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80 THE LIFE SCIENCES
virus, SV40, and seven different human adenoviruses, continue to syn-
thesize viral-specific mRNA, as demonstrated by the formation of DNA-
RNA hybrids when their pooled mRNA is mixed with pure viral DNA.
A surprisingly large amount of the total mRNA in the polyribosomes of
acenov~rus-transtormea cells Is v~ral-specific, 2 to 5 percent, suggesting that
a small amount of viral DNA present in the tumor cell is preferentially
transcribed while most of the host RNA goes unexpressed. This selective
transcription during viral carcinogenesis may represent only a specialized
case of the more general phenomenon occurring during cell differentiation,
or it may occur by an entirely different mechanism. It seems likely that
these viral mRNA molecules are translated into proteins, some of which
account for the altered growth and antigenic properties of the tumor cell.
Host-cell DNA synthesis is inhibited during the cycle of infection with
most DNA viruses. However, infection of nondividing cells with polyoma
or SV40 virus induces the synthesis of host-cell DNA, a phenomenon
thought to be of importance in viral transformation.
The oncogenic RNA viruses, including the avian and murine leukemia
and sarcoma viruses, are capable both of transforming cells and of replicat-
ing within the same cell. Particularly intriguing are those viruses that are
defective in the genes for synthesis of viral coat protein; they transform
cells without the production of infectious virus. Others are defective only
within certain host cells. Co-infection of tumor cells induced by such a
defective virus in conjunction with a second virus ("helper virus") is re-
quired for the synthesis of infectious virus; newly synthesized virus then
contains the genome of the transforming virus and the coat protein of the
helper virus.
FORM AND FUNCTION
For the isolated cell, structural form is correlated with its simplest needs-
to remain alive in the face of adversity, to grow, and to reproduce by
fission. To accomplish these simple ends, cells possess a variety of sub-
structures, each specialized for the performance of a specific chemical task.
Multicellular organisms man himself-are made possible by the collective
structures, and the functions they permit, of organized groups of cells,
organs that serve the entire organism much as cellular organelles serve the
cell. One need consider only the brain, the gastrointestinal tract, the
cardiovascular system, the kidney, the musculoskeletal system, and the
genitalia to recognize the extent of this subdivision of labor. The goal of
practitioners of the anatomical sciences and of physiologists has been to
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FRONTIERS OF BIOLOGY
obtain detailed understanding of these correlations of form and function-
to understand how nerves conduct, muscles contract, kidneys regulate the
composition of the extracellular fluid, the gastrointestinal tract degrades
foodstuffs into metabolizable nutrients; how joints permit motion; how
gases are taken into the body or removed; and how the organism is inte-
grated into a harmonious whole through the operation of the nervous and
endocrine systems. The last two decades have witnessed an immense
expansion of research in these areas, which has been made possible by new
awareness of the nature of the problems, by new experimental tools such
as the electron and phase-contrast microscopes, fast multichannel recorders,
microspectrophotometers, the hying-spot microscope, x-ray analysis, and
radioisotopes and techniques for their detection and measurement, as well
as by the entire armamentarium of the biochemist. In no area of the life
sciences is the melding of such classical disciplines as anatomy, physiology,
pharmacology, anthropology, and biochemistry so clearly evident. Review
here of the multitude of accomplishments at this level of biological con-
sideration is impossible; accordingly, a few examples will be cited only as
illustrations of current approaches to a few classical problems.
Muscular Contraction
For decades, muscular contraction has been an attractive object of study.
Although it is easily amenable to experimental approach, no useful working
concept of the fundamental mechanism was developed until two quite
independent approaches revealed complementary information that, com-
bined, led to a highly satisfying model of the nature of this process.
As shown in Figure 22, phase-contrast and electron microscopy revealed
the presence in muscle of two quite distinct types of fibers: In skeletal
muscle, filaments of about 200 ~ are each surrounded by six filaments
about 100 ~ in diameter. When muscle is stretched, the two sets of fila-
ments pull away from each other, and when muscle is contracted, they
telescope into each other. The individual filaments do not themselves
shorten but appear to interact with each other by a "clawing" action that
pulls the filaments past each other. The thick filaments are constructed of
the protein, myosin; each molecule of myosin (mol. wt. 480,000) is an
elongated multiple-stranded helix, about 1,800 ~ by about 20 A, with a
"knob," oriented at right angles to the fiber axis at one end. The knob
portion has the properties of an enzyme capable of catalyzing hydrolysis
of ATP. The thin filaments are formed of a second protein, actin, the
fundamental unit of which is a simple globular molecule (mol. wt.
60,000), which polymerizes into a filament analogous to a string of beads
81
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82 THE LIFE SCIENCES
Skeletal Muscle
Muscle Fasciculus -- "
, , ~ -,,#
Am_
_ ~ ,_ ~ Hi_
,,' Z Sarcomere ; I"` Myofibril
"` G-Actin Molecu le
11 1
11 1
,' 'I
I
I /
1 /
I /
I !
/
!
O~Booo °°° ~ °°° °~° K
~~ ooo~ooo~ooo
F-Actin Filament
__~ L
Myosin Fi lament
\ \ Myosin Molecule
\ H ~ I
~ ·-~-~-. v
· · - ~ ~Li 9 htHeavy
· · · · · · Meromyosi n Meromyosin
~\
\ \
~\
\ \
FIGURE 22 Structure and function of skeletal muscle. F. G. H. and I are cross sections at the
levels indicated. (From W. Bloom and D. W. Fawcett, A Textbook of Histology, 9th ea., 1968.
Copyright (I) 1968 W. B. Saunders Company. Drawing by Sylvia Collard Keene.)
OCR for page 83
FRONTIERS OF BIOLOGY
with two such strands wrapped around each other in a double helix. In
solution, purified actin and myosin react rapidly with each other to form
a tightly bonded complex, bond formation occurring between the knobs
of the myosin and some aspect of the actin molecule. Addition of ATP
permits transient separation of the actin-myosin complex, which is re-
formed as the myosin hydrolyzes the ATP. Presumably, some equivalent
interaction is responsible for the ratchet-like action of actin and myosin
in contracting or relaxing muscle, although the details of this process remain
obscure.
How then does an intact muscle contract? The process begins with the
arrival of a nerve impulse, itself the consequence of a rapid change in the
surface properties of the nerve such that sodium ions leave and potassium
ions enter. At the muscle-nerve junction a similar wave of excitation
commences and rapidly sweeps over the muscle surface. This wave is essen-
tially of similar character- a change in the distribution of sodium and
potassium ions near the muscle cell surface. A few milliseconds later the
entire cell begins to contract.
In a brilliant series of experiments, microelectrodes with tips less than
a micron in diameter were touched to the muscle surface, applying shocks
too small to cause a general excitation. Local contraction responses were
obtained, but only at particular spots on the cell surface. Electron micros-
copy revealed these activating spots to be narrow indentations of the
surface membrane, which penetrate deep into the cell. These structures,
"transverse tubules," carry the change in surface charge into the cell in
proximity with the contractile elements- the actin and myosin filaments.
Contraction itself therefore occurs in consequence of a change in the local
ionic environment of these proteins. To some degree, it is the change in
sodium and potassium concentration that is meaningful, but more im-
portantly, these changes act to release calcium ions from some bound form,
and it is the increase in calcium ions, specifically, that stimulates the ATP-
hydrolyzing activity of the myosin and makes contraction possible. Unless
the ionic changes were reversed, the cell would continue to remain con-
tracted until all available ATP had been utilized. However, in close rela-
tion to the transverse tubules is a network of extremely tiny tubes, the
"sarcoplasmic reticulum," a system that, utilizing the energy of ATP,
sequesters the calcium inside the tubules, thereby bringing contraction to a
halt and permitting the muscle to relax until the next wave of excitation
arrives. Numerous details of this fundamental life process remain to be
unraveled. But, in the main, the totality is a satisfying concept, consistent
with all known evidence, and represents the ultimate convergence of
physiological, biochemical, and anatomical studies.
83
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84
THE LIFE SCIENCES
THE CONSTANCY OF THE Milieu Interieur
The free and independent life of vertebrate animals became possible when
their ancestral forms first developed closed circulations, which assured
that all cells of the body, no matter how remote from the external environ-
ment, had a nutrient supply, removal of waste products, and an environ-
mental composition compatible with life. In turn, such an arrangement
renders imperative some device for assuring the constancy of that internal
environment, despite the vicissitudes of life. On some days, one may drink
little or nothing; on others, rather prodigious quantities. Salt intake may
vary equally widely. Some diets are effectively alkaline; some are acid.
Changes in the rate of respiration may affect not only the oxygen supply
but also the rate of removal of carbon dioxide and hence the acidity of the
blood. That we survive and scarcely notice such variation is a tribute to a
remarkable organ, the kidney.
Until relatively recently, thoughts concerning renal function rested on
speculations based largely on the appearance of the anatomical structure
of the kidney. More than a century ago it was recognized that the funda-
mental operating unit of the kidney is the "nephron," of which millions are
arrayed, in parallel, in the kidney cortex (Figure 23~. Each commences
with a small arteriole that is branched rapidly from the main renal artery
and becomes a tuft of capillaries (the glomerulus) that coalesce in a venule.
Surrounding the tuft of capillaries is a structure made of connective tissue
that leads into a miniature tubule. The latter goes straight down toward
the renal medulla, makes a hairpin turn, returns toward the outer surface,
and then descends again into a thicker channel, the collecting duct, which
drains into the hilum of the kidney. Particularly noteworthy is the fact that
the blood in the venule formed by coalescence of the glomerular capillaries
also surrounds the ascending tubule and the collecting duct before entering
into the larger veins for exit from the kidney. From the appearance of this
structure it was deduced that the glomerulus must be a filter through which
passes an "ultrafiltrate" containing all the plasma constituents except the
relatively large plasma proteins. It was further assumed that, as the glomer-
ular filtrate traverses the tubules, materials are removed from it, ultimately
leaving the presumptive urine.
Slowly, over the first two thirds of this century, evidence accumulated
suggesting the essential validity of this concept. Indirect techniques that
permitted measurement of the magnitude of these operations were devised.
In a 160-lb man, the overall rate of glomerular filtration is about 125
milliliters per minute, or about 180 liters per day, a volume 65 times that
of the entire volume of plasma. Almost all (99.5 percent) the water and
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FRONTIERS OF BIOLOGY 85
Art .
it. -
Glomerulus
Proximal
~_ Proximal
Distal
Thin Segment ~
Collecting
Duct
FIGURE 23 The nephron fundamental unit of the kidney. (Adapted from H. W.
Smith, The Kidney, Oxford University Press, New York, 1935.)
its solutes are reabsorbed as this filtrate passes along the tubules, for urine
output is only about one liter per day.
The experimental challenge has been to ascertain the mechanisms by
which this versatile organ so alters its behavior as to assure excretion of
very dilute urine when water intake has been copious or extremely con-
centrated urine when water intake has been meager or salt intake excessive,
to excrete alkaline or acid urine as may be appropriate to physiological
circumstance, and to assure that none of the material in the glomerular
filtrate that is valuable to the body, e.g., glucose, is lost. Although indirect
evidence in these regards was accumulated over a long period, the detailed
picture now available has been the consequence of recent development of
techniques for micropuncture, originally used in frogs and mud puppies
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86
THE LIFE SCIENCES
but since extended to mammals, permitting direct sampling from precise
locales within the minute renal tubules under a variety of conditions. Ten
years were then expended in perfecting adequate microanalytical techniques
for the examination of these tiny specimens (0.01-0.1 r11. Once the tech-
niques were developed, thousands of such determinations were undertaken,
and from them has emerged a detailed blueprint of the modus operandi
of this organ. A few aspects of this operation warrant summary.
First it was established that the pressure in the glomerular capillaries
is unusually high (about 60 mm Hg) and thus sufficient to ensure filtration
through the capillaries. As the fluid passes through the descending proximal
tubule, a large fraction of the total is removed; with it most of the desirable
organic compounds, e.g., glucose, are removed by processes of active trans-
port similar to those operating in most living cells. Only about 10 percent
of fluid remains at the level of the hairpin turn. The fluid in this region is
decidedly more concentrated than earlier in the proximal tubule, largely
due to removal of water by simple osmotic forces because of the high
concentration of salt in the surrounding region. As the fluid rises in the
ascending limb, specific facultative adjustments are made in the sodium,
potassium, and hydrogen content. In large measure, sodium ions removed
in this region are exchanged either for hydrogen or potassium ions. It is
in this region also that the tubular cells manufacture ammonia (NH3),
which is secreted into the duct fluid, to combine with hydrogen ions that
the same cells have secreted into that fluid. By this process a considerable
amount of acid can be secreted without unduly acidifying the presumptive
urine. Final adjustments are made in the early portion of the collecting
duct, where the final salt concentration is achieved.
A series of controls assures that the composition of the final urine is
commensurate with physiological requirements of the moment. Foremost
among these is the ingenious mechanism that makes salt concentration pos-
sible. It was long known that man can excrete urine about four times as
concentrated in salt as his own blood plasma. Other animals, particularly
desert-dwellers, are considerably more adept at this task than are we; for
example, the kangaroo rat need never drink water and survives by excreting
urine 14 times as concentrated as his own plasma! The principal feature
that distinguishes the kidney of the kangaroo rat from that of man is that
in the kangaroo rat the descending tubule dips much farther down into the
cortical and medullary tissue of the kidney; i.e., the tubule is decidedly
longer relative to kidney size than is that of man. Inspection of the kidneys
of a variety of species indicated that, in general, concentrating ability is a
function of tubular length. It was this observation that suggested that the
entire apparatus is patterned after the principle used by engineers in the
design of heat-exchanging apparatus i.e., as a countercurrent multiplier.
