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The Chairman. Thank you.

Josh Lederberg, we are delighted to have you back here
before our Committee. We have always welcomed your
comments. We look forward to them today.

Dr. Lederberg. Thank you, Senator Kennedy.

The Chairman. I want to recognize Senator Harkin who
is a new member of our Committee who has joined us now here
at the hearing. We are delighted to have Senator Harkin.
He has always demonstrated great interest in health care in
the past, particularly health care in the rural areas and
agricultural communities of this country. He has always
been helpful.

Dr. Lederberg. I am very privileged to have an
Opportunity to respond to your leadership and that of your
Committee in undertaking a very statesman-Like overview of
our overall problems in health.

As you have indicated, there are three main pillars to
support our health goals: access to care, prevention and
research. It is my task to say something about the research
part of that.

If you had three or four hours, I would enjoy an
opportunity to tell you some of the highlights of the
wonderful and exciting advances in medical science over the
last decade that really are starting to bear fruit. A lot

of were signing a Lot of promissory notes over the Last
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couple of decades about what the new insights into the
biochemistry of the cell and the area that we called
molecular biology were going to do for us. Those promissory
notes are being paid off.

Every day in the press we see accounts of new
diagnostic or new therapeutic procedures, of new materials
coming out of biotechnology, of very exciting new insights
about every aspect of human physiology and of human health.
I just do not have time to go into that kind of detail at
this point.

I would Like to say that health research is informed by
a sense of strategy. It is not always as clearly
articulated as one might Like. We have a multi-dimensional
matrix of concerns that guide the allocation of resources
and the time and attention that individual investigators
will be providing for the various kinds of problems.

We have already had some review of the public health
challenge, and we have objective statistics on the elements
of mortality and morbidity that tell us where some of our
priorities are. Heart disease is our major killer, but
cancer comes next to that. And those killer diseases do, as
they should, occupy a very substantial part of our concern
and our research efforts.

We cannot confine ourselves to those killers. There

are many other ills that do not have such high mortality,
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but make Life so miserable as to be hardly worth Living.
The deterioration of joints, body tissues that seem to go
along with aging, the deterioration of mental functions,
loss of capability, those are things that have to be
attended to as well.

We have enormous human misery that comes out of
psychiatric and behavioral disorders: schizophrenia,
depression of various varieties. We have an epidemic today
of anorexia and bulimia, particularly among the young women.
And we have all the problems of substance abuse that have
been mentioned very eloquently before. Those all require
close attention to the fundamental knowledge that is needed
to find amelioration.

We have problems with the newborn. We have the major
anomalies, the major birth defects that are all too
prevalent, and we have a universe of ignorance about the
very subtle impact of prenatal damage, the disease during
pregnancy, the effects of nutrition and of toxins, and even
the circumstances of delivery, whether our children are born
with all of the potential that they deserve.

Besides the outlook that is given us by the public
health challenge, we also have to know about the scientific
Opportunity. It would be very gratifying if we could
respond to these challenges one by one, know exactly what it

is that we need to learn and what we need to do in order to
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respond to each of these conditions. The fact is we are
still too ignorant to know how to proceed along those Lines.

If we are to pursue the problems of psychiatric
disorder, it is not enough to Look at the behavior of
schizophrenic patients or to try chemicals at random to see
which are going to improve their behavior. We have to
understand the fundamentals of how the brain is organized,
how the neuronal system works, and we are often very much
guessing in the dark and playing very long hunches in trying
to understand exactly what it is that goes wrong in
particular manifestations of disease.

To do all of these things, we need new analytical
approaches that can tell us what it is that is going on
within the cell, at the boundary of the synapses between
nerves and other elements of biochemical analysis.

Then, of course, we have Limited resources, Limited not
only in funds from year to year but in the larger
institutional framework in which research is to be done. We
have Limitations of facilities. We have the need to sustain
those institutions that have dedicated themselves to all the
problems connected with health. And above all, we have to
have those skilled and educated people who need to be
trained and need to be motivated and need to be sustained so

that they can devote their career to these problems. And

those resources cannot be turned on and off with a given
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year's budget.

And then, finally, we have to recognize that all of
this research operates within certain inevitable, necessary
restraints. Some diseases are going to be solved much more
slowly than otherwise, simply because they are rooted deep
within the human organism, and we have Limited opportunity
of access to them.

Alzheimer's disease is a very tough nut to crack
because we simply do not have a way to take biopsies of the
human brain at different stages of the development of the
disease in order to look closely at what is going on in a
given patient. And we do not have an animal model.

When animal models are available, we are under
increasing constraints. They come about concern for animal
welfare, those concerns that I share. Of course, tn order
to deal with them, we also have to have the funds to provide
the facilities, and those are not always available in the
Same measure as the complaints about the way in which
animals are being dealt with for experimental purposes.

Then I would like to turn to some of the elements of
scientific opportunity, and I would Like to stress what has
become the mainstream of biomedical research in the Last
several decades, which happens also to have been the center
of my own career which is in the area of molecular biology.

That is perhaps a slightly less formidable phrase than to
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talk about deoxyribonucleic acid, but I think even that
needs a little bit of explanation,

What we have found during that interval is that the
basic blueprints of the cell can now be understood in very
accurate chemical terms. The chemical involved is the
deoxyribonucleic acid, DNA. We have learned the code; we
have learned the way in which the messages of the blueprint
are stored within the cell, how they are replicated as the
cells divide, how they are expressed in instructing the celt
to produce various kinds of proteins.

This, in turn, has spawned a new biotechnology, and
this is what we are reading about in the papers every day:
the production of powerful physiological agents not
otherwise avaiiable. We have on the market today a
pituitary growth hormone, tissue plasminogen activator,
which is a very exciting approach to dealing with blood
clots. We have the interferons and the interleukins which
are under trial with various kinds of immunological
disorders, virus infections and for cancer, and the enzymes.
And many new vaccines which could not have been feasibly
produced by any other means are coming available through the
new biotechnology.

We have had something approaching a national emergency
in the health field in the last few years with the emergence

and alarming spread of the disease AIDS. Five years ago, we
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were not even sure what it was. In a remarkably short time,
with the mobilization of resources that the basic research
for preceding decades alone has enabled--we have been able
to discover that this is a virus disease, learned a great
deal about the nature of that virus, to learn a Little bit
greatly constrained by fundamental knowledge of exactly how
it impairs gene function.

Unfortunately, most of the news we get is bad news, but
at least it is accurate in terms of what it is that we have
to face as a challenge in dealing with this virus.

Fifteen years ago, had this emerged at that time, we
would have been substantially helpless in even comprehending
the nature of the challenge. We would not have had the
basic tools for laboratory investigation to allow the
isolation of the virus, its characterization, what its
effect is on various kinds of cells. I know you are having
separate hearings on that particular subject, so I will not
elaborate.

An important set of the DNA in the cell has to do with
the inborne potentiality within cells to become cancerous.
These bits of DNA that are related to cancer are called
oncogenes. We have come to recognize that oncogenes can be
brought into the cell, can be activated by becoming part of
viral agents that can be transmitted from organism to

organism. But the more important function of oncogenes in
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research today is the understand that they give us of
cancers that are not of viral origin but are of endogenous
origin, where oncogene, related bits of DNA, in the normal
cell can be activated either by chemical irritants that come
from outside or by physiological changes or by radiation,
and then take over and result in the non-regulation of these
cells where they can become cancerous and a threat to the
overall organism,

We have seen the isolation of a couple of dozen of
these specialized bits of DNA that provide the potential for
cancer. They have really given us our first substantial
clue as to what cancer really is. And from the tracing of
the pathway from the change of the DNA of ultimate origin of
cancer to the nature of the change of the gene products
within the cell really is our most substantial hope of
trying to find fundamental therapies and a fundamental
understanding of what is needed for the prevention of
cancer.

If there is one biological concept that has emerged in
the last five years, it is the concept of receptors. We
have understood that for the cells of the body to be able to
function as an organism, to function as a well-regulated
society, that they have to have ways of signaling one
another, or providing outputs from cells that would

determine what the state of the organism was and providing
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receptors that would be responsive to those inputs.

Receptors used to be a rather vague philosophical
concept. They have become very, very material. Receptors
are proteins that are responsive to specific chemical
Signals, that have very definite chemical structure. There
are probably dozens, if not hundreds, of different kinds of
receptors on different cells of the body, and we are now
Starting to isolate them. We can actually isolate them as
chemical entities only because of the availability of the
techniques of molecular biology, the biotechnology mentioned
a Little while ago.

Receptors have to do with everything in well-ordered
bodily functions, whether it is blood pressure or the rate
at which cholesterol is taken up, or whether the growth of
cells is involved in cancer, or the stimulation of the
immune system, or the transmission of the nerve impulse from
one cell to another, or the state of activation within the
brain, or how viruses infect cells.

The isolation of receptors has probably had the most
immediate impact on the way we think about pharmacological
intervention and, in a very practical way, in the
development of a whole slew of new drugs. Ten years ago, if
you had asked me about the realities of new pharmaceutical
development, I would have said, well, the future is going to

bring about some change, but if you actually look at the
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list of what is in the Pharmacopoeia, the new entries of
that year, they were all produced by hit-and-miss methods,
by the very old-fashioned techniques of trial and error.

Just within this last decade, the weight of progress,
the advantage has shifted just in the other direction, and
every important new drug that has come out in the last five
years has come out from an understanding of receptors and
Looking for specific agents that can either inhibit them or
stimulate them.

This applies to the drugs Like Somitadine--

The Chairman, Can I just on that point, Doctor?

Dr. Lederberg. Sir?

The Chairman. Does that argue for more targeted
research or less, or does it relate to that or not? If you
are getting most of the breakthroughs as a result of just
the broadest kind of basic research, and now that you are
talking about the changes in terms of the biomedical
research, does that say anything to whether there ought to
be a greater kind of targeting or not? I am just interested
in what you think.

Dr. Lederberg. Well, we have an opportunity to target
that simply did not exist awhile ago. So that if there is a
given investigator or pharmaceutical laboratory that wants
to go after drugs that are related to lowering blood

pressure, well, we have at least some inkling of what
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Systems in the body have to be influenced in order to be
able to have that done.

The Chairman, That has changed significantly, has it
not, in the period of the Last ten years?

Dr. Lederberg. It has changed dramatically in this
last decade, and it is working. You do not have to instruct
people to target if the opportunity exists to solve a real
Live problem out there. Our whole system is geared up to
try to maximize that opportunity.

The pharmaceutical industry has primary responsibility
for that. Its work rests on what comes out of the basic
research laboratories, but there really is no problem of
knowledge transfer or technology transfer, They are eager
to find every opportunity to exploit these kinds of
opportunities.

Well, besides these developments in receptors, the
notion has emerged that we can now count--what is the
fundamental complexity of the human cell> There are three
billion units of DNA in every cell of your and my body. If
you stretch that out, it would be two meters Long. The DNA
is so thin and so tightly coiled up that that string of two
meters’ length, as high as you and I are, gets wound up into
a Little body that is less than a thousandth of an inch in
diameter. But therein is the fundamental information of

what it is that allows us to be human.
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About 99 percent of that DNA, fortunately for research
purposes, is probably essentially inactive, as ballast or
some structural material. So the essential component of
that total DNA is only about 30 million units Long. That
will encode for about a hundred thousand different gene
products. In order to know the architecture of the human
cell, we will have to know about a hundred thousand
different building blocks. At the present time, about 300
or perhaps 500 of them have been characterized to some
degree. So we have got a Long, long way to go in order to
fulfill that objective.

It has been suggested that we go after mapping the
entire human genome and just get on with it and move from
that 500 to that hundred thousand, move from the one million
nucleic acid units that have been so far described and get
the whole three billion of them and so forth.

As an overall objective, I would subscribe to it. I
think we might do better to organize our work so that we
focus on those building blocks, on those elements that are
the most immediate biological and medical and physiological
Importance, And then as we do that, we develop improved
instrumentation. We can accomplish that task more
efficiently, and the end result will be that full map of the
entire genome. But some parts of the genome count for much

greater importance than others, and I think that is where
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some of the targeting that you were talking about a moment
ago would come in very, very appropriately.

There are many other important innovations in
biomedical research. We have all read about the monoclonal
antibodies that have given us new reagents of just
extraordinary specificity and sensitivity. And these can be
used for development of diagnostic procedures that were
unthinkable some while ago. The protection of our blood
supply depends on immunological reagents designed along
these Lines that can detect the AIDS virus. And we are
seeing the development of similar reagents for the diagnosis
of abnormalities Like cancer and Like high risk with respect
to a variety of other diseases.

I think perhaps this would be a point to conclude with
because I could go on almost indefinitely. And I think you
very much.

CStatement follows:].