Winding Your Way Through DNA Symposium

Saturday Morning, September 26, 1992.

Questions from the Panel for David W. Golde, MD. Head, Division of Hematologic Oncology, Memorial Sloan-Kettering Cancer Center, New York City, New York.

Questioner: Dr. Golde, I was wondering if perhaps you could address the fact that as much progress as has been made in understanding the molecular basis of cancer and devising new approaches to recombinant technology, a lot of people are now beginning to say that we need emphasis on prevention and in fact the National Cancer Institute, which currently only devotes 2% of its budget to understanding prevention, is concerned about this. With about 75-80% of all cancers having some environmental factor, do you think that this is probably a legitimate concern?

Golde: It is most definitely a legitimate concern. The question that may not be appreciated will by the public is that we don't know how to prevent many tumors. Some we do know how to prevent but we seem incapable of doing so: for example, smoking and lung cancer. But the ones that we don't know how to prevent will require additional research in the areas I've shown so that we'll know how to intercede. A lot of the basic research that's been done in cancer is equally applicable to treatment of established disease as well as the prevention of disease, so I agree with you.

Questioner: We would like to get Dr. Golde to address another question that has to do with the variety of natural products that he referred to now being employed to boost host defense and treat various diseases. These are an array of proteins and cytokines and so forth, growth factors. Taking the example of alpha-interferon, first applied successfully to a rare disease called Hairy Cell Leukemia and approved for that and only later found useful to treat a number of other conditions such as genital warts, AIDS-related Kaposi's Sarcoma. I'm wondering if you think it will take some time for doctors to learn how best to use these natural products and for them to find their true niche in medicine?

Golde: Yes, it will take time. The structure of how drugs were approved in this country was based upon more classical pharmacology. These agents are not classical, they're new, they're natural products that exist in the body and they're regulatory products. But still, the paradigm for the FDA is efficacy and safety for a given indication and alpha-interferon, as you pointed out, was approved for hairy cell leukemia, a very rare disease, but obviously its use is much wider. Now, legally, physicians can use any approved drug in any disease even if it is not written as an indication on the insert for the package. There is some danger there but in fact physicians are better educated now, perhaps than ever, and they are joining the experimental effort and it takes many years before the actual application of some of these agents to the wide spectrum of diseases is ascertained and alpha-interferon is a great example, now it's approved for many indications including hepatitis.

Questioner: These substances are often described as magic bullets, or at least in the public sense are acknowledged as such but in many instances they are not effective for a large number of patients in whom they are tested. Could you discuss that a little bit, why it might be that some patients don't respond?

Golde: That's an important concept. What's happened in the last five to ten years is that the technology for producing these agents has outstripped our capacity to test them clinically so that many proteins were cloned, known to be important somehow in human physiology but it was clear where their importance lay. Again, the pharmaceutical companies are driven by the need for FDA approval and so they search for "the indication" which is the disease state the agent will treat. Well, that may be hard to do when you don't know specifically the physiology of the protein. So we're now in a period where basic technology has outstripped physiology. We clone and express genes and derive proteins and hormones. This function is very poorly understood. It'll take a while for the physiology to catch up with the molecular biology.

Questioner: I wanted to ask you a question about gene therapy. You mentioned at the end that gene therapy for sickle cell anemia is potentially possible by replacing a defective hemoglobin gene. You also mentioned that blood cells are turning over all the time, so does one have to keep adding the gene again and again?

Golde: No, as I showed, if you can insert the gene into the stem cells, then the gene will be duplicated every time the cells divide and that new gene will appear in every single blood cell.

Questioner: How does one access the stem cells? In gene therapy in general, blood cells seem relatively easy to work with, but in general in gene therapy is there a problem with getting the genes into the right cells?

Golde: That's precisely it. The late Charlotte Friend, who was a wonderful investigator, once sent me the recipe for using the Friend virus and her secretary wrote on top of the recipe, "First, get a mouse." Yes, first you have to get the stem cell to put the gene in and there is technology being developed where stem cells can be isolated. The technical problem here is to get the stem cell to divide enough to accept a new gene and still not go on to specialize too quickly. If that were to happen then the gene would only appear in certain of the mature cells and ultimately die off. So, isolation of the stem cell is a technical problem. It will be overcome, though, in the next few years.

Questioner: There's been some concern lately with the use of colony stimulating factors to help with bone marrow transplants. CFS's look to be some kind of panacea for a lot of different tumors where if you could give a patient sufficient radiation and chemotherapy and then help bring them back with bone marrow transplants, that would be a new approach. But it's turning out to be a little bit disappointing for a lot of tumors, breast cancer, for example, because a lot of tumor cells turn out to be resistant. Could you address this issue?

Golde: It's a very good question and the answer is similar to my answer to a previous question. Technology has outstripped conceptualization. We have tools that we don't know exactly how to use. It would be equivalent to a repairman opening his tool kit and not recognizing three-fourths of the tools in there and how to use them. So, we're in that position now in medicine. We don't know how to apply this. We can make the white blood cell count any number we want; we just don't know what we want. We don't know what is appropriate for what disease. An so, in clinical science, very much like laboratory-based science, a good scientist wanders around. Perhaps he wanders a little less than other scientists. But the scientific process involves some blundering and that goes on in the clinic also.

Questioner: When you speak of blundering, and you're talking about testing these substances in patients, how do you decide at which point you're being too aggressive about what might be considered human experimentation--in other words, really trying out things that you don't entirely understand on human patients?

Golde: Well, that's the ultimate question. I use the word 'blundering.' My colleagues may assassinate me later. In order to avoid excess in clinical investigation, in order to avoid going too far, you have to understand that there is a certain amount of blundering and that understanding is what guides the speed and direction that you move in. Thankfully, also we have committees that are independent ethical committees and we have the Recombinant Activities Committee that looks after these things independently and says, is this the right time? Is there enough technology at hand? Enough data at hand to justify doing this experiment? In some cases not, in some cases yes. I think it's an admission of our own lack of knowledge that leads to a certain discernment in regard to that important question.

Questioner: You mentioned in your talk that you consider the treatment of cancer through gene therapy a somewhat more speculative proposition than the potential curing of single gene defects such as sickle cell anemia. Could you expand on that a little bit?

Golde: Yes. In replacement, that is, providing a patient missing a specific protein either with the protein or with the gene that makes the protein, one has a clear strategy in mind. There are technological hurdles but the path is clear. With regard to gene therapy of cancer, there are technological hurdles but the path is not clear. It reminds me of the quote, "I came to a 'Y' in the road and I took it." Again, we don't know precisely which way to go and we have to go with care, based on the pre-clinical data that we have at hand.

Questioner: Briefly on the issue of human guinea pigs as it were, as a newspaper reporter writing about cancer and some of these therapies you are discussing, I always get these desperate calls from patients or fathers and mothers of people with terminal cancer asking how they can get these patients on these therapies. It's such a difficult thing because it seems like we're giving them a sense of hope yet at the same time we're not really giving them hope. This is such a difficult problem and I'm wondering how you address that when you're treating patients who don't have a very good chance. I mean, when you're talking about success stories, you're talking about maybe one or two patients. How do you deal with that? It's a problem that cancer patients around the country are confronted with.

Golde: Firstly, the clinicians don't advertise for patients for these studies. The patients tend to think that what's new must work and must be better. Part of the clinical scientist's role is to disabuse the patient of that idea. Any clinical experiment is simply an experiment. We don't know. If we knew, we wouldn't be doing it. Hope springs eternal and people may have unclear, or at least, exaggerated expectations at times. On the other hand, however, the physician has to be absolutely clear on what's known and what's not known and this has to be communicated precisely to the patient and the patient's family so there aren't unreal expectations and disappointments.

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