BIOENGINEERING: SHORT TERM OPTIMISM
AND LONG TERM RISK

 

Dr. Christian B. Anfinsen
Department of Biology
The Johns Hopkins University
Charles & 34th Streets
Baltimore, Maryland 21218

NOBEL CONFERENCE XIX
Gustavus Adolphus College
October 4 and 5, 1983
Bioengineering: Short Term Optimism
and Long Term Risk

 

Whatever our background or occupation, most of us
do not hesitate to make profound statements on philosophical
and ethical matters. The subject of our current conference --
"Manipulating Life; Medical Advances and Human Responsibility" --
is ideal for crystal ball gazing. The technology of gene transfer
and modification is very much in a state of flux, and the medical
and evolutionary consequences are unpredictable. It would be
difficult to rule out any reasonable prognostication.

Quite by accident, I came across a lecture by an old
friend, Ernst Chain, who shared the Nobel Prize for the dis-
covery and production of penicillin, in which he gives his
opinion on the use of genetic engineering in man. The lecture
was given just six years ago, in 1977. I would like to quote
from the remarks by this eminently reasonable man:

There exists no method, at present,
nor is there the likelihood that one
will be discovered in the foreseeable
future, by which it would be possible
to alter the nucleotide sequence, and
thereby the genetic properties, in any
gene of any mammalian cell in a controlled
manner which could be termed 'genetic
engineering.’ Any speculations that
such a process may be near at hand and
could influence the heredity of man

must be dismissed as science fiction.

The unpredictability of discovery in a fast-moving field
such as mammalian genetics is underlined by recent observa-
tions in exactly the field of research that Professor Chain
considers in this quotation. We have all read or heard about
the production of "giant mice" by genetic engineering. In these
experiments, the gene for mouse growth hormone was injected
into mouse eggs that had been fertilized, and the eggs were
then allowed to mature in utero. The resulting animals apparently
looked more like rats than mice, and the whole experiment is
not only interesting but somewhat amusing. This experiment
emphasizes how quickly the development of new techniques for
the preparation and study of biological materials can lead to
astounding biological results. The next step, of course, will
be a set of similar experiments on cattle and sheep, and other
animals of interest to man. The very existence of the "giant
mouse" experiment immediately predicts that similar experiments
could be done with humans. The controlled injection of the
gene for human growth hormone into fertilized human ova could
easily lead, in twenty years, to a Minnesota football team
made up entirely of nine-foot players. Although the experiments
I have just mentioned have a certain humorous quality, I will,
in this lecture, take a moderately gloomy view of the possible
undesirable consequences of genetic engineering as applied to
man.

Being a scientist, myself, I have some insight into

what makes a research worker tick. The qualities that characterize
and motivate a good scientist do not necessarily have any
bearing on the ethical or sociological sequelae of discovery.

An investigator who is worth his salt will attack an interesting
problem for its own sake, and with increasing enthusiasm as the
project proceeds. I am sure, for example, that Enrico Fermi,
when he discovered the consequences of slow neutron bombardment
of atoms -- or Otto Hahn, when he studied the fission of heavy
atoms -- did not for a moment think ahead to the Hiroshima bomb,
or for that matter, to the difficulties that sooner or later
might present themselves in connection with nuclear power. In
my view, as long as there are medical advances to be made, and
diseases to cure or alleviate, research workers in the biomedical
field will continue to explore the promising leads.

Before considering the many beneficial aspects of
genetic engineering, I would like to continue just a little
longer on the topic of the responsibility of the scientist for
his own discoveries. I am sure that any reasonable scientist
would fight against the use of his research products for thought-
less or criminal ends. Although no set of rules has yet been
devised for the control of experimental genetic manipulation
of human beings, I would guess that such a code will eventually
be devised, and will, of course, depend on the cooperation of
investigators in the field. The unfortunate fact is that the

public cannot imagine the rate of progress in a field such as
genetic engineering, and it might be quite difficult to devise
supervisory rules and regulations that would be sufficiently
flexible and au courant to keep up with advances in knowledge
and clinical trial. Even with a high level of understanding
and cooperation, one can imagine situations in which control
would be deliberately sabotaged. Consider, for example, the
deranged scenarios that existed in the concentration camps in
World War II. If current techniques had been easily available,
experimenters involved with captives would almost certainly
have tried the modification of human fertilized eggs by exposure
to purified genes or to heterogeneous mixtures of DNA fragments.
This technique which, at the present time, is somewhat limited
by the shortage of normally shed ova, could easily be speeded
up by the use of ova obtained from ovaries following surgical
procedures. I apologize for such a gory example, but I do feel
that rules will have to be promulgated, and some world-wide
control system will have to be devised to restrict misuse.
At the moment, world peace and the Golden Rule are about all
we can suggest. I must add that, even though I feel that regula-
tions must be invented, I do not predict more than mild success.
The situation is very much a case of Murphy's Law, which states
that if something bad can happen, given enough time, it will.
For a change in pace, let me review some of the good

things that have happened as the result of the development of
the very sophisticated procedures of gene cloning in bacterial
cells. The procedures for the controlled introduction of specific
human genes in rapidly growing species such as Eschericia coli,
which can subsequently manufacture and secrete the material

of interest, are now the basis of a flourishing industry involved
in the production of various peptides and proteins that can

serve as weapons against human disease with essentially no risk.
One very popular item of interest, at present, is the protein
known as interferon, which is produced by a number of different
types of cells in the human body when these cells have been
exposed to viruses. My colleagues and I spent about ten years

on the isolation and purification of interferon from human cells
in culture, but the introduction of the cloning methods more

or less outmoded this more classical approach. When the puri-
fied gene for interferon is introduced into the genome of the
bacterial cell, along with the proper genetic start signals,

the cells secrete fairly large amounts of the substance, and
purified interferon can be obtained by relatively simple pro-
cedures. Interferon promises to be of use in the control

of a number of viral diseases, including hepatitis, conjunctivitis,
and possibly some forms of cancer. The availability of inter-
feron also makes possible the large-scale production of anti-
bodies against this substance which can be used to remove

interferon from the circulating blood in certain diseases such
as lupus and rheumatoid arthritis where the levels are abnormally
high, and may be involved, somehow, in the dangerous aspects
of these diseases.

Another substance that has been prepared by gene cloning
in bacterial cells is insulin. The cloned gene is for human
insulin since one of the problems that can arise in diabetes
is the dangerous immunological effect of insulin taken from
the pancreasglands of other species.

Most of the materials so far produced in bacterial
culture have been fairly small proteins or polypeptides. It
seems certain that the procedures will be improved to a point
where large human proteins can be made in quantity. Many human
diseases result from the absence of a particular gene, and
therapy for such gene deficiency diseases might well turn out
to be the introduction of human proteins made by the cloning
method.

In some cases, genetic diseases attributable to the
absence of critical genes in the chromosomes of patients involve
only one, or a very few tissues. Thus, for example, sickle cell
hemoglobin is produced by abnormal cells in the bone marrow,
lacking the normal hemoglobin gene. These cells produce a form
of hemoglobin that causes severe damage, pain, and frequently,
early death because of its propensity for precepitating out

of solution within the red cells of the patient at low oxygen
pressures. A large number of single gene deficiency diseases

are known that result from the inability to produce a specific
protein product in the cells of one tissue such as brain or
pancreas. In such cases, one would like to try to introduce

the correct gene into the cells in question without having this
genetic material inserted into other cells of the body that

are not associated with this particular gene-protein system.
Research is underway on techniques that might permit this tar-
geted sort of gene delivery. The experiments are based on the
fact that all cells of the body have, on their surfaces, specific
receptor sites which can be recognized in a unigue way by the
proper molecule. One could, in principle, attach the missing
gene to a substance which would recognize the surface of the cell
type in question, and thus deliver the gene to its proper location.
This type of manipulation carries with it the possibilities of
bad results, as well as good. Should such a circulating gene

be taken up by tissues other than the one for which the targeted
gene was devised, it could create a genetic defect worse than
the defect the gene therapy was intended to correct.

Lewis Thomas, in his book, The Medusa and the Snail,

 

has pointed out that current advances in the understanding
of biological phenomena make it possible to begin thinking
about a human society free of disease. Because of the nature

of science and of scientists, research directed at the
achievement of such a medically utopian state will undoubtedly
continue in an inexorable (and a scientifically fascinating)
way, not only through the use of the newer methodologies for
manipulating and modulating life, but also through the more
classical techniques of synthesis and testing of drugs. However,
the concept of a world nearly free of disease, considered in the
context of our current sociological inadequacies, is frightening.
The uninhibited increase in the population of the world, and
the almost inevitable increase in hunger and crowding, are the
real problems. It is unfortunate, therefore, that the study
of the modulation of human behavior and of the rate of human
multiplication are not subjects with the level of popularity
enjoyed by biomedical science and the curing of the sick.

The field of biotechnology is most heavily concerned
with the bioengineering of bacteria to produce useful items
such as interferon. Surprisingly little effort or money are
spent on using the new biotechnology in areas of food production
and population control. We tend to forget that the number of
sick people in the world is really rather small when compared
with the number of relatively healthy people who go to bed hungry
every night. For this reason, I strongly advocate a greater
attention to the application of biotechnology to our food sources.
The subject does not have the "crowd appeal" of cancer cures

or even "giant mice," but perhaps the manipulation of plant
rather than human life might ultimately prove to be the most
Significant direction for research to take.

Let me return for a moment to my central theme: the
misuse -- or overuse -- of scientific discovery. Scientists
are motivated, generally, by 1) intellectual interest, 2) the
thought of making a living in a pleasant profession, 3) the
desire for satisfaction of personal ambitions and the need
for accolades, and 4) societal forces most frequently stemming
from military and economic pressures. I maintain that we will
find it impossible to legislate against scientific research of
any particular sort, including genetic engineering, by simply
admonishing or lecturing to people who have no real desire to
listen. It appears to me that only political, economic, and
occasionally, ethnic or religious pressures can force large-scale
changes in behavior patterns. It is possible that the physical,
mental, and psychological makeup of the human animal is such
that there will be no solution to the dilemma of how to preserve
the human species in the backwash of his own inventions. One
factor that might help is the control of population, and if
possible, diminution to a much smaller level than now exists
on the surface of the planet. Since it would be preferable to
achieve a greatly diminished population by some means other
than systematic nuclear bomb-dropping, an international effort

to educate the people of the world in the direction of a negative
population rate should be a first priority. Parenthetically,
there might be considerable resistance to such a move by those
whose fortunes depend on an ever greater population of purchasers.

I feel free, in the context of the conference title,
to speak of population control because much of the problem might
be solved by products of contemporary biomedical research and
biotechnology. There is, of course, the eternal problem of
people in the impoverished agricultural areas desiring to have
large families, particularly strong males with a liking for
digging in the fields. We might need entirely new answers to
world food production and distribution. In this connection,
I am reminded of the conversation I had recently with Professor
Dennis Powers, of The Johns Hopkins University, who is intrigued
with the use of the growth hormone gene in the production of
"giant fish." He points out that numerous countries, including
China, Israel, and others raise a great deal of animal protein --
in the form of fish -- in ponds. A beautiful blend of nutritional
need and modern bioengineering would be the introduction of the
gene for fish growth hormone into the fertilized eggs of the
edible species, with the subsequent establishment of a bio-
logically competitive subspecies. In modern biology almost
anything goes.

Some months ago, Dr. Esbjornson, our organizer, wrote

to each member of the panel, listing some preliminary reflections

-10-
on the theme of the conference. Many of his reflections took

the form of questions which I should like to try to answer

along the lines of the remarks I have just made. Dr. Esbjornson
asks, "What do we want to know about life processes?" "Everything."
He asks, "Are there limits we cannot or should not violate?"

I would answer this question "No" in the context of basic research
aimed at understanding more about our universe and about the
nature of living things. At that time when the application

of certain classes of scientific observations is contemplated,
careful control by suitable panels of academic, legal and
governmental experts should certainly be imposed. "Are we
disturbing the universe by our probes?" I would say that we
certainly are. Let me once again mention giant mice and nuclear
bombs. "Are we capable of carrying the burden of responsibilites
for the new knowledge we are gaining?" I would answer, "probably
no" to this question. In the short run, and during times when our
planet is not being wracked by world wars or devastating epidemics,
we seem to be able to manage. I sincerely believe that we can
maintain adequate surveillance of the application of bioengineering
to human beings so long as the human hunger for power and material
gain does not become overwhelming. I think it would be difficult
and inadvisable to attempt to control the normal progress of
scientific research and application. In my view, the problems
that arise because of advances in human knowledge in general, and
biotechnology in particular, must be dealt with by those among us
who are properly experienced in the moral and legal facets of

our society.