something goes really wrong? Or you put in edited cells and they grow out of control or in places that you don't expect them to establish?  So, of course, there are a number of things that you can try to do technically to make these kinds of changes reversible or build in the possibility that you could essentially turn off a new allele or a new gene that you're putting in.  Things like that.  You sort of have to judge that on a case by case basis because it depends on what kind of modification you're trying to make.  Are you trying to take genes out? Are you trying to modify existing genes? It depends on what you're trying to do.  I think the important point in terms of research oversight is that the oversight committees have to be asking that question. 

 What kinds of technological and other backstops do you have in case something goes wrong?  And so, actually, I just can say really quickly there's this concept of suicide genes, right? That you can modify genes in ways that if you expose the person to a certain chemical or something like that, then the gene would cease to function.  You know, it's so clear to me in humans how well that works.  Whether it, you know-- Under what conditions we could get that to work.   So, some people might think that it's sort of random.  So the governance for research, and particularly for somatic cell research, many people think, well, okay, there are risks and there are uncertainties, but essentially every country where biomedical research is done seriously has a governance process for doing it, has oversight committees that apply certain regulations as we do in the United States.  They're called Institutional Review Boards.  Institutional Review Boards apply a set of regulations that the federal government has put forth.   They function in most research settings, not all.  So, what kind of criteria should be applied if you're going to be doing first-in-human trials? So, I'm putting out here the idea that there are criteria, and we need to think about them seriously.  Somebody who has developed a set of criteria and really elaborated on them is Jonathan Kimmelman from Canada who did this in the context of stem cell clinical trials. 

 And when is it appropriate to move from the pre-clinical models into first-in-human trials, right? And so in his model we talk about evaluating the pre-clinical trials.  I'm looking for internal validity, first of all.  So the methodological rigor of those studies.  And there are a lot of things that happen in pre-clinical studies.  So these are in vitro studies or animal model studies that we could do better, right? So one thing we don't often do is that the researchers are not necessarily blinded to, for instance, which animals have the treatment and which don't, which have the control.  If we want to improve the reproducibility of pre-clinical research, one thing we might think about doing is really making sure that the basic science or bench researchers in pre-clinical research are actually blinded.   So, that might be, when we're talking about things like internal validity and methodological rigor, that might be one thing we would consider.  External validity.  So, was it the right animal model? Was it a good model of human disease? Was it a good model for the particular human biochemical pathway that you are proposing to intervene on? And that, of course, depends on exactly what disease and what biochemical pathway.  And then, finally, were the research questions that are asked in the pre-clinical context, were they the same kind of question using the same kind of genetic constructs or cells or whatever that you are proposing to use in the human being? So the correspondence, how well did the pre-clinical research really model what you want to do in you clinical trial?  So that is one set of criteria that has been proposed, and I actually think it's quite a good starting place. 

 And Jonathan has written a number of papers where he has elaborated on this.  So I recommend those to you.   All right, so that's a little bit about sort of the research ethics piece of this.  There's another piece that is sort of whether it was research or clinical application that concerns people.  And, again, this is something that crosses both somatic and germ line.  It's the possibility that people might try to enhance themselves or become enhanced in various ways, whether that might be-- And so one of the issues with enhancement is, what do we define as enhancement? Some people would say that giving people vaccinations is a kind of enhancement.  You are causing the human body to basically do something that it can't do on its own and or to resist disease better than it might do on its own.  So some people would even count that as enhancement.  You know, most people when they think of enhancement, they think of you want to try and make yourself or your child, you know, faster, stronger, smarter.   You know, if you wanted your child to be a musician that you would try to, or yourself, you would try to improve the qualities that make a good musician. 

  Or that you might try and give a person capacities that no person has had before.  So people have talked, again, about building in kind of genetic modules that would permit people to be resistant to certain infectious organisms that we're susceptible to now.   Or you might think about, for instance, giving people more active smell receptors so that they could do things that we can't do now.  There are all kinds of things you could imagine as possible enhancements.  People are not necessarily going to agree about what counts as an enhancement or whether an enhancement would be desirable or undesirable or whether we should ever attempt it.  In fact, the Hinxton Group apparently deliberated about enhancement and couldn't even come to agreement about what counted as enhancement and didn't say much about it in their ultimate report because they couldn't get agreement.   So I think I've pretty much said this.   And so, you know, whatever counts as an enhancement for you, we have to ask the question whether it's categorically wrong to ever try and do it.  And that is not a question that people agree on.  I think we can have-- People have concerns about justice, right? That if somehow enhancements are not available to everybody, then you might sort of build a permanent genetic overclass. 

  That assumes that...   that the qualities that create an overclass are known and transmissible through genomes, which may or may not be true.  I think we don't want to put too much-- We don't want to be genetic determinists.  We don't want to assume that we could make, you know, somebody truly and actually smarter, stronger, faster-- Stronger probably, but smarter, faster necessarily, just by doing a genetic modification.  Even if you did genetic modifications to make somebody faster, they still probably have to work out a lot, right? And they might be motivated to do that.  So just because you made the genetic change doesn't mean you're actually going to be or have a child who is faster.   So we shouldn't put too much emphasis on genetics At the same time, I think even if all you're doing is increasing chances for some people.   If certain groups and societies systematically increase their chances of having desirable qualities, then, in some sense, you could pass, you could potentially create some kind of genetic overclass.  So there are real justice issues there, if everybody doesn't have access to it.  I also think it's worth asking yourself whether you feel the same way about a somatic enhancement. 

 More difficult to do, probably more limited in what you could do, and those are enhancements that would only affect the person who did it to themselves versus germ line enhancements, where you would be enhancing, potentially enhancing an offspring and anybody in that lineage.  So, a lot of people feel, even if they think some enhancement might be okay, they might think that germ line enhancement, not so okay.   The other thing I think about a lot is that, because I do some research oversight, and so one thing to consider is how we would do experiments, like credible, legitimate, human subject experiments on enhancement.  So one of the things you have to do when you do research oversight is think about do the risks-- Are the benefits in terms of advances in knowledge and potential benefits to individuals, if any, individual participants, are those--  Do those benefits justify any risks that people are susceptible to? But it's not so clear, like for some of these enhancements, like you might have to follow somebody for years and years to know whether that enhancement ever materialized, and if it didn't materialize...   that might just mean that the person wasn't motivated to act in ways that caused the genetic change to actually eventuate as a benefit, right? It's not so clear how you actually weigh the benefits or measure the potential benefits in the case of enhancement.  It's a lot easier when you're talking about intervening on a human being to treat some disease or condition or attempt to do that as part of research because you have this idea that you're basically-- You have things that you know you can measure.  Whether it's drops in blood pressure, longer life, better functioning, right? That comes closer to sort of average person functioning.  It's a little easier to measure those things when you're talking about research where we're attempting to treat a disease or condition versus research where we would be trying to do enhancements.   So enhancements is one set of questions that weighs on people's minds.  All right, now I want to get to the thing that is perhaps most disturbing to people, which is germ line modifications, which might be enhancements, which might be attempts to really do what some people have perhaps crassly referred to as one and done treatment. 

 So if you have an inherited Mendelian condition in your family, the idea might be, well, if the best way to treat this was with some genetic modification, how does it make sense to say that you do a somatic modification on a born person? That person's going to grow up and have some probability, either 25% or it depends on what kind of genetic problem it is, they're going to have some probability of having offspring with the same problem, right? So, what? Then you have to treat all their offspring also, potentially, or some proportion of their offspring potentially.  Why not just modify the germ line and be done with it?  So, although there are perhaps a lot more ethical concerns that people have about modifying germ line, there are also reasons people think, oh, you know, it would make sense under certain circumstances to do it.   So the concerns that people have about this are that it could introduce a harm that was, first of all, difficult to get.  It might perpetuate through generations.  Or even if you could undo that harm, now you have sort of made somebody who is born worse off in ways that you might not be able to fix.   Because if it's something that happens early in development, there might not be any good way of undoing the problem.   So there's that.   One thing I hear a lot, future people can't give consent.  People who do not yet exist can't give consent to having their genomes interfered with in some way, and so that makes this wrong.  I personally find this argument less than compelling because almost everything we do, whether it's changing our environment, whom we choose to have children with, everything we do is going to affect future people's genome. 

 And it's true that they don't consent to any of it, right? That doesn't make gene editing particularly unique, and since they can't consent to anything we might do ever, does that mean we should not make any attempt to give birth to children who are likely to have a better life? Or give birth to children who might suffer less than somebody else to whom we could have given birth? Right? So, for me, the argument about consent from future generations, I think it's just not very compelling, but it's an argument that you hear a lot.   Another set of concerns has to do with the sort of world we would be creating, if we modified our children and our children's traits became sort of the subject of marketplace values, and that might then cause our children themselves to become treated like widgets that we buy or coach bags or something, right? Where the same kinds of values that we bring to consuming other things begin to apply to our children.  That is one whole set of concerns...   and so coming along with that is this concern that then we might actually treat our children worse than we otherwise would have, right? Because we begin to view them as consumer commodities and not as beings whose particular special individual qualities are ones that we need to interact with and nurture, but rather as beings whom we have shaped according to our preferences and desires.  And, again, this idea of baking in injustice, not just for the existing generation, but by baking in I mean somehow sort of genetically making that injustice more intrinsic in a sense, or making inequality more intrinsic.   All right.  So, that's just a little tiny overview of some of the ethical issues that people have raised in the somatic cell, the germ line intervention context, in the research context, and in the application context.  I think in the real world, the biggest concern is that it's not as much about researchers.  There's a fair amount of oversight over researchers.   A bigger concern, perhaps, is with assisted reproductive clinics, where there is already a history of sort of rogue clinics for things like stem cells and where assisted reproductive clinics in many countries are not that well regulated or barely regulated. 

 And where there might be really desperate people wanting to have children and willing to pay almost anything to do that.  You know, or willing to have children with certain characteristics or without certain diseases or something and willing to pay, even willing to break laws if there are existing laws.   And so, you know, the question is, what kind of infrastructure should we have to oversee this set of activities now that, you know, CRISPR Cas9 is simple and cheap and it's being done already all over the world.  It's not like it's just being done in one place.  And if we're concerned about sort of nefarious uses or uses that could be truly harmful, especially in, you know, assisted reproduction clinics, many of those clinics are in developing countries, in places that don't have good oversight systems necessarily, or they might have good laws but very little capacity to enforce those laws.  And, by the way, that's not only developing countries.  In the United States, the FDA purportedly has jurisdiction over attempts to use stem cells as medical therapy.  I think it does have jurisdiction over that.  Nonetheless, sort of some stem cell clinics and some medical uses of stem cells have popped up.  They are happening even in the United States probably because the FDA doesn't have enough people to go out and inspect and find and catch them all. 

  So enforcement can be a problem across the board.  If there's enough demand for some of these kinds of genetic interventions, then, you know, the fear is that clinics will pop up and try to do it even though, from a scientific point of view, we are not ready to move into first-in-human, especially not in the reproductive context.  You know, in certain somatic cell contexts, like the adoptive T cell transfers, I think we are already doing adoptive T cell transfers using genetically modified cells.  They were just modified in a different way, right? There, using CRISPR Cas9, it doesn't seem beyond the bounds at all, but going into reproductive context is a completely different thing.  So, how do we do this? Well, I'm just going to say really quickly that in the somatic context most people think that the oversight is sufficient, right? That there are ethical questions, but that every country has systems to deal with that.  I worry that there might be a little bit of complacency around that.  Just the complacency that, you know, with a little bit of irrational exuberance about how wonderful and great and cool and potentially lifesaving this technology is that people might go into human trials too quickly or in a way where the oversight processes are not as scrupulous as they could be.  Nonetheless, I think it is correct that we do at least have good oversight infrastructure in most countries.  And it's really for germ line that there's the biggest concern because of these clinics that are much less regulated and because there might be very strong demand.  And so then the question is, what is an acceptable path forward? And I think we really have two domains that we need to think about governing. 

 They wouldn't necessarily be governed together.  In the United States, they are not governed together, the research community and reproductive clinics.  And the thing about these two domains is research communities, you know, they're very separate socially, right? So, among researchers, you can govern in part by influencing people's reputation within their scientific community because that matters to us a lot.  It affects our-- As scientists, it affects our future prospects quite a lot.  It affects our funding prospects and so forth, right? Our reputations within the scientific community matter.  And that's true even across national boundaries.  So just through reputational signals there is a way to kind of keep most of the scientific community within a certain set of norms, but it's a very different community than the community of people who work in reproductive clinics.  And they might have a completely different set of reputational norms, like it's super cool if you get a baby born.   And the idea that that might be jeopardizing research by causing a huge backlash might not matter to them that much, right? Whereas the people who are in the research community, and who can genuinely imagine all kinds of amazing applications for this technology but who want those applications to be developed in a thoughtful and rigorous way.  You know, if you tell somebody that going off to do that could jeopardize our opportunities to do all these other kinds of research because of public backlash, that matters to people in the research community. 

 It does not necessarily matter to people in the reproductive clinic community, or not to all of them at any rate.   So I just want to say something about governance models because there are a number of these models that have been developed over the years and by governance scholars in political science and law.  So one model thinks of governance as a kind of top down activity that uses a lot of rules that are set by a regulator and enforced by that regulator and maybe these soft law tools of governance, such as reputation, such as kind of education and voluntary standards.  Those are things that we call soft law or, you know, they're kinds of governance tools that you use to shape the behavior of a regulated industry or group of people or governed group of people.   But they don't necessarily-- There's no statute or regulation.  They're not necessarily enforceable.  In fact, most soft law is not legally enforceable, but it still works to shape people's behavior.  So the first model of governance doesn't really focus on those soft law tools very much.  And it assumes that there are some strong central authority.   Another model thinks about governance as not having a single strong central authority but having many nodes of authority that have influence over at least some of the regulated people or some of the people who are trying to be governed. 

 And there are sort of networks of power and influence and governance.  In the network or network within network model, the authority is more diffuse, and there are more soft law tools that are typically used in that model, right? So, more things that are not actually law but are things like voluntary guidelines and standards.   Community engagement where groups of stakeholders and maybe publics come together to discuss this and set some boundaries on what the activities might be.   And then, finally, we have what's often called sort of the furthest extreme.  The furthest away from the top down authority model would be what some of us call experimental governance, where the power is sort of very, very diffuse and, essentially, most of the governance tools are not regulation or statute, are not legally enforceable but they are soft law kinds of governance tools.  In the so-called experimentalist model, there is lots and lots of consultation at many different levels.  And people have said that this model is mostly effective where the people who come together and want to shape behavior, such as different country's governments, where those people don't have a good idea of what mechanisms will best shape behavior, then this kind of a model, the third model, might work better or people might gravitate toward it.  So, as I said, substantial consultation.  Both model one and model two are often viewed to some degree more like something that incorporates a quality improvement approach, where part of the reason you don't want hard law, like regulation or statute, is because you want standards that can be updated as you get more information about how you're governance is working.  So where are the problems? Okay, then you want to be able to modify the standard. 

 That's a lot easier to do if it's not a regulation or it's not a statute.  And so there's a kind of quality improvement concept.  Of course, to do that, you actually have to be getting information back up from the ground, right? You have to have some metrics for measuring whether or not the governance is working.  So I would say with CRISPR Cas9 we are definitely not in the first model, in the sense that there is no central authority internationally who can make laws and everybody in every country has to follow it, right? We are not in that model.  We are going to be more in the second or third model.  And just to give you some examples, in Europe-- So, 15 of the 22 nations, last I looked...   prohibit every kind, and in any context, germ line genetic modification.  And there is actually a UN document that a number of those countries have signed on to.  Whether it's in the research context or in the clinical context, many European countries, people are not so worried about germ line modification necessarily because they just think it couldn't happen because it's just against the law.   The UK is a little bit different. 

 They have the HFEA.  It's a regulator.  It reviews proposals, whether those are research proposals to do something where you might modify an embryo or whether they are actually proposals from reproductive clinics to do things that might modify, genetically modify an embryo.  The HFEA operates within a UK law, but it also develops new sorts of ethical frameworks as the technology advances.  So at least some kinds of embryo modifications might be possible in the UK.  When they take a big step, they tend to do lots of consultations.  They recently took a big step of permitting what some people-- It's a kind of genetic modification where you allow the fertilized egg from a couple where the woman has a mitochondrial, a disease that is caused by problems in her mitochondrial genome.  She and her husband or her partner, they have a fertilized egg.  Then they take the nucleus of that egg, and you put it into the enucleated oocyte from a woman whose mitochondria is fine, or are fine, I guess.  So that's a kind of-- Now that child will be born effectively having three genetic parents because it has the mitochondrial genome of one woman and the then combined nuclear genome of two other parents, right? So that was viewed as a very big step. 

 They did a lot of public consultations before they decided that that was an okay thing to try and do.  Those public consultations have been criticized, but it seems to me every time I've seen any government or any agency or any authority try and do public consultations, they are always criticized, right? I've never seen one happen where people were truly happy with it.  Still, almost everybody thinks doing it is way better than not doing it in terms of working on governance in a pluralistic society and in a democracy where people are going to have differing viewpoints, then how do we set the boundaries? How are we respectful to the people whose values and beliefs are not necessarily reflected in the way we set the boundaries? It doesn't mean that we just ignore them or trample them, right? And so consultations are something that people, I think, still value and think are important even though they're never happy with them when they're done And, actually, I've just put the website for the HFEA, so you can go on there.  You can see they actually have a listing of what kinds of experiments, for instance, they've approved.   All right, so in the United States, on the other hand, what are the legal constraints? Well, the federal government can't fund research that harms human embryos.  And this is actually the language So, basically, you can't do anything to an embryo.  You can't destroy it, discard it.  You can't create embryos for research purposes only, and you can't do something to it that would be more dangerous than what you might do if you were trying to do some treatment to a fetus in utero to help save it, basically.  So, that pretty much constrains any kind of federally funded embryo research.  Now, there is still privately funded research on human embryos, as we well know at this university, right?  So, in other words, some human genome--  Some germ line genome editing research could go on in the private context in this country, in the privately funded context in this country. 

 The other thing about this country is that assisted reproduction clinics are regulated very separately from research.  So, in the UK, they focus on its embryos, and they regulate both assisted reproduction and research on embryos all through the HFEA.  But, in the United States, we don't focus on the fact that it's embryos.  We focus on, in one context, that it's research, in another context that it's medicine and assisted reproduction.  And those are regulated very differently.   So the FDA says that it has jurisdiction over any attempt-- Anything that uses a transgene in humans, basically.  Any sort of genetic modification of humans, the FDA, at least for the attempts to treat or cure a condition, the FDA asserts jurisdiction over that.  Again, whether they can actually find-- The limits of their jurisdiction are perhaps not entirely clear, and whether they could actually enforce, if people started doing this, is another question.  And then we have the question of what about China, Singapore, Thailand, and other places where these technologies are also being used? So, as I understand it from some conversations with Chinese scholars...   it's not legal to modify human embryo for reproductive purposes in China. 

 It's still not clear to me, though, what the limits are on doing it for research purposes.   And, you know, it's also purportedly not legal, for instance, in China to have a stem cell therapy clinic, and yet there are numerous well documented examples of those clinics.  So, again, we might have this distinction between a law on the books and what actually happens in real life and that there might be a very significant distinction there.  So, I'm just going to give you a little bit of an overview of what people are thinking about governance in this context, which is that, of course, a lot of that governance is-- I mean it has to be soft law in the sense that there is no international authority, international legal authority.  And so, basically, that means you have to have persuasive groups of people who are persuasive to huge communities, like the research communities that might use this technology or assisted reproduction clinic communities, right? Or to national governments at the very least.  So you need international consultations, you need experts committees, you need to develop principles and then more specific guidelines for specific applications.  Right? But all of that is going to be persuasive.  And then that is going to be implemented by national governments instantiating those guidelines and recommendations and so forth into national law and oversight processes for overseeing both research and reproduction by professional societies that will then adopt these as their own guidelines.  And, for instance, in the United States, medicine is really regulated state by state.  State medical societies set enforceable rules for the practice of medicine in that state. 

 So, state medical societies could adopt some of this in the United States and actually create enforceable rules there, just as national governments can create enforceable rules.  And then we might think about a number of other things.  One thing that I've thought about a little bit is the idea of citizen monitoring, which is done in other contexts, where people out in the world who have an interest in the subject are following scientific literature or in other ways paying attention to what goes on and reporting that back to various authorities.  So this is used in the environmental law context in a number of countries, including this one, where you have some citizen monitoring, for instance, of points sources of pollution where people can get these pollution monitors from the EPA and if a factory near them is producing too much pollution, they can then report that to the EPA, right? So you have ideas like that.  I think in various contexts, for instance in the biomedical world, we have patient advocacy groups who do actually follow the scientific literature, who could notice what is being published and what technologies are being used.  It's harder for me to see exactly who the relevant players would be in relation to assisted reproduction clinics, which is where we have a lot more concern, but there might be some.  So, then what do you need to do with all of that? You need to feed it back to the international consultation because this has to be some kind of ongoing process, right? The technology is changing very rapidly.  The applications are ever more numerous.  And so there are a lot of issues that we will not be able to foresee at the outset.  So it has to be a set of ongoing processes where you're actually getting information from the ground and feeding it back into the oversight system. 

  And so then we just have some questions here, some of which I've already brought up, you know? So, how do we actually measure what is working and what doesn't work? The last thing I really want to tell you is that, in the US, the National Academy of Sciences is really pushing...   with a big initiative on gene editing.  So there will be, on December 1st through 3rd, there's going to be a three-day meeting on human genome editing.  That meeting will be live streamed.  So if you are interested in watching it, you can go to the National Academy's website, and you can find the information for the live streaming of that meeting.  There will be lots of-- There will be leading experts in the science and also in ethics and governance from around the world.  The meeting is being co-sponsored by the Chinese National Academy and the Royal Academy of Sciences or the Royal Academy? Yeah.  Of Sciences from the UK, right? So that is happening in December.  Then there will be a study committee that will do a sort of standard National Academy study and put out a report.   The US National Academy is also doing a study and a report on gene drives and the use of genome editing for agricultural purposes and outside of the human context. 

 So there's a lot going on, and you can go online.  There are reports published.  There are talks already that are online where experts have talked about different applications of gene editing, different problems that they've run into.  You can watch all the videos.  So, if you're interested in this topic...   there's a lot going on that you can have access to.  And with that, I will finish and invite any questions.  And here is my cartoon for finishing.  The music of life.  We are strumming a chromosome. 

 All right, thank you.  (audience applauding)