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Extended Interview: Irving Weissman

Dr. Irving Weissman, a Stanford University professor and cofounder of the biotech company StemCells Inc., is working on inserting human nerve cells into mice to investigate how human brain cancers form. The following is an extended interview with Weissman.

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    What's the value, what's the point of putting human brain cells in mice?


    Well there's two main reasons. The first reason is to be able to understand for the first time how human cells function in the context of a brain. So if you can get human cells out, especially human brain stem cells, that you can grow, genetically modify and put in a mouse brain, if they respond as they would in a human brain or as mouse brain cells in a mouse brain, then you can learn a lot about their normal development, their normal function their normal migration.

    But more important for us since we want to translate our discoveries to medicine are to understand and treat human diseases, mainly neurological diseases. So if we can have mouse brains that have genetic diseases than we can ask whether the human cells we put in have a chance of curing them so right now we're doing a disease called Batten's disease, that's a disease, a genetic disease, where a child that gets the disease first knows he or she has the disease at about one in the most severe form, then starts to lose sight, then starts to lose balance, then starts to lose thinking, then goes into a coma and inevitably dies. There's a single gene mutation that causes that and we're lucky enough that the product of that gene, an enzyme, can be made by one cell and then transferred over to another cell.

    So we've done preliminary experiments and this — we in this case is a company called StemCells — where human brain stem cells put into the brain of a mouse with this disease transfers enough enzyme to stop the disease at that stage.

    So that's one, but there are diseases that you know about, Alzheimer's, Lou Gehrig's disease, Parkinson's disease, spinal cord injury, stroke, multiple sclerosis, and a whole host of others that we can't study of course in the patients that have the disease, because we're not going to interfere with their lives, but if we can study it in an animal model than we can find out where we're going down the right track and when we're not going down the right track.

    And the final reason we do it and what we're mainly concentrating in my lab is to try to find out how human brain cancers form, what are the most dangerous cells within the brain cancer, we call them cancer stem cells, how they move from part of the brain to the next and how we can intervene to try to treat them.

    We've now done at least three kinds of human brain cancer. Glioblastoma, which is probably the most common and almost always fatal, Astrocytoma, Medullablastoma and so on. We found that when we put the human brain tumor directly from the surgery into the brain of an immunodeficient mouse it settles there and then over a period of two, three, four months it grows like it was starting in the human brain.

    When we show our pathologists who are experts at looking at brain cancer, they can't tell the difference between the brain cancer growing in the human brain that it comes from and the brain cancer in the mouse. We are well down the road, we and others, to isolate the cancer stem cell, that rare subset of cells that make more of themselves and are therefore dangerous and although the cancer stem cells unfortunately spread rapidly through the brain and therefore you'll never cure that by surgery or radiotherapy alone, we now have those cancer stem cells in our hands.

    Now let's say we wanted to try a therapy against that cancer. We get out the cancer stem cells, they're pure, they're only 1 percent of the cells from the brain cancer. We can now ask what genes they express and what proteins they make that are unique to the cancer stem cell and by reading that through we can say, ah here's a target. Whether it's a target for a drug or a target for what we call a T-cell immune response or an antibody response and we can test it.

    Because we got that cancer and we got the animal that's growing that cancer and it looks just like in the human. So what I like to tell people is if you're not interested in understanding and treating brain cancer, spinal cord injury, the genetic diseases like Batten's disease, the one we're trying, Parkinson's, Lou Gehrig's, Alzheimer's, and a whole host of other diseases, then tell me which one of those we shouldn't study because you think it's wrong morally, or objectionable in some way to be doing these experiments.

    But I can tell you that those of us who are dedicated to understand and treat disease look at these advances, normal human brain stem cells in the brain of a mouse, cancer human brain cells in the brain of a mouse, curative therapies, attempts for curative therapies. We're seeing this as a new way to work that we never had a chance before.


    Why did you stop and seek ethical advice before proceeding with your experiment?


    Well I wanted to make sure that if we ever went to the step of putting the human brain stem cells that didn't have these minor damages that we're looking at now, but had it damaged early in life where most or all the neurons die, I wanted to make sure if we ever tried to do the experiment to try to see how the human neurons grow there, that we checked carefully with anybody who felt they had legal, ethical, moral, religious input.

    So I went to Hank Greely, who is the head of our bioethics and I — what's that maybe four years ago — to get that opinion. Now unfortunately the post-doctoral fellow in my lab, who really wanted to work on it, has gone on to another career by now, but I think this was important because there are certain junctures where you know that if you make the next step unless it's completely disclosed to a totally informed public you're going to get to a barrier that's gonna disturb people.

    We haven't done that experiment, that is to put the human neural stem cells into a mouse that's going to lose all its neurons. We'll probably start with one that's just going to lose the balance neurons in the cerebellum. Hardly anybody or nobody thinks that thinking mind consciousness human characteristics exist in the balance part of the cerebellum. The real question will come when you get to the point of replacing neurons within the context of a mouse brain within the architecture of a mouse brain that are human instead of mouse.

    So we're waiting for Hank and the others to opine on it. I have a pretty good idea of how they're going to do it. I'm pretty sure where we're gonna go. It would be step-wise, if we did the experiment and we haven't, we would put the cells into a mouse halfway through the pregnancy of the mouse and then three-quarters of the way through the pregnancy we'd interrupt the mouse pregnancy and we'd look at the brain that was forming.

    Since we have markers for human cells versus mouse cells we'll know the extent to which human cells would replace mouse cells. We'll know if their starting to reconstruct a mouse-type brain architecture or a human-type brain architecture. Will it have the complexity, the many more layers, the many more interconnections that occur in the large human brain? Or will they because the limits of the architecture of a mouse brain, simply be human cells replacing mouse cells?

    When we get to that point, whichever way it comes out, I mean the most likely is that it won't repair the brain at all, but if it starts to repair, whether it's mouse-like or human-like, and we go back to the ethicists and say "OK now, what's next?" If it's fully human are you convinced that it's not a human persona growing up in that brain and if you are, tell us how.

    Because I can say, on the other hand, when they say, "Well, why do you do this at all? Why are you even thinking about it?" We have centuries of development of drugs that work on human brains, that work on human brain cells. We have mind-altering substances, we have pain relieving substances, this is a big deal and I'd hate to say this but the pharmacology of human diseases whether they're psychiatric, pain and whatever is extremely primitive. It's extremely primitive because we don't know what's going on and we can't do the experiments to find out what's going on.

    But if you have a human set of neurons, pain, hippocampus, learning, whatever in the context of the mouse brain you could try a drug and say, "What does this do to a simple learning task? What does this do to perception of a smell?" and so on.

    So I can tell you the benefits if they say to go forward. They've got to tell me the risks of going forward in their mind ethically, but they've got to be real about it because we're working at an edge where stopping the work means a very big thing. It means you're gonna leave aside those people who might have been treated for a horrible disease in that tiny time window that they could have been treated.

    So stopping research is not what I think is an ideal outcome. Regulating it, having ethicists oversee it, having legal people oversee it, that's fine. We're willing to do that. We, in fact, as I said look for it, but stopping research — think about this. If somebody in a position of authority, say Sen. Sam Brownback puts in a bill to say I don't like this research for these, these and these reasons and it actually stops the research. Then I would say, "You better be right, Sam, because what you're doing for sure will affect the lives of people and are you willing to accept the moral responsibility for the lives lost and damage because you didn't like some human cells in a mouse brain?"


    In some sense, are scientists like yourself treading very carefully through an ethical and moral minefield concerned about public reaction?


    Absolutely, absolutely. I mean from embryonic stem cells to this nuclear transfer, what the South Koreans have done, we should have but they did to human neural stem cell research. We are treading on grounds. It's a good thing we're treading on ethical grounds it means we're getting close to important issues.


    Are you concerned that scientists might self-censor themselves in terms of not pursuing certain avenues of investigation because of those sorts of concerns?


    Well they are, they are. I mean how many young people are deciding which field to go into on the basis of whether it will be a field in the future or not? A lot, and so they got lots of choices they can pursue science one way or another and that's the most effective kind of censorship, lack of bright young minds coming into a field.


    So what's the solution to this? How do you go about beyond just talking to lawyers? I mean what's the large, if there is a larger solution in society to make people more accepting of this kind of research?


    I think that both the legislative and the executive branch of the federal government needs to get absolutely objective advice about science as it confronts these ethical issues. This particular administration has chosen not to take objective advice so Leon Kass and the president's bioethics counsel is a political group chosen for their political opinions and when a scientist on the group said, " You're not really making judgments based on real science," she got fired, Liz Blackburn. So this is a very disturbing departure from what we would call the American way of thinking and doing things.

    Usually when the president asks, for example, the National Academy of Sciences or Medicine to opine on a subject, to give them objective responses the committee experts are experts in the field. The committee members have to say before they even look at the data that they're gonna look at data but have no pre-judgment as to the outcome. The third and important one is they keep their mouth shut until they can have seen all the data and make this opinion. None of those fit the president's bioethics counsel.

    So let me just take it one step further because it's very important for Americans to understand this and I'm an American. In the 1970s and early 1980s, huge genetic discoveries, Stanford and UCSF, Pallberg, Stanley Cohen, Herb Boyer found a way to splice together DNA and put a human gene into a bacterial chromosome.

    They first self-censored the people doing this kind of recombinant DNA research to make sure it was safe, but all the time that the announcement that this research was going on, lots of political opinions were forming and religious opinions were forming and this research was almost banned. It was almost banned in Berkeley, almost banned in Cambridge, almost banned in Congress but then some smart people said why doesn't the NIH get a regulatory body to look case-by-case every time you wanted to do a recombinant DNA experiment and for commercial entities the FDA and that's what they did and that's how biotechnology was born.

    We regulated rather than banned the line of research. Well, all of biotechnology came from that. If you know anyone who gets insulin or erythropoietin or herceptin or any of these fantastic drugs, proteins. It all came from there. In Russia in the 1920s and 1930s, a maverick biologist named Lysenko convinced Stalin that Darwin was wrong about natural selection and genetics and some French philosopher Lamarck was right. We won't go into what those differences are. … We won't go into the actual science although it's not too hard to explain but to say that Stalin chose Lysenko's Lamarckism. Banned Darwin and genetics research, the two heads of the genetics research institutes in Russia and by the way Russia at the time was equal to us in genetics, were fired. One went to jail and died in Siberia or Mongolia or wherever — Siberia I think it was. All of the others either changed jobs or left the country.

    A great American geneticist there Muller came back to the U.S. A great young Russian geneticist Dobzhansky came to Caltech, together they with the U.S. group established the U.S. as the pre-eminent country in genetics research and that led to everything we know about the genome project, recombinant DNA, counseling families and for 50 years in Russia the crops failed because they picked the wrong way. They didn't teach Darwin genetics so nobody could come up understanding what the real world genetics was. They didn't produce a geneticist worth spit and all of that because of an ideological opinion of what was right.

    Now you tell me the difference between that ideological opinion and the Brownback-Welden bill which is an ideological opinion. So we're confronting something that has historical precedence. It is really important for the American people. It's important because we're going to sit and watch South Korea or Japan or Singapore or especially mainland China or the UK or Sweden go forward and all of these kinds of experiments, they're being just as careful I think as we are in approaching the bioethical, the medical ethical, the legal issues but we're gonna watch somebody else do it if we don't proceed. I should have added the state of California. We're going to watch it happen in the state of California.


    Briefly talk me through the process of how you go about putting these human cells in the rodents.


    What you do whether it's normal human neural cells or brain cancer is you get cells out of the brain; you destroy the connections between cells by an enzyme called Collaginase and another enzyme call Tripsin, now they're single cell suspensions. We wash them free of all the debris and we like to say we want to see only the subset that are the neural stem cells or the brain cancer stem cells.

    So we actually have made a whole panel of what's called monoclonal antibodies, each one of which sees only a certain kind of molecule on the surface of the cell. And we label some green, some red, some blue, some yellow and we run it through a machine invented at Stanford by the Hertzenbergs called the florescence activated cell sorter. And it sorts out green and yellow but not blue if that's what you want.

    Now we take the tube that has what we think are the candidate normal or cancer stem cells and it's just trivial. You have a mouse at birth that is genetically immunodeficient. Has the bubble boy disease that John Travolta played, can't make an immune response against humans and you inject anywhere from a thousand to a million of those cells into the inner fluid containing cavity of the brain, the base of the brain called the lateral ventricle. They have to do it under very precise conditions, it's called stereotaxic to get the needle exactly in the right place do a small injection, take out but the whole process probably takes what five or 10 minutes? Yeah good, having never done it myself. So that's it.

    Then you put the animals back. They grow up with their mom, they get weaned and you follow them. They follow the cancer ones by magnetic resonance imaging to try to see can they tell before they see a tumor is it grown.

    Another way to do it, which we're just starting out, you can put an enzyme into the cancer cell which emits light, light so strong that it can go through the skull and Chris Kontag and his group here at Stanford know how to image that light precisely so we hope to be able to follow the growth and the spread of the tumor so that at the right time we can stop the experiment and see what happened. So that's you know A to Z what the experiment might be.


    Chimeric animals have been around for a long time, why do you think the public is so concerned about it now?


    Well in the past the chimeric animals were mainly animals that we constructed with an organ wasn't seemingly so important, skin a bit of heart, a cancer. Now we're getting at the center of the issue, the brain and since the brain most of us believe is the place where the human properties of mind, consciousness, learning, memory, emotion … of course we should be interested in it.

    The sad thing is that this isn't so far just an objective interest. It falls along a political gulf that I just described to you, you read the names of the people who found this disturbing it's the same people who are opposing nuclear transfer research or embryonic stem cell research. A lot of them still oppose recombinant DNA even though it could save them and their families.

    So it's a bigger line now and of course for at least the embryonic stem cell research and the nuclear transfer research they have the president on their side and it's not like the president is totally neutral. The president has said he backs the Brownback-Welden bill to criminalize embryonic stem cell research of the type we haven't talked about but it's an important issue. Criminalize meaning if you do the research, a million dollars fine and 10 years in jail. If you're a patient that goes say to Europe to get a therapy based on that research, million dollar fine, 10 years in jail, the doctor who prescribes it, million dollar fine, 10 years in jail.

    I think that the issue of brain chimeras piggybacks on the whole issue of embryonic stem cell research, nuclear transfer research that has politically divided the U.S. largely because as I said, the president has made his position known, he's taken a hard stand on it and unfortunately a number of senators and congressmen and congresswomen have followed him.


    What's your reaction to the recent publication by the NAS of their guidelines?


    Terrific terrific, so the National Academies of Science and Medicine and so on came out with guidelines to think through each of the issues whether it's embryonic stem cells or even the neural stem cells, thought through the chimera issue.

    Now that's the right thing for the National Academies to do. Usually the National Academies they are asked by the federal government to do it, not this time. Why? Because the federal government is not in the game for embryonic stem cells or nuclear transfer, so the normal place you would seek for that advice, you can't get it. So the kind of advice they can give doesn't have the force of the executive branch of the government right?

    If their recommendations could be accepted by the government as part of a process they ask for then you'd have all the guidelines. You'd have institutional review boards at every university looking at the issue of the experiment. You'd have Supri institutional ones looking at it. The NIH would look at it. The FDA would look at it. You'd have everybody who should be involved, involved. None of them are involved, none.

    So they had to say our guideline is you should develop those institutions of review, oversight, ethics, legal issues at every institution that you do this research. They couldn't say more because there's no other device to do it. So I'm glad for the advice. I'm glad they thought through the issue. I'm glad they decided that the research was important enough to keep going.


    Talk us through what you know about what happens when the stem cells are implanted.


    When you put human neural stem cells into the lateral ventricle of a mouse, this fluid bathing space, they adhere to the wall of the ventricle, that's lucky, that's just plain luck for us, because that's where just under the wall of the ventricle the normal neural stem cells reside. These respond to the cues and they go into those sites. Like the normal neural stem cells that are there they start dividing. When they divide on average, one neural stem cell will give rise to one more neural stem cell, the other daughter cell will start going down the process of differentiation. One of the steps of going down that process, still we don't understand it is to commit to become a neuron and maybe to commit to become a neuron that's found in the olfactory bulb and secretes a particular factor, GABA something else that is a transmitter, a neurotransmitter. Well, amazingly the human cells that have made that commitment to be a neuron in the olfactory bulb follow a path discovered by Arturo Alvarez Bouilla now at UC San Francisco, and they go right down that path and land in the olfactory bulb and become neurons.

    Now when you look carefully at the anatomy of that pathway it's actually a tube and we didn't know that the cells were on the outside of the tube that helped guide the neurons to go through the tube to the olfactory bulb. When Lori and Sam and I looked at this tumor called an anaplastic astrocytoma, we got the answer. That cell, that cancer could make astrocytes but couldn't make neurons, genetically couldn't do it anymore. It made the tube; it made the tube in the mouse. So now we got the tube without the neurons. That's an amazing finding. We have to publish it you guys, we have to write it up.


    Do those human cells when they're in the mouse brain function the same way that the mouse brain cells do?


    We suspect. We won't know until we can have a robust enough system to bring in the neurophysiologist to put little probes in each cell. You have to mark the cell so we have to put a gene that makes a jellyfish green fluorescent protein so that when you look at that part of the brain you'll see exactly the cell, you could put a probe into it. We're still looking for the neurophysiologist to do that part with us so we can't answer that question, but in general as Eric Shooter here at Stanford was first to show neurons don't stay alive unless they're connected. If they don't connect correctly they die and another neuron takes it place to try to make the right connection. So we can imply but not say for sure because we see neurons throughout the brain and every part of the brain derived from the human precursor a lot of them must have connected appropriately.