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
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
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
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.