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C H A P T E R T W O
BIO LO G Y IN
TH E SE RVICE
OF MAN
Progress in biological understanding has proceeded at a spectacular rate
for two decades. The deepening insights into the nature of man and his
diverse living kin could well be reward enough for the large investment of
effort and funds. Such understanding is more than a highlight of our
culture; it is a primary tool of our working civilization. In the pages that
follow we shall seek to illustrate and document that statement. Only a
small sampling can be offered here, but it should become evident that the
life sciences have dramatically altered our life style, contributing to our
security, our health, our comfort, and our enjoyment.
BIOLOGICAL RESEARCH AND MEDICAL PRACTICE
The impressive and rapidly growing, though fragmentary? conceptual struc-
ture of biology has greatly increased understanding of disease mechanisms;
presumably, as the conceptual framework becomes more general and more
coherent, comprehension of disease will grow correspondingly' thereby
enlarging opportunity for the alleviation and prevention of many disorders.
142
OCR for page 143
BIOLOGY IN THE SERVICE OF MAN
In considerable measure, the history of biology is the history of attempts
to cope with disease. Many disorders have fruitfully been viewed as
"nature's experiments" and, as such, have proved to be cardinal clues in
elucidation of major fundamental phenomena. Thus, vitamin-deficiency
diseases e.g., pellagra, beriberi, sprue, and scurvy were the clues to the
very existence of vitamins and, hence, to the coenzymes of metabolism;
investigations of diabetes and glycogen-storage diseases revealed the hor-
monal control of carbohydrate metabolism and, indeed, the pathways of
that metabolism; the prevalence of pernicious anemia revealed the existence
of vitamin Be., and of the unique biochemical reactions it makes possible;
the requirement for agents to manage infectious diseases stimulated the
discovery of antibiotics, and these, in turn, proved to be powerful tools in
the elucidation of the mechanism of operation of the genetic apparatus and
the synthesis of bacterial cell walls; the dramatic changes in the volume,
pH, and salt concentrations of blood plasma in such disorders as infantile
diarrhea, pernicious vomiting, diabetic coma, and Addison's disease have
been both the primary stimuli and the major "experiments" in revealing
the complex homeostatic mechanisms that control the volume, acidity, and
electrolyte composition of the body fluids of both the intracellular and
extracellular compartments; the variety of cardiac disorders has revealed
the fine mechanisms and neural control of the cardiovascular system; and
the existence of sickle cell anemia and other instances of altered hemo-
globin structure were the first demonstration that a "point" mutation results
in a specific amino acid replacement in a protein, as well as the demonstra-
tion that the genetic code in man must be identical with that in the bacterial
species in which it was first determined. In each instance, the knowledge
so gained, abetted by insights from other areas of biology, has resulted in
expansion and improvement of the therapeutic armamentarium to the great
benefit of those afflicted with the very disorders that served as clues.
This mutual feedback has characterized much biomedical practice.
Advances in practice have come only when the intellectual stage was set
and suitable methods were in hand. Painstaking analyses of the electrolyte
composition of the blood in health and disease, over a period of 40 years,
contributed much to current understanding. But the analytical methods
required were tedious slow, and unreliable in the hands of any but highly
qualified experts. In the last decade, these were replaced by a variety of
thoroughly reliable, semiautomated procedures allowing the benefits of
this understanding to be brought to virtually all those requiring it. The
precise control thus afforded, symbolized in the bottles of intravenous in-
fusions so common in modern hospital practice, has dramatically reduced
mortality in a variety of illnesses and has been a major contribution to the
success of current heroic surgical procedures. Hence, one no longer en
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144
THE LIFE SCIENCES
counters the once painfully exact irony, "The operation was successful but
the patient died." The new analytical methods and their use in guiding
parenteral fluid therapy are the fruit of thousands of painstaking investiga-
tions. This chapter cannot hope to provide a comprehensive summary of
such contributions but will, rather, describe a few recent noteworthy illus-
trations.
The National Health
The dramatically altered national health picture since the turn of the cen-
tury broadly illustrates the changes man has wrought through his science
and suggests those yet to be accomplished. Fifty years ago the major medical
problems afflicting individuals in the United States were similar to those
now facing developing nations. In 1900, both influenza and pneumonia
killed more persons than any other disease. Tuberculosis came next. The
combined death rate (deaths per 100,000 of population) from these diseases
was greater than that from heart disease today, a malady that killed more
than 712~000 persons in 1965, when cancer took the lives of an additional
300,000 individuals. In the early 1900's, the death rate from tuberculosis
exceeded that from either of these causes, while diphtheria, now almost
unknown, was the tenth leading cause of death. For three decades, pellagra
deficiency of the vitamin nicotinic acid-was the leading cause of death
in eight southeastern states, whereas cases of this disease have rarely been
reported since 1945, and mortality is zero.
Diagnosis, Disease, and Drugs
SULFONAMIDES AND ANTIMETABOLITES
Quite evidently, many people who would have succumbed to infectious
disease in an earlier day now survive to die, at a later age, of degenerative
disease or cancer. The advent of antibiotics deserves major credit for cur-
rent ability to cope with infections. Moreover, antibiotics have played a
major role in the development of drugs and approaches to the treatment of
other diseases, including cancer, by illuminating the broad principle of
drug design, which is fundamental to much current research.
From understanding of the mechanism by which sulfonamides inhibit
the growth of bacteria came the concept of antimetabolites and new insights
into the essential relationship between molecular form and physiological
function. Simply stated, an antimetabolite inhibits the activity of an enzyme
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BIOLOGY IN THE SERVICE OF MAN
that cells need for growth or other normal activity because it closely re-
sembles the natural substrate of that enzyme. However, the antimetabolite
cannot be affected by the enzyme and remains attached to its surface; in
consequence, the enzyme cannot perform its normal function. The discovery
of specific bacterial inhibition has a long history. In 1904, Paul Ehrlich,
a German scientist, postulated that infectious diseases could be treated if
chemicals could be found with a greater affinity and toxicity for parasite
organisms than for host cells. Using dyes against trypanosomes and arseni-
cals against spirochetes, he demonstrated the validity of his hypothesis and
provided the earliest useful treatment for syphilis. In 1935, a dye called
Prontosil was shown to be effective in treating streptococcal infections in
patients, though it had no effect on bacteria in a test tube. The demonstra-
tion that individuals treated with Prontosil excrete sulfanilamide, a degrada-
tion product of the dye in the body, was soon followed by observation that
this compound inhibits both infection in patients and the growth of organ-
isms in laboratory test media. A vigorous program of chemical modification
of the basic structure led to a new class of drugs, the sulfonamides. Even
now, these are the drugs of choice in the treatment of gastrointestinal and
urinary-tract infections.
Early empirical success with sulfanilamide rendered it imperative that
the mechanism of its effect be understood, so as to permit design of even
more effective congeners. A lengthy series of observations, conducted in
a multitude of laboratories at home and abroad, yielded the following con-
clusions:
Sulfonamides inhibit bacterial growth by preventing the organisms from
synthesizing folio acid, a vitamin for man, lack of which results in sprue.
Normal synthesis of folic acid by bacteria and plants commences with the
incorporation of p-aminobenzoic acid. In molecular structure, p-amino-
benzoic acid and the sulfonamides are distinctly similar.
NH2
COOH
p-aminobenzoic acid
NH2
SO2NH2
sulfanilamide
When a sulfonamide attaches itself to the enzyme responsible for the
normal reaction with p-aminobenzoic acid, synthesis is blocked, and, for
lack of folio acid, the bacterium cannot survive. Because man is unable to
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146
THE LIFE SCIENCES
synthesize his own folio acid, the sulfonamides do his metabolism no harm,
selectively attacking bacteria while leaving human cells undamaged. It was
these observations that gave rise to the concept of antimetabolite drugs.
Many have since been usefully synthesized, but no better example of the
concept is yet available.
ANTIBIOTICS
Penicillin was discovered in 1929 when a British bacteriologist observed
the inhibitory properties of the fungus Penic~ll~um notatum' which secretes
penicillin into surrounding media. This substance, destined to become the
most widely used antibiotic, was, however, originally discounted as im-
practical because of its seeming chemical instability. But by 1940 other
British scientists showed that it was reasonably stable when partially purified
and dried. Their material, only 50 percent pure, proved to be nontoxic to
man and very active against susceptible micro-organisms, including staphylo-
cocci. Although effective, penicillin was tedious to purify, and problems
of mass production seemed insurmountable when the calamity of war
prompted members of the British group to look across the Atlantic for help.
The mass outbreak of typhus during World War ~ and the loss of count-
less wounded to secondary bacterial infection, followed in quick succession
by the influenza pandemic of 1917-1918 gave urgency to the search for an
effective antibacterial agent as we entered World War II. It took the crisis
of the Second World War, which harnessed the potential of the American
drug industry, until then running a distant second to Europe as a source
of new drugs, plus the resources of the Department of Agriculture, to create
the antibiotic age. The results were nothing less than spectacular. Success
was based upon already developed techniques for large-scale cultivation
of micro-organisms, the isolation of Penicill~um strains that secreted large
quantities of penicillin, and the development of suitable growth media. By
September 1943, there was enough of this drug to supply all the Allied
forces. This phenomenal accomplishment not only markedly reduced mor-
tality among the wounded but also launched a new and fruitful search for
other antibiotics.
After elucidation of the chemical structure of penicillin, in due course
natural penicillin was replaced by semisynthetic penicillins, which are com-
paratively simple to manufacture and which retain the essential molecular
configuration of the parent molecule, which is so eRective against Gram
. . .
positive organisms.
The attempts to prepare semisynthetic penicillins bore an additional
fruit. The earliest such attempts, which seemed entirely rational, failed.
When the explanation was found, it proved to be an important extension
OCR for page 147
BIOLOGY IN THE SERVICE OF MAN
.
of the antimetabolite principle. Sulfanilamide and p-aminobenzoic acid
are essentially planar molecules; thus the analogy suggested by the two-
dimensional formulae above is indeed valid. But the unsuccessful semi-
synthetic penicillins, which appeared to be reasonable analogs of natural
penicillin as these structures are conventionally represented on paper-
differed significantly when three-dimensional models, based on x-ray evi-
dence, were constructed. Since then, chemists engaged in the synthesis of
new drugs have been acutely aware of the fact that, to be effective, the drug
must attach properly to the surface of the enzyme or membrane to be
affected, and this must be a property of its three-dimensional conformation.
Extensive screening of soil samples, largely by drug manufacturers, then
led to the discovery of an ever-increasing family of antibiotic agents, among
them streptomycin, chloromycetin, aureomycin, and terramycin. Although
there is as yet no universally effective agent, one or another of these drugs
can mitigate virtually all known infections.
Antibiotics have drastically altered the patterns of medical practice. Prior
to 1940, thousands of hospital beds were occupied by patients with infec-
tious diseases. Today, in the main, these patients receive a prescription for
antibiotics and return home. The morbidity associated with postoperative
infections has dropped sharply. And the damaging, once frequent, chain
of events that began with a "strep throat" and went on to scarlet fever,
. . .
rheumatic lever, and serious heart disease has been broken. The search for
new and better antibiotics continues in an effort that counts on both ration-
ally exploited chance and accumulated skills and understanding. New anti-
biotics are still discovered by screening methods in which activity is sought
in extracts of thousands of yeasts and fungi and soil samples of unknown
microflora from around the globe. Modified, improved semisynthetic com-
pounds then follow as drug designers attempt to deal with the two most
critical problems posed by these drugs.
As predicted by scientists familiar with the physiology and genetics of
bacteria, as use of antibiotics spread throughout the population, so, un-
fortunately, did bacteria that are antibiotic-resistant. The antibiotic boom
fostered selective processes that bred resistant organisms. Among a normal
population of bacteria there are, almost invariably, a few organisms that
have spontaneously mutated, the mutation rendering them immune to the
bactericidal action of a given antibiotic. As the drug suppresses the growth
of sensitive members of the colony, resistant mutants flourish. In some
cases, simultaneous use of two antibiotics with differing modi operandi is
effective to a limited degree. But the problem is compounded by the fact
that resistance, like an infectious disease, is catching. Both by sexual mating
and by transduction, a process in which a virus carries a bacterial gene
from one cell to another, bacteria can spread their resistance among related
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148
THE LIFE SCIENCES
strains, and some organisms have been isolated that are resistant to several
antibiotics at once. Recent work describing transduction may open the way
to "outwitting" this threatening phenomenon, as should continuing improve-
ment of semisynthetic antibiotics that are of greater potency and specificity
than natural antibiotics but that are insensitive to the enzymes that destroy
the latter.
The spectacular success of these antibiotics gave sharp stimulus to inquiry
into their mode of action, an inquiry that continues with increasing intensity.
In a few instances, partial answers are already available. Thus, penicillin
selectively inhibits one specific enzymatic step in the complex process
wnerecy tne ceil walls of Ram-positive bacteria are fabricated. Each such
wall is a single "bag-shaped" macromolecule built of 10 different kinds of
subunits. As the cell grows, or divides, linkages must be broken and addi-
tional subunits inserted. Interruption of this process leaves the cell without
a casing and, hence, renders it susceptible to damage by diverse physical or
chemical changes in its environment. since mammalian ~ ~mninv an
^~ ~u ~ a:_ ~ ~C ~ ~ ~ 1 1
quell ~db111g, LIl~y dE~ UIla~eCtea By penicillin. Actinomycin D, which has
found only limited use as an antibiotic, operates by interference with the
mechanism by which RNA is made on the surface of DNA. Because it
affects mammalian cells in the same way, it has found little clinical use as
an antibiotic. Streptomycin in some manner so affects the ribosomes of
Gram-negative bacteria that they make mistakes in translating RNA into
protein, and hence make useless, nonfunctional proteins. As this field
progresses as the secrets of naturally occurring antibiotics are revealed-
it should be possible to improve on antibiotics, permitting synthesis of
chemical entities that are lethal for invading organisms yet relatively innocu-
ous for man. In each case, the new drug must be so constructed as to fit,
sterically, onto an enzyme or a membrane surface in such fashion that it
will seriously limit normal function, presumably by extension of the anti-
metabolite principle.
A more sophisticated understanding of the operation of the pathways by
which products are synthesized in the body has offered a new approach to
drug design. Early attempts to block the synthesis of a given product, e.g.,
cholesterol, sought to inhibit an enzyme known to be vital to its biosyn-
thesis. Research generally was directed at finding a drug that mimicked
the substrate with which a specific enzyme reacted, as noted earlier. How-
ever, a new avenue of pursuit was opened by the understanding that the
"committed step" in most synthetic metabolic pathways (pathways that
involve a series of consecutive reactions) is subject to allosteric feedback
inhibition by the final product, which bears little resemblance to the sub
strate of the enzyme responsible for the committed step. It is clear that
ingestion of cholesterol drastically inhibits its own biosynthesis. Patently,
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BIOLOGY IN THE SERVICE OF MAN
a foreign molecule that, in low concentration, could accomplish the same
event might serve as a potent drug for prevention of atherosclerosis, and
a series of other such possibilities is also under active investigation. But
until the principle of allosteric feedback inhibition had been revealed in
studies of bacterial metabolism, this approach could not have been con-
ceived.
There is good reason to expect a considerable increase in the sophistica-
tion of drug synthesis in the near future. In addition to the factors con-
sidered above, it is evident that many drugs- e.g., morphine and digitalis-
work by attachment to specific loci on cell membranes or intracellular
membranous structures. Partial understanding of how a drug interacts with
a cell membrane at the molecular level has only evolved in recent years.
As this field matures-as the structures of membranes are revealed it may
well become possible to alter them usefully in specific states. Quantitative
information about the biochemical events in metabolic disease is badly
needed, permitting construction of mathematical models of metabolic events
in a form manageable in a computer. Such information can be applied in
testing new drugs for a given disorder and in determining suitable dosage
regimens. For years, the interrelationships between levels of blood glucose
and secretion of insulin after the administration of sugar to normal volun-
teers and to diabetics have been crudely understood. More recently, a
carefully constructed mathematical model describes the effect of admin-
istered insulin on the uptake of glucose by the tissues, with resultant
changes in blood-glucose levels and in the release of insulin from the pan-
creas. Use of this model permits more nearly normal regulation of the
blood-sugar levels of diabetics. The benefits to man to be derived from
this advance are not yet certain, but the potential is huge. The insulin
regimens available since 1920 have sufficed to maintain the lives of hun-
dreds of thousands of diabetics. In time, however, they progress to a series
of highly undesirable sequelae cataract, peripheral vascular disease, hyper-
tension, atherosclerosis, and a disease of the lining of the minute filters of
the kidneys. A generation will be required to establish whether the dosage
schedules suggested by the new mathematical model, which, far more than
in the past, mimics the release of pancreatic insulin by normal individuals,
will also prevent the physical deterioration that is characteristic of diabetics
treated with insulin for the last half century.
As understanding of disease has dramatically increased, so have demands
for better comprehension of what disease is on the molecular level. Simul-
taneously, the development of a new drug has become a considerably more
complex operation due to the effort to meet increased requirements for
specific details about mode of action, specificity of action, safety, and effec-
tiveness in man. From the time a scientist arrives at an idea of the phar
-
149
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150
THE LIFE SCIENCES
mycological potential of a new compound to the time that compound
actually reaches the market a period of five to ten years a pharmaceutical
house must invest between $5 million and $10 million. Yet, this is our
ultimate hope for useful new drugs, and increasingly such developments
must rest on sound fundamental studies.
VIRAL DISEASES
In contrast to the great success of antibiotic therapy for bacterial infections,
only trivial progress has been achieved in coping with viral diseases. A
virus consists of a relatively small amount of genetic information, as either
DNA or RNA, with a protein coat. This coat is shed as the nucleic acid
enters the cell, where it usurps the normal genetic apparatus, shutting off
normal production of cellular RNA and proteins so as to turn out many
copies of the virus itself. Patently, any drug or procedure calculated to
interfere with this process must also similarly interfere with normal opera-
tion of the genetic apparatus. Although this is probably tolerable for brief
periods in a tissue such as muscle, it could be highly injurious to such
rapidly dividing tissue as that of' the bone marrow or the intestinal tract.
Clearly, drugs intended to serve these ends must possess a very high degree
of specificity and, despite much work, only a few useful leads are available.
One noteworthy example is the treatment of viral eye infections' e.g., the
herpesvirus, with a halogenated pyrimidine compound, S-iododeoxyuridine.
Although quite toxic systemically, it can be safely applied as eye drops. In
the eye this compound is incorporated into the new viral nucleic acid, which
then, as if mutated, directs the synthesis of inappropriate proteins, and
the infection cannot sustain itself.
A recent finding of considerable promise is that an antibacterial anti-
biotic, rifampicin (rifantin), also has very significant antiviral potency. Its
mechanism of action is highly interesting; for unknown reasons, in the
presence of this compound, the coat proteins of several viruses cannot
assemble on the viral nucleic acid surface. Hence, although both nucleic
acid and coat proteins are made in the infected cell, the full virus cannot
be assembled and fails to leave the cell in which its components were syn-
thesized, and thus the infection is terminated. Since there is no analogous
assemblage in the metabolism of mammalian cells, the antibiotic can be
used in animals, in adequate dosage, as an antiviral daunt without c~nrfArn
that it will interfere with any vital process in the host animal cells.
For the present, the major defense against virus infection must remain
man's own principal defense mechanism the immune system. The efficacy
of this system was long evident in the list of diseases that strike but once
in a lifetime, e.g., smallpox, measles, mumps. In each case the 'antigen
the foreign material that is "recognized" as foreign and that both elicits
formation of antibodies and combines with them is the viral protein coat.
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BIOLOGY IN THE SERVICE OF MAN
Effective defense is possible either by deliberate immunization in advance,
or by enhancing the immune response early in natural infection. Deliberate
immunization has long been practiced, as in smallpox vaccination, while
enhancement of the immune response has, until recently, consisted largely
of administration of antibodies from someone who has already had the
disease, as in administration of pooled ~y-globulin to prevent a suspected
case of measles.
Understanding of the nature and behavior of viruses, coupled with
methods for culturing them, lay behind the development of the polio vaccine.
As recently as 1954, this crippling disease struck 20,000 Americans an-
nually. Eleven years later, only 61 cases were reported in the United States,
the dramatic achievement of a mass-immunization campaign. Although
the general principles of immunization had been known since Jenner intro-
duced smallpox vaccine, much fundamental knowledge had to be acquired
before it could be applied with impunity to the polio virus. It was first
necessary to develop a cell system monkey tissues grown in culture-in
which polio viruses could be grown. Initially, viruses grown in this way
were chemically inactivated and then administered. The subsequent per-
fection of live polio vaccines depended upon an independent line of research
and the discovery of three mutant forms of the virus that could no longer
cause disease but retained their immunizing effect.
A development of molecular biology that may yet offer large dividends
is the recently acquired knowledge of a material called "interferon." This
is a protein, perhaps an enzyme, that is produced in small amount by ani-
mal cells infected with a virus. In sufficient quantity it increases remark-
ably the efficacy of the immune response. Until techniques become available
for its large-scale production, the best hope has appeared to be stimulation
of the mechanism by which one's own cells engage in interferon synthesis.
The primary trigger seemed to be the viral nucleic acid. Following this
clue' it was found that synthetic double-stranded RNA (a simple polymer
devoid of meaningful genetic information) is at least as efficient a stimulus
as viral nucleic acid. When given early in an infection-e.g., mice given
sufficient virus of hoof-and-mouth disease to assure 100 percent lethality-
such material has offered complete protection, not only sparing lives but
preventing the disease. This may yet prove to be the basis of a truly
useful clinical approach to viral infection with the happy property of being
generally useful without regard to the specific virus in question in any riven
patient.
CANCER THERAPY
Insights into the nature of DNA, its biosynthetic processes, and its role in
cell growth and development have had wide application in recent cancer
research. Coupled with recognition of the antimetabolite principle, these
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52
THE LIFE SCIENCES
insights stand behind the development of a series of anticancer drugs that
are able to check the growth of tumor cells, prolonging the lives of some
patients by several years.
Cancer, second only to heart disease in the mortality tables, Is not one
but many diseases. Slow-growing solid tumors, such as lung cancer, are
extremely difficult to treat unless the tumor is localized so that it can be
removed by surgery or destroyed by irradiation. Significant progress has
been made in treating by chemotherapy fast-growing tumors such as leu-
kemia or other blood or lymph cancers. Cancer of both types is character-
ized by abnormal, uncontrolled growth of cells. Successful therapy depends
upon an understanding of the metabolism and synthetic activities of those
cells and rests on the principle of attacking them when they are in a vul-
nerable state.
The process of cell replication occurs in four stages: two pauses or rest-
ing states, a period of DNA synthesis, and one of mitosis and cell division.
Dill Brent chemical agents selectively inhibit cell metabolism at different
stages in this cycle and, because the cancer cells in an individual are not all
synchronized that is, they are not all in the same phase at the same time-
judicious use of a combination of antimetabolites is necessary to destroy the
maximum number of tumor cells.
=~1; - ^~;rl ;^ .~,1 1~.w ~ __
(Ella d\;1U 15 used any man as a coenzyme in the process of synthesis of
DNA precursors. Therefore, it was reasoned, an antimetabolite that could
disrupt this sequence would inhibit the growth of tumor cells in the DNA-
synthetic phase. Of a series of structural analogs that were tested, one
called methotrexate ~ amethopterin ~ is clinically useful. Its drawback is
its lack of specificity; it acts against all cells in the DNA-synthetic phase,
whether they are cancerous or not. The turnover of normal cells, however,
is distinctly less than that of rapidly dividing cancer cells; in weighing risk
versus benefit, it was concluded that the toxic effects of methotrexate are
less than its benefits, particularly in the treatment of leukemia.
Another agent in the arsenal of anticancer agents is actinomycin, origi-
nally found as an antibiotic, which checks cell growth by limiting RNA
synthesis on DNA. When used against choriocarcinoma, an all too fre-
quently fatal cancer of Vouno wom~.n of rhilrlh~rinc~ ~ it ~f[=,~o ~
50 percent cure rate (remission of symptoms for five years). In combination
with methotrexate, cures are achieved in close to 80 percent of cases. The
same combination effects a 70 percent cure rate in Wilm's tumor, a kidney
cancer, and a 25 percent cure rate in cases of Burkitt's lymphoma, a malig-
nancy of the lymph glands first identified in children in Central Africa but
now known to be widespread. Patently, without knowledge of the mode
of action of actinomycin as an antibiotic, there could have been no reason
to consider it as a potential anticancer agent.
= .. ~^ _~4 ~V~4A~= ~l ~11~LO a
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166
THE LIFE SCIENCES
the pharmacology of the existing drugs is imperfectly understood. Knowl-
edge of the electrical basis for the formation and conduction of impulses
within the heart gained impetus when it became possible to record the
transmembrane potentials of single cardiac fibers by implanting micro-
electrodes within cells. By means of this technique and associated studies,
it became possible to characterize the ionic basis of cardiac electrical ac-
tivity, to identify the unique properties of certain specialized cells, and to
observe the influence of, for example, quinidine and digitalis on these param-
eters. Now, from studies of the electricity of the heart and of the ionic
processes associated with it, highly detailed, though not yet complete, pic-
tures have been drawn of each of the major clinical types of arrhythmia,
a new beginning is under way, and suitable test systems are available for
the search for specific antiarrhythmic drugs.
Critical to ultimate management of these disturbances is improved under-
standing of the underlying electrical activity, which is the result of the
operation of the cellular "electrolyte pump." It must be more than fortui-
tous that the "cardiac glycosides," particularly ouabain, which can assist a
failing heart are the most effective known inhibitors of the cellular transport
system, which, in cardiac muscle as in all other cells, achieves the outward
movement of sodium ions and the inward movement of potassium ions
using the energy of ATP. The responsible protein is associated with cell
membranes; the model proposed in Chapter 1 for transport processes seems
an adequate description of its function, viz., binding of 3Na+ and lATP, a
conformational change that permits rotation in the membrane, hydrolysis
of the ATP, discharge of the Na+, binding of K+, and rotation to the original
position. Control of this basic life function, which is adapted to the special
purpose of "electrical" conduction in nerve and muscle fibers, appears
central to progress in a variety of cardiac disorders. Parenthetically, one
may note that hyperactivity of this system in the various secretory glands
is one of the manifestations, now used as a definitive diagnostic sign, of
cystic fibrosis. In yet another context, it is the genetically controlled syn-
thesis of this same transport protein in kidney tubules that is regulated by
aldosterone, the adrenal hormone that, in excess, causes (:ushing's disease
and lack of which occasions Addison's disease.
The advent of cardiac surgery (and indeed, of cardiac transplantation)
is one of the most dramatic episodes in the history of medicine. Clearly,
these heroic procedures could not have been attempted until all the neces-
sary knowledge, skills, materials, and tools were at hand. Illustrative is the
instrument that has become the sine qua non of modern heart surgery-the
heart-lung machine.
When the heart is opened for repair of a valve or closure of a hole be
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BIOLOGY IN THE SERVICE OF MAN 167
tween the two ventricles (pumping chambers), the heart-lung machine is
temporarily employed to assume the function of the heart and lungs, to
pump blood, supply oxygen, and eliminate carbon dioxide. First used
successfully in man in 1953, its origins can be traced through preceding
centuries to the 1500's and 1600's, when double-valve, one-way pumps
were designed to draw water from deep mines. These, in turn, apparently
inspired William Harvey to recognize the true nature of the heart, which he
likened to a water pump. In the 1800's, physiologists attempted to duplicate
the work of the heart by perfusion of various animal organs such as the
liver and kidney, using a pump to better understand the functions of these
organs. In time, physiologists tried to add oxygen and remove carbon
dioxide from the blood used in perfusions, thus experimenting with crude
forerunners of the heart-lung machine. Their glass, rubber, or metal parts,
however, severely damaged the delicate red blood cells, a fact of little con-
sequence in short-term experiments on isolated organs but of obvious
import for human application. The plastics industry solved this problem
by offering virtually inert, smooth plastics with nonwetting surfaces, which
minimize damage to the blood cells as they pass through the pump.
Once developed, successful application of the heart-lung machine awaited
solution of one other problem. When blood comes into contact with sur-
faces other than normal blood vessels, it clots. Indeed, this would happen
in the blood vessels themselves were they not coated with natural anti-
clotting compounds. Among these is heparin, which can be obtained in
quantity from beef lungs. Heparin inhibits the clotting mechanisms, per-
mitting blood to course through the tubes and chambers of the machine
for hours.
Many refinements in recent years have made the heart-lung machine
safer and more readily available. Artificial heart valves and plastic blood
vessels, developed in collaboration with engineers, are available to surgeons.
Even totally implantable artificial hearts have been tried in man. And long
years of animal experimentation, coupled with the availability of immuno-
suppressive drugs and techniques for determining tissue matching, make
human heart transplantation a feasible, though still highly experimental,
procedure. Yet the road ahead is long. Oxygenators causing less damage
to blood than those currently available are needed if heart-lung bypass is
to be applied for long periods of time. Such an instrument is essential to
save patients with serious but reversible lung diseases, such as hyaline
membrane disease in newborns. The use of artificial pumps either partially
or completely to support the circulation of patients during a heart attack
is a logical move that has already been attempted, but it is far from routine
and demands considerable refinement. Significant progress toward pro
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auction of totally artificial hearts is thwarted by our inability to produce
compact, long-lasting power sources capable of responding to the bio-
chemical signals that control muscle blood flow. But there is reason to hope.
Remarkable as all these accomplishments are, it must not be forgotten
that a large fraction of the conditions that impose these requirements for
drastic surgery are the consequence of one process, atherosclerosis, the
deposition of mushy lipids on the surface and within the walls of the
arteries, which then calcify, become brittle, and serve as foci for clot for-
mation and infection. In the long run, it is to be hoped that understanding
of this process will permit its prevention, thereby obviating the need for
many current surgical and therapeutic procedures. The alternative, more
than a thousand cardiac transplants per day in the United States alone, is
scarcely an appealing prospect. Meanwhile, the efforts of thousands of
scientists have brought surgery to this remarkable peak.
If the physiologist originated the idea of a heart-lung machine, he also
has greatly benefited by its sophisticated use in the hands of surgeons and
engineers, for today he uses the same instrument as a tool for learning still
more about the intricate mechanisms of the heart and lungs. And, even-
tually, the information he gathers will further enlighten the physicians and
surgeons in their battle against disease.
Diuretics A serious, occasionally life-threatening, complication of heart
failure, liver and kidney diseases, and hypertension is edema, the excessive
accumulation of salt and water in body tissues at large. Today, diuretics,
drugs that interfere with the mechanisms by which kidneys retain sodium,
and hence chloride and water, control edema rather successfully in most
patients. A major class of modern diuretics was made possible by observa-
tions during the early history of sulfanilamide. Ironically, no one would
have predicted that the background essential to the rational development of
diuretics would be supplied by research quite unrelated to the function of
the kidney or to the need for such agents.
Early in the clinical use of sulfonamides, it was noted that such patients
excreted an alkaline urine and developed a mild acidosis (acidification of
blood plasma). Then, biochemists observed that sulfanilamide inhibits the
enzyme carbonic anhydrase that catalyzes the simple hydration and dehy-
dration of carbon dioxide, a process necessary to the escape of carbon
dioxide from the blood as it travels through the lungs. When carbonic
anhydrase was then found to be present in quantity in the kidney, it became
apparent that this enzyme plays a role in kidney mechanisms for excretion
of acid and that sulfanilamide's inhibitory effect on the kidney enzyme
accounted for its effect on urinary secretion, with consequent acidosis.
Accumulation of acid is the consequence of excretion of sodium ions. In
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otherwise normal individuals, e.g., the sulfanilamide-treated patients, this
effect is undesirable. But in patients whose kidneys are failing to excrete
salt (sodium ions) normally, the same process could be decidedly bene-
ficial. At that point, chemists had a rational test system for fashioning a
drug that would be a more effective inhibitor of carbonic antydrase than
sulfanilamide by modifying the structure of sulfanilamide, and designed
acetazolamide (Diamox), which, in 1950, became the first useful oral
diuretic. Incidentally, it also became a remarkably successful agent for
treatment of glaucoma, excessive secretion of fluid into the anterior chamber
of the eye, by interfering with the carbonic anhydrase of the overactive
secretory cells.
While Diamox was safe, it was not an ideal agent because it could not
be used continuously. Five years later, by continuing modification of the
basic structure, another diuretic, chlorothiazide (Diuril), was constructed
and proved useful not only for treatment of water and salt retention in
ambulatory, nonhospitalized patients but also in lowering their blood pres-
sures. In the five-year period following its introduction, prescriptions for
diuretics in the United States increased sixfold. But Diuril, too, had limi
tations, particularly limited ability to cope with massive edema and excessive
stimulation of urinary excretion of potassium and sodium. Pharmaceutical
chemists then looked to aldosterone, the adrenal hormone that normally
occasions retention of sodium and loss of potassium from the body. Several
compounds that structurally resemble aldosterone, yet are sufficiently dif-
ferent that they do not possess its pharmacological actions, were synthesized
to displace the hormone from sites where it is normally bound in the kidney.
By thus occupying the effecter sites of the natural hormone, they function
as antimetabolites and prevent excessive secretion of potassium.
Meanwhile, another approach resulted in a diuretic of an entirely dif-
ferent class. It had long been known that mercurial compounds are diuretic,
but their toxicity precludes their use. These agents were known to work
by reacting with sulfhydryl groups of proteins in the lining of the kidney
tubules. Accordingly, a compound was sought that also reacts with such
groups but lacks the toxicity of mercurials. The result, ethacrynic acid, is
so effective that it must be used with great caution. Happily, like Diuril it
can be taken orally. With this armamentarium it is now possible to treat
successfully virtually all forms of salt retention except for those that reflect
primary disease of the kidney itself. Such cases can be managed only by
dialysis with an "artificial kidney," itself the product of two decades of
research, entirely dependent upon growing understanding of the role of a
normal kidney.
As is so often true in science, new discoveries seldom have only a single
application. Investigations of sulfanilamide culminated in establishment of
169
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the antimetabolite principle and development of Diamox, and Diamox, in
turn, became an important tool for fundamental research. First, it repre-
sented the beginning of a rational scientific approach to seeking diuretics
by relating chemical structures to kidney mechanisms. Second, it became
extremely useful as a device enabling renal physiologists to evaluate the
role of carbonic anhydrase in kidney-transport processes. It was of prime
importance in elucidating the renal mechanisms of bicarbonate reabsorption
and hydrogen secretion. The concepts thus developed were then amply
supported by direct renal-micropuncture experiments. This development
had an important influence on clinical care of patients because the new
understanding of physiology enabled scientists to predict the specific elec-
trolyte losses in the urine produced by various drugs.
Much public concern and attention is directed to the problem of pro-
viding the best of medical care to all Americans, a concern we fully share.
But the nature of medical care and its relation to research should be clearly
understood. The component of medical practice that makes the greatest
demands on our resources measured in the time of physicians, nurses,
paramedical personnel, hospital beds, and the ever more complex technol-
ogy of intensive medical care is the management of those disorders for
which research has, to date, made possible only palliative or physiologically
corrective measures, termed by some "half-way medical technologies." When
research has provided a definitive therapeutic or preventive regimen, it
is invariably cheaper and simpler than the palliative treatment previously
available for the same disease. This is surely true for a wide range of
infectious diseases such as lobar pneumonia, poliomyelitis, tuberculosis,
bacterial endocarditis, typhus, typhoid fever, and diphtheria, to name but a
few. Almost all nutritional diseases e.g., pellagra, beriberi, rickets, and
scurvy and a variety of other ailments such as pernicious anemia, Addi-
son's disease, goiter, juvenile diabetes, Parkinsonism, and glaucoma fall
within this category. Only a few years ago, it was these disorders that
dominated the efforts of the health care system. Most remain serious, but
they are but a minor aspect of medical practice. The diseases that now
overwhelm the health care system are those for which research has not
yet provided the understanding required to design truly definitive pro-
cedures. It is not lack of physicians, nurses, technicians, or hospitals that
limits our capability to manage such problems as most forms of cancer,
coronary occlusion, myocardial infarction, stroke, acute rheumatic fever,
osteoarthritis, pyelonephritis, bronchial asthma, schizophrenia, muscular
dystrophy, cystic fibrosis, and multiple sclerosis; it is lack of understanding
sufficient to permit development of a really therapeutic procedure. Bio-
medical research, which represents only 1.5 percent of total expenditures
for health, is, therefore, both the biggest health bargain one can purchase
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and the only hope for future progress. If this opportunity is neglected or
minimized for shortsighted fiscal reasons, then, by the turn of this century,
our nation must double the number of physicians, nurses, technicians,
hospital beds, and sanitaria and learn to live with the equivalent increment
in human suffering. Grim prospect indeed!
Population Control
While biomedical scientists pursue greater sophistication in the under-
standing and treatment of disease, this attempt must be matched by a con-
certed effort to solve the crisis being brought on by the continuing increase
in human population. No matter what contributions scientific investiga-
tion and new technologies make in the coming decades, it is hard to imagine
that they will come quickly enough or be sufficient to meet man's needs
if his sheer numbers continue to mount unchecked. The problems of popu-
lation control are both biological and sociological. From studies in repro-
ductive biology must come new and better contraceptive procedures, which
must then be put into general use.
The oral contraceptives that became widely available in 1961 are con-
sumed by millions of women the world over; they symbolize society's
recognition of the need for birth control. They also illustrate the beneficial
results of concentrated, deliberate research. Birth-control pills in current
use are usually a combination of the two hormones that regulate the repro-
ductive cycle a synthetic estrogen and a progestin, a synthetic version of
natural progesterone. If taken as prescribed, they appear to be almost
invariably effective, although reproductive biologists are not entirely certain
why. That these agents strikingly alter the output of the related regulatory
pituitary hormones is certain. Beyond that, explanations of their mechanism
of action are tentative. They may not actually prevent ovulation each
month, yet exert their contraceptive effect nonetheless. The appearance
of the endometrium that lines the uterus is somewhat altered in women
taking these drugs; perhaps this relates to the failure to conceive. Another
possibility is that the progestin in the combination products stimulates the
release of cervical secretions so viscous that they effectively entrap sperma-
tozoa. Indeed, there is some evidence that progestin alone is an effective
contraceptive, and various experiments with low-dose progestational com-
pounds are under way. Unfortunately, it was one of this class of compounds
that was recently shown to induce tumor formation in dogs; hence, the
future of this program is uncertain.
The availability of the current pill is the culmination of 70 years of
study of the operation of the mammalian reproductive apparatus. Step by
tedious step, understanding of the nature and function of the two pituitary
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THE LIFE SCIENCES
hormones the estrogen of the ovary and the hormone of its corpus luteum
-as well as the progesterone of the uterus was achieved. The accumu-
lated information found its way into pregnancy tests, diagnoses of abnormal
pregnancies, and correction of faulty development of secondary sex char-
acteristics. Natural sources of estrogens and progesterones were inadequate;
substitutes were synthesized that were more effective than the natural forms
and that could be taken by mouth. Detailed studies revealed the precise
cellular changes occasioned by each natural and synthetic hormone; slowly,
the precise clockwork that governs the menstrual cycle and the stabilization
and climax of pregnancy was elucidated.
With such knowledge came successful diagnosis of the cause of a large
fraction of all instances of sterility imbalance of the two pituitary hor-
mones. Therapeutic trials failed until it was realized that only human hor-
mone is effective. This is available in urine, and a modest supply now
permits pregnancy for many childless wives. But the supply is limited and
one must await precise establishment of the amino acid sequence of this
hormone, followed by synthesis using the recently developed methods for
polypeptide synthesis, to overcome this shortage.
It was with this slow and difficult accumulation of understanding that
the search for a contraceptive pill began, both estrogens and progestins
being tested separately before it became clear that a combination might
be required. Most important is the realization that, until the whole stage
had been set, the final undertaking could not have been possible. There
has been no better illustration of the culmination of many years of interac-
tion between clinical observation and clinical and basic research. As use
of the pill increased, reports of clotting disorders and breast tumors
became more frequent. Even at this writing, the validity of such claims is
somewhat uncertain, and the adverse effects of the pill remain to be estab-
lished with certainty. Assuming the reality of such effects, there remains
the societal decision of weighing hazard against benefit the death rate
due to pregnancy versus that associated with the pill and the risk entailed
versus the societal imperative that population growth be brought under
control. Meanwhile, the search for other, less hazardous but still effective,
measures must be prosecuted vigorously.
The search for contraceptive drugs began with animal studies and now
returns to the laboratory to create the next generation of pills. In addition
to seeking an explanation of the mechanisms of current agents, investigators
must explore the phenomenon of conception itself even further. A quite
subtle interruption in this delicately balanced sequence of biological events
may well prevent conception just as surely as the grosser effects of present
agents.
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BIOLOGY IN THE SERVICE OF MAN 173
The newly established Center for Population Research at the National
Institutes of Health has initiated a program focusing on four targets:
1. The reproductive physiology of the male, particularly the processes
that permit the maturation of sperm cells. Only a mature sperm can pene-
trate and fertilize an egg. If the biochemical events surrounding this process
could be controlled, a new approach to contraception would be available.
2. The structure and function of the oviduct through which an egg
travels from the ovary to the uterus.
3. The function of the corpus luteum, the yellow body, formed after
ovulation, that produces progesterone for the maintenance of pregnancy.
4. The biology of the fertilized egg cell before and during implantation
in the uterine wall.
Prior to the introduction of oral contraceptives, reasonably satisfactory
methods of mechanical or physiochemical contraception existed. Human
nature limits the success of these methods; all too often they are used
improperly or not at all. They are not, however, to be discarded, nor are
the increasingly satisfactory intrauterine devices. If population control is
to be achieved on an acceptable scale, a variety of contraceptive methods
will be required. This will be possible only in the light of additional knowl-
edge.
If indeed a promising lead for the development of a new contraceptive
drug does emerge from research, there will remain an extremely lengthy
process, prescribed by the Food and Drug Administration (FDA), before
it can be brought to market. Such research and development is performed
in the laboratories and under the auspices of pharmaceutical companies,
which spend collectively, even now, more than half of all funds devoted to
research on reproductive physiology, quite apart from the high costs of
prolonged toxicity testing and development. Precisely because such a drug
would be taken by "normal" women over many years, the FDA procedures
are conservative, demanding prolonged test trials to establish safety, side
reactions, and so on. At best, there can be no way to shorten the testing
trials in women and the world's population will have increased by at
least one billion before widespread, unrestricted use of such a new drug
could be considered, even if the structure of the compound were known,
its synthesis worked out, and its general biological properties known at this
writing. The great expense of the necessary prolonged procedures is a
serious deterrent to the undertaking of such activity by the drug manufac-
turers, who must somehow be assured that they will at least recover their
investment. Meanwhile, the needs of humanity are so great that we suggest
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that the Secretary of Health, Education, and Welfare develop some new
set of relationships wherein the government joins with the drug manu-
facturers in funding such research activities, utilizing to the full the orga-
nized multidisciplinary capabilities of these organizations, underwriting their
costs, and pooling their competence. Confronted by the crisis of population
growth, the government is justified in taking emergency measures.
The Early and Latter Years of Life
Half the individuals born today will die before their seventieth birthdays;
yet, for all the hazards that beset man during his middle years, the gravest
threat remains with the first year of life. Infant mortality (deaths in the
first year of life) has been declining steadily in the last half century as a
result of significant advances in infant care, but it is still higher in the United
States than in several other countries 22.1 deaths per 1,000 live births
in 1967.
Human biological potential is conditioned, in large measure, by the
events of prenatal and early postnatal life.
The quality of adult life is
predetermined by such phenomena as inherited defects, environmental
influences, including disease, exposure to radiation or drugs, and the
quality of nutrition. The first stages of man's life are the object of growing
scientific attention, yet there are few areas in which clinical applications
are as severely handicapped by lack of fundamental understanding.
There is, as yet, no precise description in biochemical terms of the notating
of sperm and egg. The fetus, in the protective environment of its mother's
womb, nourished through the placenta, is particularly susceptible to environ-
mental influences as its cells differentiate and become specialized tissues,
and it is subject thereafter to the health of its mother. Diabetes, toxemia
of pregnancy, and blood-group incompatibility can threaten its health, and
even its survival. Parturition must come neither too early nor too late,
and the newborn must then adjust to his world. Whereas a significant
fraction of infant mortality may be eliminated by applying available under-
standing, further progress will be entirely dependent on improved knowledge
of the entire process from conception to the early years of life.
No problem appears more urgent than definitive establishment of the
consequences in later life of early nutrition. This problem first came to
attention with respect to peoples of developing nations as it became evi-
dent that the apathy, stunting, s~.ntihili~v to inf~.~.tion lack of ~.n~rav
~. . . .
_ < ~_J _ ~_ _ __ ~_ ~=~ ~
and, perhaps, limited intelligence of certain tropical populations were re-
lated to their nutritional status, since this characteristic is particularly
obvious among those groups in which kwashiorkor (generalized protein
deficiency) is rife. Significantly, the data also indicate that there is no
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BIOLOGY IN THE SERVICE OF MAN 175
genetic basis for this problem. Accordingly, there is urgent need to learn
how protein deficiency results in these sequelae, whether there are key
amino acids, what level of nutrition is required to prevent the process, etc.
Early evidence strongly indicates that the brain of the protein-deficient
individual may contain as many as 30 percent fewer than the normal num-
ber of neurons (nerve cells). Since the process of neuron generation is
completed within the first two years of life, this deficit can never be over-
come. Solution of these problems could go a long way toward helping
protein-deficient people to help themselves. Equally important is the need
to establish the extent to which similar nutritional influences are at work
in the United States. Animal studies will continue to be revealing, but safe
and sensitive techniques for monitoring the physiological state of the fetus
as it develops are sorely required.
To know the mechanisms of genetic and environmental effects and to
comprehend the role of nutrition, the influence of hormones in fetal life,
and the interactions of tissues, these factors must be measured and charted.
Efforts to accomplish this are under way. New methods are now being
applied to measurement of maternal excretion of hormones, particularly
estriol (an estrogen), and relating it to fetal development, to monitoring
of fetal heart rates and correlating these with the fetal condition, and to
analysis of fetal blood, even during labor itself, by obtaining microsamples
that are examined by new microchemical procedures.
At the opposite end of life's scale, the process of aging is even less well
understood. Indeed, it has yet to be described adequately. What processes
are responsible for the progressive decline in the structure and function of
an adult organism? What aspects of the process are intrinsic to the organism,
i.e., the consequence of its initial genetic complement, and what aspects
result from environmental assaults? How would we age in the absence of
intercurrent trauma or infectious disease? In both young and old organ-
isms, muscles contract, nerves conduct, glands secrete, and so on. The
changes occurring in tissues that distinguish youth from age are too subtle
to be detected by currently available techniques. How does deterioration
in structure and function become incompatible with life? Has anyone ever
died of "natural causes"?
One aspect of aging seems incontrovertible. With the passage of time,
cells die in certain organs the brain, the muscles, the lymphatic system-
and are not replaced. Is aging merely the consequence of this one-way
process? If so, what clockwork fixes the norm for a mouse at one year,
for man at three score and ten, for the giant sea tortoise at 500 years, and
for the sequoia at several millennia? Can this clockwork be reset?
One prominent theory of aging holds that it reflects a developed insta-
bility of the genetic apparatus of individual cells, i.e., that aging occurs
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THE LIFE SCIENCES
because of highly specific deviations within single cells rather than among
whole cell populations. Perhaps, for example, in the course of time, subtle
errors in the self-duplicating process of DNA accumulate. Perhaps the
accuracy of transcription fades, though it does not fail completely. To
date it has been possible only to refine these questions, not to subject them
to rigorous test, for lack of a reasonably short-lived but acceptable model.
Current efforts utilize mammalian cells in tissue culture and such organisms
as the thousand-celled rotifer. A suitable test model should have a short
life-span and well-established standardized nutritional requirements, should
be maintained in freedom from infections and other external insults, and
must possess genetic uniformity.
An alternative hypothesis suggests that, whereas cell death and failure
of replacement do indeed lie at the heart of the aging process, the reason
may not be intrinsic in the cells themselves but may be secondary to changes
in their environment. Certainly, with the passage of time, connective tissue
becomes tougher, thicker, and less elastic. If such changes also occur on
a minute scale at the level of capillaries, this could result in local nutritional
failure or intoxication by the products of the cells' own metabolism.
Regrettably, all such studies are in their infancy. Only when they have
produced sufficient understanding will it be clear whether man may aspire
to a prolonged span of enjoyable, fruitful years.
This brief summary has only touched upon the approaches to biomedical
research that may be anticipated in the next decade. Predictions of the
future direction of clinical investigation, like those of other human affairs,
are hazardous, but the record suggests that the greatest benefit will accrue
from the slow accumulation of basic knowledge concerning the nature of
normal and pathological physiological and chemical processes. Obviously,
one cannot apply knowledge to the prevention and treatment of disease
until that knowledge exists.
Biomedical research has come of age. In the intensively managed, highly
instrumented clinical research units of our great hospitals, clinical investi-
gation has become a legitimate science. Human biology is being explored
with unprecedented vigor and sophistication, and the information net of
the biomedical community assures that scientific discovery in all dis-
ciplines is readily applied to human disease.
This endeavor, the focal activity of university medical centers, is less
than two decades old. How, then, shall one measure its success? Not alone
by the large and small insights into the nature of life or the pathogenesis
of disease, nor by the pain alleviated or the lives saved. We are all too
aware of the woeful limitations of medicine, of the anguish of suffering,
tortured humanity, including those who are left behind after death. The
Representative terms from entire chapter:
uric acid
