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Extended Interview: Hank Greely

Hank Greely, a law professor at Stanford, heads a group of ethicists who are keeping track of Dr. Irving Weissman's work transferring human brain cells to mice. The following is an extended interview with Greely.

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  • TOM BEARDEN:

    How did you get involved in this field? What happened?

  • HANK GREELY:

    Oh it's a long story. Chance really more than anything else. I married a physician and that led me to start teaching health law — the university was putting on a symposium on the human genome project in 1992; they wanted someone from the law school to be on the planning committee. I was the only likely person to be on the planning committee, had a wonderful time, loved the scientists I was working with, ended up giving a talk at the symposium that became a book — chapter in a book and that launched me into a really fascinating field.

    So I've been doing — I don't think of it so much as bioethics per se, but as more legal, social and ethical issues around bioscience since 1992, mainly genetics, but increasingly in recent years — stem cell issues, assisted reproduction, neuroscience, cloning, a host of really interesting issues.

  • TOM BEARDEN:

    How about chimeras? How did that start?

  • HANK GREELY:

    Well the chimera story started with a phone call from a colleague here at the medical school, a Dr. Irving Weissman. Irv Weissman was planning to do an experiment and he is a savvy guy and he thought he needed some advice about whether or not he should do this experiment because he was afraid there would be headlines "Stanford scientist makes mouse with human brain." So he asked me if I would, A) if I was interested. I said "sure." B) whether I would put together a group to give him some advice on ethical issues about this experiment. I said I would and I collected four other Stanford colleagues.

    We met for the space of about six months or so and we wrote a report giving him some formal advice about the experiment suggesting that he could ethically go forward with the experiment, but proposing some guidelines and some limits some checkpoints along the way to make sure that the experiment was staying within ethical bounds. Irv accepted our advice, but he has not yet done the experiment.

  • TOM BEARDEN:

    What were the checkpoints?

  • HANK GREELY:

    Well, the underlying experiment is to create a mouse whose brain has human neurons in it, functioning and working inside it. Dr. Weissman has found an isolated human brain stem cells, human stem cells that make not just the neurons in the brain but the other cells as well, the glial cells. And he'd like to be able to use those to study how human neurons work inside organisms.

    We humans are very bad experimental animals. You can't slice us up and dice us up the way you can lab rats. You can't treat us the way you do laboratory animals, but it would be really interesting to see how human neurons are affected by drugs, by chemicals, by radiation, by a bunch of different insults or possible treatments.

    You can't do very much with the human cells inside humans for fear of hurting the humans. You can put the cells inside a Petri dish inside laboratory equipment, but we know that cells that are isolated from bodies act differently than cells in bodies. You can study mouse cells in mice and hope that it tells you something about human cells but what Irv thought was, let's try to study human cells in a mouse. We can see the human cells inside a living organism but a living organism that unlike humans we can treat as a laboratory animal.

    He had previously successfully done that with human immune cells creating something called the "Skid U Mouse" which is a mouse with severe combined immune deficiency that's then given a human immune system. He came up with this along with a colleague in the late '80s and it's been used for a significant amount of research on the human immune system — originally planned for a studies on AIDS and it's been used for some HIV studies as well as other things.

    So his idea was let's do the same thing with human neurons. Let's make a mouse that has living functioning human neurons so we can examine and study those neurons inside a living system.

  • TOM BEARDEN:

    Why was he concerned about headlines and and do you share that concern?

  • HANK GREELY:

    Well, you know, I was. I was perhaps a little flip in describing it just as headlines he was concerned, not just about the fact that there would be headlines, but the fact that the headlines would reflect people's genuine concerns.

    And frankly if we made a mouse that had a fully human brain in it, I would be concerned. Part of what we did was to try to understand what the result would be if his experiment worked and our conclusion was he might make a mouse that had a brain made up of human neurons, but it almost certainly would be a mouse brain made up of human neurons.

    From our discussions with neuroscientists, including one on our working group, we learned that it's thought that it's the architecture that's important in brains not the building materials. If you make a building with red bricks to a cathedral specs if you follow an architect's design to build a cathedral it doesn't matter if it's red bricks or gray bricks, it's still a cathedral. If it's a gas station plan, it's a gas station. Well, if you make a mouse brain with human cells it's still going to be a mouse brain. Similarly, if you made a human brain with mouse cells, presumably it would still be a human brain.

    So what's important is the size, shape, structure of the brain because the mouse skull is much, much smaller than ours. Mouse brains are a thousandth the size of ours. They have different organization and they have different microstructure.

    So for example, mice have structures in their brain called whisker barrels, the whiskers on a mouse are sense organs, they use them to feel their way around in the dark. And so in their brain, the nerve that comes in from the whisker is surrounded by a bunch of other brain cells to transmit sensory information, locational information to the brain. Even we humans who have whiskers, don't have those kind of structures those whisker barrels. Mouse brains have whisker barrels, human brains don't.

    One of our checkpoints with Dr. Weissman's proposed experiment was when he first created the mice, killed them and looked in their brains and see if they're making whisker barrels or not. If everything in the brain looked like a mouse brain then we said the experiment can go forward. If, on the other hand, there were things in the brain that looked wrong that looked like human structures or that looked like very odd misshapen mouse structures, our advice was stop the experiment and talk about it.

    Decide what's actually going on in the brain and then discuss more broadly ethically whether one should go forward with the experiment given the facts that you've got. Our view was it's much better to try to decide these issues with some facts in hand rather than to say in advance, "Always go forward, never go forward."

    So our advice was the first checkpoint is before the mice are born, sacrifice them before birth, look in their brains and if there's anything that doesn't look like a normal mouse brain structure, stop the experiment. If everything looks like a normal mouse brain, let the mice be born, let them develop and do two things; watch their behavior, for things that are not normal mouse behavior.

    And then secondly, again kill some of them, look at their brains. Look to see whether their brains are developing in mouse shapes or developing in human shapes and once again if there's anything non-mouse about their behavior or about their brain, stop the experiment and talk about it.

  • TOM BEARDEN:

    Based on the reading I've done as background for the story it seems that there is a great concern in the scientific community about the reaction of the general public. The "yuck factor" is frequently quoted. Why is there so much concern about that?

  • HANK GREELY:

    Well I think there's concern on two levels. One is scientists are people too and share some of that "yuck factor." I'm not sure why the idea of a human brain inside a mouse would be so distressing to me, but a fully formed human brain inside a mouse seems to me really troublesome. It bothers me and I think scientist share that.

    They also, though, are concerned about political reactions leading them to not be able to do the science. They're worried about a political reaction that limits the science they can do and I think particularly these days with the whole controversy over human embryonic stem cells, scientists are particularly aware of the fact that what they can and can't do gets affected by politics. It's the political results is affected by whether average Americans think that scientists are trustworthy and doing good work or whether they're out-of-control mad scientists. There's a lot of reluctance to do anything that feeds the mad scientist stereotype.

  • TOM BEARDEN:

    Do you think that the recent release of the National Academy of Sciences guidelines will go a long way toward providing the guidance that some of these scientists obviously want?

  • HANK GREELY:

    I think so. I certainly hope so. I thought that they were very balanced and well thought through guidelines. Their guidelines on chimeras I thought were very useful. They suggested a couple of things that clearly no one wants to do and shouldn't be done. Any animals non-human animals that human embryonic stem cells have been put been put into should not be allowed to breed because you're always going to be a little worried that those human embryonic stem cells, you may have put them in the skull but they may have moved elsewhere and we don't want mice with human sperm or human eggs to be breeding. So that's something relatively easy to do. They can be sterilized or otherwise treated in a way that they don't breed.

    The other thing the NAS report suggested was particularly sensitive was putting human brain cells into a non-human animal. They didn't say that should be forbidden, they didn't say it should always be allowed, they said it should be considered very carefully by the ESCRO Committee, the Embryonic Stem Cell Research Oversight Committees that they recommend be created, and I agree entirely with that.

    In fact, to some extent I think what our working group did was the kind of investigation that an ESCRO should do in trying to decide whether a brain chimeric experiment should go forward or not.

  • TOM BEARDEN:

    Is the ESCRO approach something that's historically common in the past in scientific research, because it would seem to me that there's a danger of balkanization. For example, one ESCRO committee may say yes, another one may say no?

  • HANK GREELY:

    You know, it actually does fit fairly well with the way the United States has regulated human subject's research. We regulate that through what are called institutional review boards or IRBs and every research institution has its own IRB, the Stanford IRB or IRBs may have different positions than the IRBs at Berkeley or the IRBs at Harvard or at Yale. But we live with that kind of variation in order to get the sort of local expertise and the responsiveness to particular conditions that having a decentralized system brings us.

    The other thing the NAS report did though was recommend that in addition to local ESCROs, ESCROs at research institutions, there should be a national panel to give overall guidance to the ESCROs and I think that's a great idea as well. Already here at Stanford we've got several committees that are set up looking at how we're going to implement human embryonic stem cell research and we fully accept the National Academy's guidelines but there are some things that are ambiguous or uncertain. It will be really nice when there's a national panel to provide further guidance on the best way to approach some of these issues.

  • TOM BEARDEN:

    You mentioned some of the concerns critics have raised, the reproduction issue, the human brain in a mouse skull. Do you think those concerns are overblown?

  • HANK GREELY:

    I think the thing that scares people the most is the idea that there'd be a human consciousness inside a non-human animal. Franz Kafka wrote a famous story called Metamorphosis, about a man who was transformed overnight into a cockroach. He had a cockroach body, but he still had his own brain and his own consciousness.

    Now if in fact we made a mouse that had a human consciousness trapped inside there, that would be a terrible thing, but as far as we can tell there's no chance that that's going to happen. … The more you look at the neuroscience the less concerned you are about a full human consciousness being conferred into a non-human animal and then if you think about how to design the experiments carefully with appropriate checkpoints, if there's anything that looks like it's headed at all in that direction, you can stop the experiment and talk it over before deciding whether to go on or not.

    So I think people exaggerate the likelihood of the worst case result. I don't think they exaggerate how bad the worst case result would be, but the worst case result is somewhere between highly improbable and impossible.

  • TOM BEARDEN:

    Even for some of these animals to escape into the environment and interact in unpredictable ways?

  • HANK GREELY:

    Well you know it's not as if the human neurons are going to migrate from one animal to another. They're not like genes or like viruses and laboratory animals don't escape into the environment. And laboratory mice if they do escape in the environment don't do very well.

    I do think that if you move from mice to say chimpanzees, then some of these issues become much more troubling. The issue of doing this kind of an experiment with a chimpanzee would I think raise much more serious questions about conferring some, some human cognitive powers on the chimpanzee.

    I don't think you'd have a chimpanzee with a human consciousness, but you'd have a chimpanzee potentially at least that had more human abilities than they have now and that's troubling. It might not ultimately be a terrible thing but it's something we certainly should not go forward with, without a lot of discussion, both scientific and ethical.

  • TOM BEARDEN:

    What about the concerns of transmittal of diseases across the species barrier? That seems to be a more plausible concern.

  • HANK GREELY:

    Yeah, I think that's a real concern. It's a particularly strong concern though moving in the other direction putting non-human tissue into humans. There is a theoretical concern about the recombination of viruses. If you put human tissue into a non-human you might then have a mixture of a non-human virus and a human virus that combine or that the non-human virus might become humanized and that's an appropriate concern and it's one that has to be watched. I think it's one that can be dealt with but it is one that deserves attention and is getting attention.

  • TOM BEARDEN:

    Do you have any sense that the scientific community in the stem cell research, and chimeras as well, is sort of walking on broken glass here that they're very, very tentative because of the reaction we talked about earlier?

  • HANK GREELY:

    I think the scientific community is worried about the chimera issue, they see it as one that has the potential for a significant public backlash and particularly the scientists who aren't directly interested in doing chimeric experiments might be less than enthusiastic about the experiments going forward.

    But one thing that's clear, is that there are times when chimeric experiments — experiments making human, non-human chimeras — can be really important ways to try to learn new science. Science that gives us both basic scientific knowledge and knowledge of direct medical significance.

    So experiments making human, non-human chimeras have been decades. They've made some important advances. I think the human embryonic stem cells give it the opportunity to do some new and important science. It's crucial that that be done in the most ethical possible way and in a way that allays public fears as far as possible, but there is important science here that needs to be done.

  • TOM BEARDEN:

    Do you think other countries who may not be as concerned about the ethics as this one is, will do things that these guidelines and these recommendations, will go beyond that and do what they say they shouldn't do?

  • HANK GREELY:

    The reactions of different countries around the world to human embryonic stem cell research have been very different with some being very restrictive, much more restrictive than the United States, some being much more liberal than the United States. I think you'll see that probably as well with chimera experiments and some countries probably won't follow the National Academy of Sciences recommendations or at least some countries may not enforce upon their scientists following those recommendations.

    One of the clever things the National Academy did, though, was to request that scientific journals only publish papers from groups that have followed those recommendations. So if you're an aspiring scientist in China, you would love to have your article published by Nature and Science. If Nature and Science will only publish articles that have met the National Academy of Sciences' standards on embryonic stem cell research, than you're likely to follow those standards whether you're government requires you to or not.

  • TOM BEARDEN:

    Do you disagree with others who want to shut down this kind of research entirely?

  • HANK GREELY:

    Yes, I do. I'm not entirely sure what their objection is other than playing on the "yuck factor." There is a concern here that somehow it's wrong to cross species lines, that species are platonic ideals that need to be preserved inviolate, but that's not a scientific reality. We are not just humans. We carry inside us more non-human cells than we do human cells, we're walking ecosystems.

    Throughout nature a blending and a sharing between species happens all the time. In science we've been using human, non-human chimeras for a long time and have done some important science with it. So I do think there are some chimeric experiments that shouldn't be done, but I think there are a lot of chimeric experiments that should be done.

    I think it's important that we look at them on a case-by-case basis and decide which ones offer enough science and medical benefit to be worthwhile and which ones have so much risk that we shouldn't try them. The kind of blanket condemnation of any human, non-human chimeric research is unnatural I think is a foolish position.

  • TOM BEARDEN:

    You don't think there's a danger of a slippery slope?

  • HANK GREELY:

    One thing that often is said is the fear of a slippery slope if we start by putting brain cells, human brain cells into a mouse, the next we know we'll have a species of half-human, half-chimpanzee slaves, and that the slippery slope will lead us inevitably from one to the other. I'm not generally fond of slippery slope arguments. I think as moral actors we live on slippery slopes. The first time you break the speed limit, you've broken the law. One could argue you're on the slippery slope to murder, but we don't fall down the slippery slope. What our duty as moral actors to do is hold our positions on slippery slopes because everything we do in life puts us on a slippery slope. It's finding and holding to the right place that makes us moral people.

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