By Alan Boyle Science editor
msnbc.com
updated 8/10/2005 3:28:43 PM ET 2005-08-10T19:28:43

To his fans, he's the "Defender of Dignity." To his detractors, he's the "Irrationalist in Chief."

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In the four years since Dr. Leon Kass was named chairman of the President's Council on Bioethics, his observations have riled those who favor going further on the frontiers of human embryonic stem cell research and therapeutic cloning — and have rallied those who worry about the frontier's ethical and moral pitfalls.

Three months ago, Kass and his fellow council members issued a white paper outlining research avenues that might yield the benefits of embryonic stem cells while staying within federal funding guidelines on the use of human embryos. During a mid-July interview with MSNBC.com, Kass discussed the white paper — as well as dramatic developments that have come to light since the report was issued.

Kass emphasized that the four alternative approaches outlined in the white paper were not meant as "recommendations" for future legislation — but in fact they dovetailed with the congressional debate over the president's policies on stem cell research.

In the interview, Kass focused on the science of stem cells rather than the politics, and he was particularly anxious to talk about recent research into cell fusion and reprogramming. That subject serves as the starting point for this edited transcript:

On cell reprogramming:

Kass: I would like to talk with you about reprogramming, because I think that’s where the gold is buried. Since the council’s white paper has been issued, we’ve been made aware of three major scientific reports that indicate to me at least that the reprogramming alternative is, A., hotly under investigation, and B., moving much more rapidly than we had any reason to suspect even two months ago when the report was issued.

Let’s remind ourselves, the goal is to get cells that are the functional equivalent of embryonic stem cells, but to do so in a morally unproblematic and uncontroversial way. And ideally this could be done also without the need for human eggs. So the most morally attractive proposal would be to try to reprogram or dedifferentiate adult cells back to the pristine condition of multipotency or pluripotency, the condition that the cells have when they are stem cells.

Since every cell in the body is genetically the same as any other, what distinguishes the liver cell from a brain cell from a heart muscle cell is not the presence or absence of certain genes, but which genes are in fact turned on and functioning, and which ones are silent. And since the process of development and differentiation going forward starts with a cell that could become anything, but specializes to become liver, or brain, or heart — presumably if you could locate the signal that produced that specialization, and run the process in reverse, you could start from liver, or heart or brain or muscle or skin, run the process in reverse and get back to the "stemcellness" of the beginning.

Lots of scientists have talked about this, but in the last two months, there have been very exciting reports from Australia, from Harvard and out of the Center for Reproductive Genetics in Chicago, that suggest that this morally unproblematic path might also be scientifically efficacious.

Let me begin with what is to me the most exciting one: Dr. Yuri Verlinsky in Chicago has at a scientific meeting in May in London announced that he has succeeded in producing a dozen new stem cell lines by reprogramming somatic cells using a technique of cell fusion. … He’s in fact applied for a patent. … Basically what he does is he starts with an existing embryonic stem cell line. He used his own, but this could be done with the presidentially approved lines, of which there are now 22 available from the National Institutes of Health and out in use in research.

You start with an existing embryonic stem cell line. Verlinsky removes its nucleus, and then he fuses the nucleus-free stem cell with a body cell — let’s say a skin cell. And the result is a cell which is genetically like the skin cell of the donor, but retains the stem cell properties of the original. So what’s wonderful about this is that you have all of the advantages of so-called cloning for research, without the need for eggs, and without producing a cloned embryo in the process.

You could in principle get stem cells from diabetics, stem cells from people with Parkinson’s disease that carry these markers, just by fusing cells taken from adults who have these diseases.

If this pans out, and that’s a very important “if,” this research would be eligible for federal funding in humans right now … providing the work was done with the eligible stem cell lines. There’s absolutely no reason why people couldn’t use those lines in these fusion experiments.

So that, I think, has been the most dramatic claim.

In Australia, a scientist named Alan Trounson reported at a meeting also earlier this spring that he has, by a process of fusing mouse body cells with mouse embryonic stem cells, produced cells that carry the properties of the adult cell but have reverted to pluripotency — have reverted to having the functional properties of stem cells. There are differences between what he’s reporting in the mouse and what Verlinsky is reporting in the humans, but this also suggests that there is something in the embryonic stem cell that is capable of influencing the nucleus of an adult cell to run backwards.

MSNBC: Is that 'something' in the stem cell's cytoplasm?

Kass: Verlinsky’s report suggests that it’s in the cytoplasm, but the striking thing out of the Australian study was that it seemed to be in the nucleus. Trounson takes stem cells and he subjects them to centrifugation, and he separates little spherical things that are bags of pure cytoplasm, and other spherical things which are basically all nucleus, with a little membrane around it. And what he’s shown, in his experiments, is that it’s the nucleoplasts, not the cytoplasts, that carry the capacity to revert the donor nucleus, the donor cells.

So there’s this difference in the studies. It may have to do with the differences between the mouse and the human, or the differences between the techniques the two men are using.

A report out of Harvard: Dr. Kevin Eggan has reported, also using cell fusion experiments with human cells, the production of a hybrid which shows the reversion of the adult nucleus to stem cell characteristics. But at the moment he’s got a tetraploid — he’s got cells that have the nuclei of both, and he’s not yet figured out how to get the stem cell nucleus out of there, but he’s managed to revert certain properties of the adult cell back to "stemness."

So here are three independent reports. Also, Jamie Thomson, who is one of the co-discoverers of human embryonic stem cells, has indicated that he too is at work on this process of dedifferentiation. And so I think this is the most exciting new development.

Other alternatives:

Along the lines of the other alternatives discussed in the council’s report: The first alternative, namely, deriving still-living cells from organismally dead embryos … That proposal has been somewhat pooh-poohed by scientists — but, I think, unfairly. Many embryos have arrested development. There is arrested cell cleavage. In a good number of these cases, it’s because there are genetic abnormalities in the embryo that simply preclude further development. But because a fair number of embryos are genetically mosaic, not all the cells turn out to be abnormal. People have shown that it’s possible to rescue viable cells from embryos that are, as organisms, arrested.

In other words, while many of the cells might be aneuploid — having an abnormal chromosome number — nevertheless the whole may contain cells which are chromosomally normal, and if you take them out of the no longer dividing embryo and put them into a different environment, those cells show that they’re still functional. That means that even dead embryos, embryos that can’t go any further, contain individual cells that are still viable and can perhaps be coaxed to develop into stem cells.

The people who have proposed this — Drs. Zucker and Landry at Columbia University — have put a proposal in to the institutional review board at Columbia to proceed with this research. I think ethically it’s relatively unproblematic. It’s on the analogy with organ donation from cadavers.

This is different from saying, “Well, they’re embryos that nobody wants any more, so why don’t we then disaggregate them.” We’re not talking about embryos that are doomed, but embryos that are really dead — that have died a natural death, so to speak. Let people try this and see whether it works. It can be attempted in humans right now, and the people who propose this are setting out to try it.

MSNBC: Some scientists have said it's difficult to know whether an embryo is dead or alive.

Kass: It’s true. And part of what they want to do is do the kind of natural history study which then might issue in the discovery of certain kinds of cell markers that say “this is now dead for all practical purposes, and it’s not going to continue to divide.” If we see these markers, then the ballgame is over for this embryo as an organism. But individual cells might still be viable.

It’s a new concept. Nobody has thought about organismic death for a little unfolding bag of cells, but we now know that it’s not just a bag of cells, that the embryo’s cell division is coordinated, that there is polarity even in the fertilized egg. Even though it looks to the naked eye as a symmetrical sphere, the place where the sperm penetrated now defines a certain pole in that embryo. These little organisms are wholes and dividing as a whole at a very early stage, and until people start to look to see whether there aren’t criteria for organismic death, I think scientists are being irresponsible when they say we simply can’t find out or don’t know when death occurs.

It’s a challenge, but it’s a scientific challenge, and skepticism about what science can show is usually not the proclivity of scientists. They usually are willing to say, well, let’s see what can be done.

The next alternative is to use a biopsy, that is, cell removal from still-living embryos, presumably in ways that will not do damage to that embryo. We now practice, at least on a small scale, what’s called preimplantation genetic diagnosis, where couples are at risk of a child with a genetic disease known to run in the family. At the roughly eight-cell stage, one or even two cells are taken out for genetic testing. And maybe 10,000 babies have already been born, more or less healthy, following this procedure. ... If you take out a couple of cells and you test them, and the embryo is shown not to carry the genetic disease of concern, that embryo is then transferred to a woman, and if all goes well, nine months later you’ve got a baby free of the disease. The thought is that maybe you biopsy these embryos, and you take out the individual cells, not for genetic testing, but to try to produce stem cell lines from them.

No one has yet converted a single blastomere from an eight-cell embryo into a stem cell line. That’s a scientific challenge. But the council was quite concerned about the ethics of this. We didn’t think that one could justify putting a child-to-be at additional risk, not for its own benefit. Until it could be proved by animal studies, or by much longer studies of preimplantation genetic diagnosis, that embryo biopsy is really risk-free to the child who results from all of this, the council is unprepared to pronounce this particular approach as ethically acceptable at this time.

MSNBC: Some feel that if you extract a cell at the blastomere stage, and somehow are able to have it proliferate, and apply this to stem cell research, then that would answer the ethical concern.

Kass: Yeah, that’s possibly the case. But the demands of the clinical decision with the genetic testing for PGD don’t really permit the kind of long-term cultivation of cells. In other words, the couples in there want to know. … It’s got to be very quickly timed. They need an answer within a day to know whether this embryo is transferable or not. And I don’t think those clinical decisions of seeking pregnancy will allow us the leisure to grow out cells in sufficient number to then harvest some for testing and keep the rest for stem cell lines.

The idea, by the way, that you could turn this into benefit for the very child much later in his life, when at the age of 50 or 60 he needs to have heart muscle cells — look, we’ve got cord blood to do that right now, and by that time answers to questions of immune rejection are much more likely to be available. I don’t think you can justify this in terms of the very benefit to the child from whom you’re taking these cells. It’s yet to be demonstrated that you can go from these single cells to pure stem cell lines. The timing of growing out enough cells to get around the ethical objection of added risk, I think, makes this logistically not a practical prospect. But if people want to try this in animals and show me I’m mistaken about this, I’m willing to look at the data.

The final alternative was in a way also a kind of reprogramming, a modified nuclear transfer. This is [Stanford bioethicist] Bill Hurlbut’s proposal. It’s since morphed into modified nuclear transfer but using oocytes for the insertion of these genetically altered nuclei. The idea there is to produce something which is not an embryo, but from which you can either derive pluripotent stem cells by growth to a certain point, or in the new modified version, you’re putting this nucleus into an egg, and the egg, we know, is capable of reprogramming a somatic cell — witness Dolly — and presumably you could get this to go directly to a stem cell.

I think that the council was divided on this. The majority of us favored allowing this to proceed in animals at this time, but there were people who found the original altered nuclear transfer program raising at least as many ethical questions as it solved. I myself am one of the people willing to see this go forward in animals.

But if I’m a betting man, I’m betting on the thing we talked about at first, which is the reprogramming. It’s ethically neat, it doesn’t require genetic engineering, it doesn’t require eggs, and it can be done with the existing eligible-for-federal-funds cell lines that scientists are now using. And these very promising and exciting results from three independent laboratories over the last few months make me think that we’re going to hear an awful lot about this.

Here would be my bottom line, and I say this not because I’m interested in influencing the vote about anything, but simply thinking about this as a moral and cultural question: Wouldn’t it be wonderful if scientific ingenuity, mindful of the fact that the research is in fact ethically controversial, comes to the table and says, “Look, we’re going to find a way to get exactly what we want scientifically, in a morally uncontroversial and unproblematic way that all of our fellow citizens can enthusiastically support, and that will not leave a bitterly divided polity.” I think any decent, public-spirited person should say, “Blessings upon that approach.”

This is not to say everybody should stop what they’re doing and do this. But I think it’s an embarrassment when scientists, because they suspect that some people are using this for political purpose, might for their own political purposes be badmouthing what are scientifically reasonable propositions. All of these proposals now have scientists trying to do them. All of them.

MSNBC: Most scientists feel that reprogramming a person’s own cells to create a cure is the desired endpoint. I suppose the differences come in how you get to that endpoint — what research avenues you pursue to gain the understanding about how these cells work their magic, and how far you can go morally and ethically while getting that scientific result.

Kass: Absolutely right, and there are lots of different approaches. There are some people who think what you have to do is to isolate the soluble cellular factors in an egg that are responsible for the reprogramming, or that are responsible for keeping the initial nucleus in its undifferentiated state. There are other people who think, “Look, we don’t to begin with need to have the factors isolated, we simply have to re-create the environment, and if we can do it reproducibly, we’ll eventually get the isolated factors. But in the meantime ... you might still be able, without having the biochemical mechanisms worked out, to get adult cells from any individual with any particular makeup you please, to revert to functional stemness by these processes of cell fusion.

I myself see no ethical problems whatsoever in proceeding to do that right now.

On the political repercussions of the council's report:

Kass: We had absolutely no idea that people would pick this up and it would somehow tie into the ongoing debate about the president’s policy and that legislation.

There are people who will say that this was just an attempt to divert attention. That’s a slander. Precisely because our charge as a council is indeed to think about ways in which we can have all of the benefits of biomedical science and uphold the highest moral principles of our society, we would be remiss in not showing the larger public that there might be just such ways.

We were fulfilling our responsibility, and to say that we were somehow trying to subvert the efforts of scientists to get more federal funding for what they’d like to do is as much a calumny as the people who say the scientists really want federal funding because they really enjoy killing embryos. The one charge is as unfair as the other.

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