This speech was delivered to the American Orthopsychiatric Association in San Francisco, California.
Number of Image Pages:
6 (615,066 Bytes)
1959-03-29 (March 29, 1959)
Original Repository: Oregon State University. Library. Ava Helen and Linus Pauling Papers
Reproduced with permission of the Ava Helen and Linus Pauling Papers. Oregon State University Library.
Medical Subject Headings (MeSH):
The Molecular Basis of Disease
Two Nobel Prizes
By Linus Pauling
Address to the American Orthopsychiatric Association
San Francisco, 29 March 1959
I like people. I like animals, too-whales and quails, dinosaurs and dodos; I am sorry that I shall never see a living dinosaur
or dodo. I like trees; I hope that the giant redwoods will not all be cut down. I like micro-organisms. I like crystals
-- minerals, such as calcite, rhodochrocite, pyrite, runyite, lazulite. I do not like to think about the tons of beautiful
crystals of galena, azurite, and malachite being mined and melted to make the load and copper used in unnecessarily great
amounts in our expending technological civilization.
I believe that Dr. Albert Schweitzer did not go far enough in formulating his principle of reverence for life. We need to
have reverence for the whole world, both animate and inanimate.
But I like human beings especially, and I am unhappy that the pool of human germ plasm, which determines the nature of the
human race, is deteriorating. The collection of molecules of deoxyribonucleic that will make the next generation of human
beings what it will be is not so good as that which determined our character; there ware more bad molecules in the collection.
The defective genes are now not being eliminated from the pool of human germ plasm so rapidly as in the past, because we have
made medical progress and have developed feelings of compassion such as to make it possible for us to permit the individuals
who carry the bad genes to have more progeny than in the past. Moreover, defective genes are being manufactured at a greater
rate than in the past, because there are new mutagenic agents operating in the world of today.
A good example of a hereditary disease is chondrodystrophy, which causes dwarfism. The gene for chondrodystrophy is dominant.
One child in 12,000 who is born suffers from this disease, as a result of his possession of a newly mutated gene. About 80
percent of them die in the first year after birth. It is likely that the incidence of chondrodystrophy is increasing, as
a result of the action of the new mutagenic agents in the modern world.
I estimate that in 80 percent of the cases of mental disease there is a strong hereditary factor. There is, of course, also
in many cases a significant environmental factor. The hereditary nature of a human being may sometimes be such that he can
withstand great environmental stress, whereas for other human beings the hereditary character is such that even the minimum
amount of environmental stress is enough to cause serious mental disease. About half the hospital beds in the United States
are occupied by mental patients. About ten percent of the American people spend some time during their lives in a mental
hospital. I believe that, as more is learned about the molecular basis of mental disease, it will be possible to decrease
significantly its incidence.
Sickle-cell anemia was the first disease to be recognized as involving an abnormality of a molecule. A dozen years ago it
was thought that all human being manufacture the same kind of hemoglobin. Then it was discovered that the hemoglobin has
an electric charge differing by two units from that of a molecule of normal adult human hemoglobin.
It was found that the parents of the patients with this disease manufacture both normal adult human hemoglobin and sickle-cell
anemia hemoglobin; molecules of the two kinds of hemoglobin are present in each red cell of these parents, in about equal
amounts. The genetics of sickle-cell anemia is accordingly clear: there are two genes involved in the manufacture of hemoglobin;
in normal human beings each of the genes is a gene for a normal adult human hemoglobin, and manufactures this hemoglobin,
whereas in the sickle-cell anemia hemoglobin, and in the heterozygotes there is a gene of each kind, and both kinds of hemoglobin
Since the discovery of sickle-cell anemia hemoglobin ten years ago about 20 different abnormal human hemoglobins have been
discovered, associated with many different diseases, previously unrecognized as distinct clinical entities.
The gene abnormality responsible for the disease is evidently a minute one. The hemoglobin molecule consists of two identical
parts, each containing about 300 amino-acid residues. It has been shown that all but one of the amino acids are the same
in normal adult human hemoglobin and sickle-cell-anemia hemoglobin, and that the 500th, located somewhere in one of the polypeptide
chains, is different: it is a residue of valine in sickle-cell-anemia hemoglobin, and of glutamic acid in normal adult human
hemoglobin. It is likely that the gene that is involved in the manufacture of the hemoglobins is similarly altered by a small
amount, one part in 300, in its mutation from the normal adult hemoglobin gene to the sickle-cell-anemia hemoglobin gene.
It is only ten years since the molecular basis of sickle-cell anemia and of the other hemoglobinemias was discovered, and
the details of the difference in molecular structure of the hemoglobins responsible for the diseases have not yet been worked
out. We may hope that as more and more information is gathered about the molecular nature of these diseases it will, in the
course of time, be possible to develop on the basis of this information an effective therapy for them, and thus to decrease
the amount of human suffering that these mutant genes cause.
It is likely that all of the disease that result from inborn errors of metabolism can similarly be described as molecular
diseases. For example, phenylketonuria results from the failure of the patient to manufacture an effective enzyme, in the
liver, that catalyses the oxidation of phenylalanine to tyrosine.
About two percent of visible children born have gross physical or mental defect because of their inheritance of defective
genes. Many more suffer from minor hereditary defects, which in the long run may cause more human suffering than the major
defects, because they are not removed so effectively from the pool of human germ plasm by the infertility of their hosts.
The rate of manufacture of defective genes by mutation is increasing, as a result of the existence in the modern world of
mutagenic agents, such as x-rays used in medicine for the diagnostic and therapeutic purposes and of the radioactivity of
fallout from the testing of nuclear weapons. The geneticists of the National Academy of Science-National Research Council
Committee that submitted its report in 1957 estimated that high-energy radiation causes about ten percent of all mutations.
The exposure of the gonads of Americans to background of radiation, from cosmic rays and natural radioactivity, amounts to
about three reoentgens during the first thirty years of life. Medical x-rays provide approximately the same exposure. The
estimate that I have made of the exposure due to radioactive fallout, for nuclear explosions carried out at the average rate
of the past few years, is about 0.3 roentgens in thirty years.
There is nothing that we can do about the damaging pool of human germ plasm by cosmic rays and natural radioactivity. It
is, of course, possible by good medical practice to decrease somewhat the exposure of the gonads to medical x-rays, as by
shielding the gonads wherever an exposure of some other part of the body is being made. Another effective way is through
the use of x-ray films of increased sensitivity, and through the limitation of roentgenographic examination to cases when
there is significant medical justification.
The damage done by radioactive fallout can be limited through the cessation of the tests of nuclear weapons. It is worth
while to attempt to make an estimate of the number of human beings who might be kept sane by the act of stopping the testing
of nuclear weapons.
The effects that we shall discuss are genetic effects that would appear in the population in the United States during the
next few generations. I shall assume that the average population of the United States during the next few generations will
be 200,000,000. Of this total, then percent, 20,000,000, may be expected to spend some time during their lives in a mental
hospital. I assume that there is a strong hereditary factor involved for eighty percent of them; that is, for 16,000,000.
If the testing of nuclear weapons were to be continued at the recent annual rate for a period long enough to expose the germ
plasm of the entire population to the fallout dose, an estimated number of mutations corresponding to an additional 160,000
cases of mental illness would be produced in the population of 200,000,000. The tests that have already been carried out
can be similarly estimated to cause mutations that will result in serious mental disease in 23,000 people in the United States.
I think that it can be a source of satisfaction to us that at the present time no nation is continuing its tests of nuclear
weapons, and that the Geneva Conference on an International Agreement for the Cessation of Nuclear Explosions is continuing,
and may soon lead to the formulation of an effective agreement.
I am astounded by the rapid progress that has been made during recent years in the understanding of the molecular structure
of human beings. Ten years ago I would have said that the discovery of the structure of deoxyribose-nucleic acid and the
formulation of a reasonable molecular mechanism for its self-duplication would be something that our children or grandchildren
might achieve, but not we ourselves; yet the Watson-Crick proposal seems to be satisfactory. The exploits of the nuclear
physicists during the last few decades show how fast progress can occur, when the time is ripe. I believe that the next fifty
years are going to be the golden years for biology and medicine. I believe that it will be possible to make great progress,
during the next few decades, in the control of mental disease.