Researchers Say Gene Therapy Increased Cancer Risk New research shows that an effort to cure X-SCID (also known as the "bubble boy disease") using gene therapy may have had an unintended consequence -- causing cancer in people who tested the therapy.
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Researchers Say Gene Therapy Increased Cancer Risk

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Researchers Say Gene Therapy Increased Cancer Risk

Researchers Say Gene Therapy Increased Cancer Risk

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From NPR News in New York, this is TALK OF THE NATION: SCIENCE FRIDAY. I'm Ira Flatow. Think human evolution is a thing of the past? Well, researchers studying our genomes say we're still evolving, with many changes to our genes within the last 10,000 years, really just a recent blip in our evolutionary history. This hour we'll talk with New York Times science reporter Nicholas Wade about how DNA analysis is rewriting our recent and ancient history.

Plus, we'll talk about a new study that explains how a successful gene therapy can cause cancer. And as global warming heats up the ocean, more and more coral reefs are dying, but scientists have found that one species of coral survives deadly bleaching by bingeing. It's all coming up after this break. Stay with us.

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This is TALK OF THE NATION: SCIENCE FRIDAY. I'm Ira Flatow. In June of 2002, researchers announced the results of a gene therapy trial for children with severe combined immunodeficiency, commonly called, The Bubble Boy disease. That's a fatal genetic disease that leaves its victims without an immune system, but there was hope.

Using gene therapy, the researchers were able to insert a healthy copy of the faulty gene into the sick children, and many of the kids went on to develop an immune system and were cured of the disease. This trial was considered proof that gene therapy worked, but then three years later came a surprising consequence.

Researchers reported that three of the boys treated with the gene therapy went on to develop cancer; leukemia. And now another team of scientists thinks they know how those boys got cancer. They report their findings in this week's issue of the journal Nature, and the lead author joins us today to talk about their study.

If you'd like to talk about it, our number is 1-800-989-8255, 1-800-989-TALK. Inder Verma is the American Cancer Society Professor of Molecular Biology, professor in the laboratory of genetics at the Salk Institute for Biological Studies in La Jolla, California. He joins me today by phone from New York City. Welcome back to the program, Doctor Verma.

Dr. INDER VERMA (American Cancer Society): Thank you, Ira.

FLATOW: Now let's talk a bit about the background here of this gene therapy to treat this disease. One gene was inserted in the children? Is that what happened?

Dr. VERMA: Right. I think the way you described it is exactly right. They took, what these children were suffering from the deficiency of one gene which made a protein called gamma C chain. That protein is necessary for formation of the immune cells--B cells and T cells--to fight infection. Without that gene product, the children have no ability to fight infection, and that's why you said David, the bubble boy, had to live all his life in a bubble.

FLATOW: Right.

Dr. VERMA: So these people, the, to the French group, take the bone marrow of these children, who would have surely otherwise not survived unless they got a bone marrow transplantation, took their bone marrow, introduced into them the gamma-C chain using a viral vector system called retroviruses, and all these children showed a remarkable improvement of their immune function as judged by their ability to make antibodies, as judged by their ability to fight infection. They went to school. They behaved normal.

And as you said, three years later came the development of leukemia, and the argument was made that why--what happened is, that when the virus gets into a cell, it really cannot be controlled where it goes. It may have gone in the vicinity of another gene--in this case referred to LMO2--which normally is not making any protein, but when it does inappropriately, it can cause leukemia. So the argument was made that the virus might have inserted itself next to this gene, thereby activating it when it should not have been activated, and that results in T-cell lymphomas.

FLATOW: Mm hmm.

FLATOW: So, based on that data, we said we will perform the same identical experiment in mouse to ask the question, can we reproduce the phenomena that happened in human and could we learn from this? So we found a mouse which is exactly the duplicate of the same disease as the gamma C chain deficiency; made exactly the same experiment, except we used a different vector--a same family of vector but slightly different--and did the same experiment; and were surprised on two counts.

First, the experiment was done the following: one, where we took just the gamma C chain alone; second, where we just took the LMO2, the gene which is the offending gene of causing the disease; third, we combined the gamma C and the LMO2 together in one vector, so we give it the best chance to make cancer; and finally, a control which had a nonspecific gene, has no business to cause cancer.

So what we found that the control, 100 percent of the animals were fine. In those which had the LMO2, 40 percent of the animals came down with leukemia, as we expected. But what surprised us the most was that where gamma C chain alone was used, 33 percent of those animals also came down with the same kind of a tumor that was witnessed in these children, except it took them six months before we could observe them and some came as late as 10 months.

So in children, it was also after three months, uh, three years. Now it's difficult to compare the life of a mouse and that of a human, but it pointed to the fact that the gene product that was being used to correct the defect, had also the ability to cause cancer by itself. And therefore, one has to be, uh, rethink the idea of using genes like this, which have the ability to cause cancer. Possibly because, this gene is just not for one gene alone. There are a number of other genes which requires the same gamma-C chain to function. So we don't understand how that works.

FLATOW: Yeah. So you don't understand why this gene could cause cancer, do you?

Dr. VERMA: We...

FLATOW: Or else you would not have put it in in the first place.

Dr. VERMA: So, what happens is that, this gene is a third leg of a receptor which requires this. In other words, there are many receptors which are needed to make T cell, B cells. They have two components, but they need the third component which is called the gamma C chain. But it turns out there are six other receptors which also need the same gamma C chain.

So when we put gamma C chain in cells--in this case, all of them got the same gamma C chain--and therefore, there was a dis-regulation. So we don't know why and how, when multiple components which were missing this gene also got it, how they might have behaved. And that's something which we'll follow on. But the surprise still remains that the gamma-C chain alone has the ability to cause about the same number of tumors as have been observed in the case of human.

FLATOW: Do you think this is gonna make everybody pause and think about...

Dr. VERMA: I think it certainly should make people think about it because the first question one will ask is could it be that the method we used made more protein than normally, and it's therefore not natural? Well, that is a reasonable argument, but you can't really say that because we can't control in the human gene therapy trials how much protein will be made. We can't control how much virus will go in.

We cannot control how much virus will integrate, and therefore, there is a concern now--that since we can't control that, and since the protein has the ability, whether we make too much or too little--it certainly has the potential to cause the disease. And therefore, it requires rethinking how we might want to do it.

FLATOW: Mm hmm. Do you think that this rethinking in these risks are true not only for this gene but for others like it? Or do you think that it's likely to happen with all forms of gene therapy?

Dr. VERMA: No, no, no, because, definitely, not. Because there's another kind of a SCID, the same bubble boy, where the deficiency is a gene called a adenosine deaminase gene, which is a known enzyme. There you just put the enzyme back, and that enzyme can do the function. So there we don't think the same function will happen. Now there, the virus that can integrate in the vicinity of an offending gene can still happen, but it can't be due to the gene product itself. It may be due to other reasons but not the gene product, so it's different than the gamma C chain.

FLATOW: What has happened since with the other kids who did not come down with the cancer?

Dr. VERMA: Well, first of all, it's a matter, it's a--I definitely hope that none of them will come down.


Dr. VERMA: It's a perfectly reasonable to assume, and maybe they made small amounts of it. Maybe they made the correct amount of it that fit perfectly, and I hope that that is the case. However, we didn't see this tumor till six to 10 months, so it's a little be more long-lasting. We need to wait a little bit longer to be absolutely certain. But it is quite possible that these kids, and I hope, are going to be ok.

FLATOW: Are they kids who have the leukemia? Are they under treatment and in remission?

Dr. VERMA: I don't totally know that. I know one case they did a new bone marrow transplant. And another case the kid, I think, is responding to that. And the third kid, I don't know what is happening. But I know one who's responding, and one got a marrow transplant.

FLATOW: Is it not possible to think, and I'm thinking as a parent, or someone who takes care of kids, that if your child had this disease you might want to take that risk?

Dr. VERMA: You know, it's very hard, because when you're a parent whether that child, and when the time comes, I don't know. But I personally, would think, yes, it's worth taking the risk.

FLATOW: Yeah. Taking the risk and trading, possibly trading one illness for another. And one--and at leukemia, you know, we don't want it to happen, but might be curable, whereas the baby-bubble-boy disease may not.

Dr. VERMA: Yeah. The only other thing one could argue in that case is, and that's been done, that if you have a matching bone marrow, that may be the easier way to do it, because bone marrow transplantations are very successful, and that that might allow these children to have a normal. But finding a successful matching bone marrow is also not a trivial undertaking.

FLATOW: Yeah. So your case doesn't make, your study doesn't make a case for halting all gene therapy trials.

Dr. VERMA: No. No. Definitely not, definitely not. The only place where we think it is worth considering rethinking is in the gamma C chain, because there's an evidence of it. But it certainly does not say, and I hope that is not the impression, that they stop gene therapy, because those other things. Here is the product itself is toxic, not the methods, the product.

FLATOW: Yeah. Because we haven't seen a whole lot of successes in gene therapy yet.

Dr. VERMA: Well, I understand there's a group in Italy, now, they use ADA gene, and they have a successful reconstitution of the immune system, also. So that's another example.

FLATOW: Oh, there's something new, then?

Dr. VERMA: Yeah. That is the thing(ph) that has been going on in Italy in San Rafaela(ph) Hospital, and under the direction of Doctor Claudio Bodinio(ph). And that's--I understand again, I would haven't seen that later(ph) data, supposed to be very encouraging results.

FLATOW: So there may be an alternative developing.

Dr. VERMA: Yeah. So there's, it's a different kind of the same technology, but a different gene product.

FLATOW: I see. Well, we can always be hopeful, that something new will happen.

Ms. VERMA: Yeah. I still am, otherwise I wouldn't be working on it.

FLATOW: All right, and, as I say, we're all waiting for some good news in gene therapy.

Dr. VERMA: And I hope you will have soon enough, and me too. You're in the same (inaudible) that I am.

FLATOW: All right. I want to thank you very much for taking time to talk to us, and good luck to you. And we'll be back talking with you with good news, sometime, hopefully.

Dr. VERMA: Thank you very much. Shall I get off the phone now?

FLATOW: Yes you can. Have a good weekend.

The truth comes out in Science Friday. That's Inder Verma is the American Cancer Society professor of molecular biology, professor in the laboratory of genetics at the Salk Institute for Biological Studies in La Jolla, California. And he was joining--on the phone from New York. And we like to thank everybody who takes time out on a late Friday afternoon to be with us and talk to us.

We're going to take a break and we're going to come and we're going to switch gears and talk about the world's coral reefs are dying. And we'll talk about one reef, one kind of coral in particular, that has found a way around this bleaching. So stay with us. We'll be right back.

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FLATOW: I'm Ira Flatow with this is TALK OF THE NATION - Science Friday, from NPR News.

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