Every year in Lindau, Germany, winners of Nobel Prizes join young researchers for panel discussions, presentations and informal conversation. This year, from June 26 to July 1, about 20 Nobel laureates in physiology or medicine and 550 rising science stars chosen from more than 60 countries are participating. To commemorate the event, Scientific American has selected excerpts from some of its most memorable articles authored by laureates in the biological sciences. The passages trace overlapping arcs of scientific discovery and progress from the 1950s onward in cell biology, medicine, animal behavior and neuroscience. For ease of reading, we have not indicated deletions within the excerpts, many of which have been condensed significantly.
The Living Cell
The evolution and machinations of cells are endlessly fascinating—as is demonstrated in excerpts addressing how the molecules of life first formed, how DNA structure affects function and how complex cells came into being.
The Origin of Life
by George Wald
Published in August 1954
Organic molecules form a large and formidable array, endless in variety and of the most bewildering complexity. To understand how organisms originated we must first of all explain how such complicated molecules could come into being. To make an organism requires not only a tremendous variety of these substances, in adequate amounts and proper proportions, but also just the right arrangement of them. Structure here is as important as composition—and what a complication of structure! The most complex machine man has devised—say, an electronic brain—is child’s play compared with the simplest of living organisms.
Recently Harold Urey, Nobel laureate in chemistry, has become interested in the degree to which electrical discharges in the upper atmosphere may promote the formation of organic compounds. One of his students, S. L. Miller, performed the simple experiment of circulating a mixture of water vapor, methane (CH4), ammonia (NH3) and hydrogen—all gases believed to have been present in the early atmosphere of the earth—continuously for a week over an electric spark. The circulation was maintained by boiling the water in one limb of the apparatus and condensing it in the other. At the end of the week the water was analyzed by the delicate method of paper chromatography. It was found to have acquired a mixture of amino acids! Glycine and alanine, the simplest amino acids and the most prevalent in proteins, were definitely identified in the solution, and there were indications it contained aspartic acid and two others. The yield was surprisingly high. The amazing result changes at a stroke our ideas of the probability of spontaneous formation of amino acids.
Recently several particularly striking examples have been reported of the spontaneous production of familiar types of biological structure by protein molecules. Cartilage and muscle offer some of the most intricate and regular patterns of structure to be found in organisms. A fiber from either tissue presents under the electron microscope a beautiful pattern of cross striations of various widths and densities, very regularly spaced. The proteins that form these structures can be coaxed into free solutions and stirred into a completely random orientation. Yet on precipitating, under proper conditions, the molecules realign with regard to one another to regenerate with extraordinary fidelity the original patterns of the tissues.
We have therefore a genuine basis for the view that the molecules of our oceanic broth will not only come together spontaneously to form aggregates but in doing so will spontaneously achieve various types and degrees of order.
The Structure of the Hereditary Material
By F.H.C. Crick
Published in October 1954
It is now known that DNA consists of a very long chain made up of alternate sugar and phosphate groups. The sugar is always desoxyribose. While the phosphate-sugar chain is perfectly regular, the molecule as a whole is not, because each sugar has a “base” attached to it. Four different types of base are commonly found: two of them are purines, called adenine and guanine, and two are pyrimidines, known as thymine and cytosine. So far as is known the order in which they follow one another along the chain is irregular, and probably varies from one piece of DNA to another. Although we know from the chemical formula of DNA that it is a chain, this does not in itself tell us the shape of the molecule, for the chain, having many single bonds around which it may rotate, might coil up in all sorts of shapes.
J. D. Watson and I, working in the Medical Research Council Unity in the Cavendish Laboratory at Cambridge, were convinced that we could get somewhere near the DNA structure by building scale models based on the x-ray patterns obtained by M.H.F Wilkins, Rosalind Franklin and their co-workers at King’s College London. To get anywhere at all we had to make some assumptions. The most important one had to do with the fact that the crystallographic repeat did not coincide with the repetition of chemical units in the chain but came at much longer intervals. A possible explanation was that all the links in the chain were the same but the x-rays were seeing every tenth link, say, from the same angle and the others from different angles. What sort of chain might produce this pattern? The answer was easy: the chain might be coiled in a helix. The distance between crystallographic repeats would then correspond to the distance in the chain between one turn of the helix and the next.
This particular model contains a pair of DNA chains wound around a common axis. The two chains are linked together by their bases. A base on one chain is joined by very weak bonds to a base at the same level on the other chain, and all the bases are paired off in this way right along the structure. Paradoxically to make the structure as symmetrical as possible we had to have the two chains run in opposite directions; that is, the sequence of the atoms goes one way in one chain and the opposite way in the other.
Now we found that we could not arrange the bases any way we pleased; the four bases would fit into the structure only in certain pairs. In any pair there must always be one big one (purine) and one little one (pyrimidine). A pair of pyrimidines is too short to bridge the gap between the two chains, and a pair of purines is too big to fit into the space.
Adenine must always be pared with thymine and guanine with cytosine; it is impossible to fit the bases together in any other combination in our model. (This pairing is likely to be so fundamental for biology that I cannot help wondering whether some day an enthusiastic scientist will christen his newborn twins Adenine and Thymine!)
Now the exciting thing about a model of this type is that it immediately suggests how the DNA might produce an exact copy of itself. The model consists of two parts, each of which is the complement of the other. Thus, either chain may act as a sort of mold on which a complementary chain can be synthesized. The two chains of a DNA, let us say, unwind and separate. Each begins to build a new complement onto itself. When the process is completed, there are two pairs of chains where we had only one. Moreover, because of the specific pairing of the bases the sequence of the pairs of bases will have been duplicated exactly; in other words, the mold has not only assembled the building blocks but has put them together in just the right order.
The Birth of Complex Cells
By Christian de Duve
Published in April 1996
About 3.7 billion years ago the first living organisms appeared on the earth. They were small, single-celled microbes not very different from some present-day bacteria. Prokaryotes turned out to be enormously successful. Thanks to their remarkable ability to evolve and adapt, they spawned a wide variety of species and invaded every habitat the world had to offer. The living mantle of our planet would still be made exclusively of prokaryotes but for an extraordinary development that gave rise to a very different kind of cell, called a eukaryote because it possesses a true nucleus. Today all multicellular organisms consist of eukaryotic cells. Eukaryotic cells most likely evolved from prokaryotic ancestors. But how?
Appreciation of this astonishing evolutionary journey requires a basic understanding of how the two fundamental cell types differ. Eukaryotic cells are much larger than prokaryotes (typically some 10,000 times in volume). In prokaryotes the entire genetic archive consists of a single chromosome made of a circular string of DNA that is in direct contact with the rest of the cell. In eukaryotes most DNA is contained in more highly structured chromosomes that are grouped within a well-defined central enclosure, the nucleus. Most eukaryotic cells further distinguish themselves from prokaryotes by having in their cytoplasm up to several thousand specialized structures, or organelles, about the size of a prokaryotic cell. The most important of such organelles are peroxisomes (which serve assorted metabolic functions), mitochondria (the power factories of cells) and, in algae and plant cells, plastids (the sites of photosynthesis).
Biologists have long suspected that mitochondria and plastids descend from bacteria that were adopted by some ancestral host cell as endosymbionts (a word derived from Greek roots that means “living together inside”). The most convincing evidence is the presence within these organelles of a vestigial—but still functional—genetic system. That system includes DNA-based genes, the means to replicate this DNA, and all the molecular tools needed to construct protein molecules from their DNA-encoded blueprints. Endosymbiont adoption is often presented as resulting from some kind of encounter—aggressive predation, peaceful invasion, mutually beneficial association or merger—between two typical prokaryotes. There is a more straightforward explanation—namely, that endosymbionts were originally taken up in the course of feeding by an unusually large host cell that had already acquired many properties now associated with eukaryotic cells. Many modern eukaryotic cells—white blood cells, for example—entrap prokaryotes. On a rare occasion, both captor and victim survive in a state of mutual tolerance that can turn into mutual assistance and, eventually, dependency. Mitochondria and plastids thus may have been a host cell’s permanent guests.
Roots of Disease
Some Nobelists who have written for Scientific American have enlightened us about the microorganisms and molecules responsible for terrible illnesses.
By F. M. Burnet
Published in May 1951
A virus can be defined as a microorganism, considerably smaller than most bacteria, which is capable of multiplication only within the living cells of a susceptible host. The practical control of a virus disease nearly always depends essentially on obtaining an understanding of the means by which the balance between the virus and the host is maintained in nature and how it can be modified in either direction by biological accident or by human design. In the approach to such an understanding two important related concepts have emerged—“subclinical infection” and “immunization.”
A subclinical infection is one in which the infected person gives no sign of any ill effect. In a population attacked by an infectious disease, subclinical infections often greatly outnumber those severe enough to produce unmistakable symptoms of the disease. For example, when a child comes down with a paralyzing attack of poliomyelitis, a careful examination of the rest of the family will commonly reveal that all the other children have the virus in their intestines over a period of a week or two, but they either show no symptoms at all or have only a mild, nondescript illness. Fortunately even a subclinical infection produces heightened resistance or immunity to the virus for a period after the attack. This capacity of mild or subclinical infection to confer immunity is probably the greatest factor in maintaining a tolerable equilibrium between man and the common virus diseases. The trouble is that viruses are labile beings, liable to undergo mutation in various directions, and a virus that causes only mild infection may evolve into one far more deadly.
One cannot claim that there is full agreement about the nature of immunity to viruses, but it is possible to offer a simplified account which most virologists would accept. This interpretation is that all immunity to viruses is mediated through antibody. Antibodies can be described as modified blood-protein molecules capable of attaching themselves firmly to the specific virus or other invading organism that provoked their production by the body. If a sufficient number of antibody molecules can attach themselves to a virus particle, they have a blanketing effect which prevents the virus’ attachment to the host cell and its multiplication within the cell. Antibody appears in the blood a few days after infection and reaches a peak in two to three weeks. The body continues to produce antibody at a slowly diminishing level long after recovery—in some diseases, such as measles and yellow fever, for the whole of life.
The Prion Diseases
By Stanley B. Prusiner
Published in January 1995
Fifteen years ago I evoked a good deal of skepticism when I proposed that the infectious agents causing certain degenerative disorders of the central nervous system in animals and, more rarely, in humans might consist of protein and nothing else. At the time, the notion was heretical. Dogma held that the conveyers of transmissible diseases required genetic material, composed of nucleic acid (DNA or RNA), to establish an infection in a host. Even viruses, among the simplest microbes, rely on such material to direct synthesis of the proteins needed for survival and replication. Later, many scientists were similarly dubious when my colleagues and I suggested that these “proteinaceous infectious particles”—or “prions,” as I called
the disease-causing agents—could underlie inherited, as well as communicable, diseases. Such dual behavior was then unknown to medical science. And we met resistance again when we concluded that prions (pronounced “PREE-eons”) multiply in an incredible way; they convert normal protein molecules into dangerous ones simply by inducing the benign molecules to change their shape. Today, however, a wealth of experimental and clinical data has made a convincing case
that we are correct on all three counts.
The known prion diseases, all fatal, are sometimes referred to as spongiform encephalopathies. They are so named because they frequently cause the brain to become riddled with holes. These ills, which can brew for years (or even for decades in humans), are widespread in animals. The most common form is scrapie, found in sheep and goats. Mad cow disease is the most worrisome. [The human prion diseases include among them Creutzfeldt-Jakob disease, a cause of dementia.]
In addition to showing that a protein can multiply and cause disease without help from nucleic acids, we have gained insight into how scrapie PrP [“prion protein”] propagates in cells. Many details remain to be worked out, but one aspect appears quite clear: the main difference between normal PrP and scrapie PrP is conformational. Evidently, the scrapie protein propagates itself by contacting normal PrP molecules and somehow causing them to unfold and flip from their usual conformation to the scrapie shape. This change initiates a cascade in which newly converted molecules change the shape of other normal PrP molecules, and so on.
The collected studies argue persuasively that the prion is an entirely new class of infectious pathogen and that prion diseases result from aberrations of protein conformation. Whether changes in protein shape are responsible for common neurodegenerative diseases, such as Alzheimer’s, remains unknown, but it is a possibility that should not be ignored.
Telomeres, Telomerase and Cancer
By Carol W. Greider and Elizabeth H. Blackburn
Published in February 1996
During the past 15 years, investigations have led to identification of an extraordinary enzyme named telomerase that acts on telomeres [the tips of chromosomes] and is thought to be required for the maintenance of many human cancers. Cancers arise when a cell acquires multiple genetic mutations that together cause the cell to escape from normal controls on replication and migration. As the cell and its offspring multiply uncontrollably, they can invade and damage nearby tissue. Some parts may break away and travel to parts of the body where they do not belong, establishing new malignancies at distant sites.
The notion that telomerase might be important to the maintenance of human cancers was discussed as early as 1990. But the evidence did not become compelling until recently. Findings have led to an attractive but still hypothetical model for the normal and malignant activation of telomerase by the human body. According to this model, telomerase is made routinely by cells of the germ line in the developing embryo. Once the body is fully formed, however, telomerase is repressed in many somatic [nongerm] cells, and telomeres shorten as cells reproduce. When telomeres decline to a threshold level, a signal is emitted that prevents the cells from dividing further.
If, however, cancer-promoting genetic mutations block issuance of such safety signals or allow cells to ignore them, cells will continue to divide. They will also presumably continue to lose telomeric sequences and undergo chromosomal alterations that allow further, possibly carcinogenic mutations to arise. When telomeres are completely or almost completely lost, cells may reach a point at which they crash and die. But if the genetic derangements of the pre-crisis period lead to the manufacture of telomerase, cells will not fully lose their telomeres. The shortened telomeres will be rescued and maintained. In this way, the genetically disturbed cells will gain the immortality characteristic of cancer.
This scenario has generally been borne out by the evidence, although some advanced tumors lack telomerase, and some somatic cells—notably the white blood cells known as macrophages and lymphocytes—have recently been found to make the enzyme. Nevertheless, on balance, the collected evidence suggests that many tumor cells require telomerase in order to divide indefinitely.
The presence of telomerase in various human cancers and its absence in many normal cells mean the enzyme might serve as a good target for anticancer drugs. Agents able to hobble telomerase might kill tumor cells (by allowing telomeres to shrink and disappear) without disrupting the functioning of many normal cells. In contrast, most existing anticancer therapies disturb normal cells as well as malignant ones, and so are often quite toxic. Further, because telomerase occurs in numerous cancers, such agents might work against a broad array of tumors.
The Animal’s World
As some biologists developed the tools required to understand cellular behavior, others observed whole animals closely, making sense of their curious activities, including their mating rituals.
The Courtship of Animals
By N. Tinbergen
Published in November 1954
In contrast to such clearly motivated behavior as feeding or flight from predators, the courtship postures of animals are altogether puzzling, because it is difficult to see at first glance not only what circumstances cause them to occur but even what functions they serve. We may suppose that the male’s display and activities stimulate the female to sexual cooperation, but even this elementary assumption has to be proved. And then we have to ask: Why does the female have to be stimulated in so elaborate a fashion, and what factors enter into the male’s performance? Our work suggests that courtship serves not only to release sexual behavior in the partner but also to suppress contrary tendencies, that is, the tendencies to aggression or escape.
Let me give a brief sketch of what happens when gulls of the black-headed species form pairs at the beginning of the breeding season. An unmated male settles on a mating territory. He reacts to any other gull that happens to come near by uttering a “long call” and adopting an oblique posture. This will scare away a male, but it attracts females, and sooner or later one alights near him. Once she has alighted, both he and she suddenly adopt the “forward posture.” Sometimes they may perform a movement known as “choking.” Finally, after one or a few seconds, the birds almost simultaneously adopt the “upright posture” and jerk their heads away from each other. Now most of these movements also take place in purely hostile clashes between neighboring males. They may utter the long call, adopt the forward posture and go through the choking and the upright posture.
The final gestures in the courtship sequence—the partners’ turning of their heads away from each other, or “head-flagging”—is different from the others: it is not a threat posture. Sometimes during a fight between two birds we see the same head-flagging by a bird which is obviously losing the battle but for some reason cannot get away, either because it is cornered or because some other tendency makes it want to stay. This head-flagging has a peculiar effect on the attacker: as soon as the attacked bird turns its head away the attacker stops its assault or at least tones it down considerably. Head-flagging stops the attack because it is an “appeasement movement”—as if the victim were “turning the other cheek.” We are therefore led to conclude that in their courtship these gulls begin by threatening each other and end by appeasing each other with a soothing gesture.
The black-headed gull is not an isolated case. We have learned that our courtship theory applies to many other birds (including various finches, tits, cormorants, gannets, ducks) and to animals of quite different groups, such as fish.
It is still an open question whether this gradual change in the motivational situation is mediated by endocrine changes, such as the growth of gonads. Future research will have to settle this. Our theory, as very briefly outlined here, is but a first step in the unraveling of the complicated causal relationships underlying the puzzling but fascinating phenomena of courtship.
The Evolution of Behavior
By Konrad Z. Lorenz
Published in December 1958
Following the example of zoologists, who have long exploited the comparative method, students of animal behavior have now begun to ask a penetrating question. We all know how greatly the behavior of animals can vary, especially under the influence of the learning process. But is it not possible that beneath all the variations of individual behavior there lies an inner structure of inherited behavior which characterizes all the members of a given species, genus or larger taxonomic group—just as the skeleton of a primordial ancestor characterizes the form and structure of all mammals today?
Yes, it is possible! Let me give an example which, while seemingly trivial, has a bearing on this question. Anyone who has watched a dog scratch its jaw or a bird preen its head feathers can attest to the fact that they do so in the same way. The dog props itself on the tripod formed by its haunches and two forelegs and reaches a hindleg forward in front of its shoulder. Now the odd fact is that most birds (as well as virtually all mammals and reptiles) scratch with precisely the same motion! A bird also scratches with a hindlimb (that is, its claw), and in doing so it lowers its wing and reaches its claw forward in front of its shoulder.
One might think that it would be simpler for the bird to move its claw directly to its head without moving its wing, which lies folded out of the way on its back. I do not see how to explain this clumsy action unless we admit that it is inborn. Before the bird can scratch, it must reconstruct the old spatial relationship of the limbs of the four-legged common ancestor which it shares with mammals.
Comparative study of innate motor patterns represents an important part of the research program at the Max Planck Institute for Comparative Ethology. Our subjects are the various species of dabbling, or surface-feeding, ducks. By observing minute variations of behavior traits between species on the one hand and their hybrids on the other, we hope to arrive at a phylogenetics of behavior.
The first thing we wanted to know was how the courtship patterns of ducks become fixed. What happens when these ducks are crossbred? By deliberate breeding we have produced new combinations of motor patterns, often combining traits of both parents, sometimes suppressing the traits of one or the other parent and sometimes exhibiting traits not apparent in either. We have even reproduced some of the behavior-pattern combinations which occur in natural species other than the parents of the hybrid.
Thus, we have shown that the differences in innate motor patterns which distinguish species from one another can be duplicated by hybridization. This suggests that motor patterns are dependent on comparatively simple constellations of genetic factors.
Inside Mind and Brain
The nervous system is dauntingly complex, but scientists over the years have hit on clever ways to figure out how it operates and how our wiring yields the mind.
The Nerve Impulse
By Bernhard Katz
Published in November 1952
Some of the foremost nerve physiologists have considered it worthwhile to study and analyze the properties of nerve fibers from the point of view of the cable engineer. The nerve fiber is in effect a chain of relay stations—a device with which the communications engineer is thoroughly familiar. Each point along the fiber receives an electric signal from the preceding point, boosts it to full strength and so enables it to travel a little farther. It is a peculiar combination of a cable (of very defective properties) with an automatic relay mechanism distributed all along the transmission line. Before the electric signal has had a chance to lose its strength, it stimulates the fiber, releases local energy resources and is renewed. The electric potential difference across one point of the fiber membrane serves to excite the region ahead, with the result that this region now contributes, at its own expense, a greatly amplified electric signal, capable of spreading to and exciting the next region. Experiments have fully confirmed this concept of how a nerve fiber transmits a signal.
When a current passes through the membrane, partially discharging the membrane surface and thus reducing the electric field, this makes the membrane more permeable to sodium. Positive sodium ions begin to flow inward and further reduce the negative charge on the inside. Thus, the electric field across the membrane is further reduced, the sodium permeability continues to rise, more sodium enters, and we have the elements of a self-reinforcing chain reaction. The flow of sodium into the fiber continues until the fiber interior has been charged up to such a high positive level that sodium ions are electrostatically repelled. This new equilibrium is precisely the reverse of the resting potassium potential. Now we can understand the basis of the all-or-none reaction of nerve cells: they generate no current until the “ignition point” is approached. Once this point is passed, the production of “sodium current” proceeds toward saturation and runs through a cycle of its own, no longer under the control of the original stimulus.
Nerve Cells and Behavior
By Eric R. Kandel
Published in July 1970
Advances in the concepts and techniques for studying individual nerve cells and interconnected groups of cells have encouraged neural scientists to apply these methods to studying complete behavioral acts and modifications of behaviors produced by learning. This led to an interest in certain invertebrates, such as crayfish, leeches, various insects and snails, that have the great advantage that their nervous system is made up of relatively few nerve cells (perhaps 10,000 or 100,000 compared with the trillion or so in higher animals). In these animals one can begin to trace, at the level of individual cells, not only the sensory information coming into the nervous system and the motor actions coming out of it but also the total sequence of events that underlies a behavioral response.
The most consistent progress has come from studies of habituation and dishabituation in the spinal cord of the cat and the abdominal ganglion of Aplysia [a giant marine snail that grows to about a foot in size].
Habituation is a decrease in a behavioral response that occurs when an initially novel stimulus is presented repeatedly. Once a response is habituated, two processes can lead to its restoration. One is spontaneous recovery, which occurs as a result of withholding the stimulus to which the animal has habituated. The other is dishabituation, which occurs as a result of changing the stimulus pattern, for example, by presenting a stronger stimulus to another pathway.
An Aplysia shows a defensive withdrawal response [to gentle stimulation]. The snail’s gill, an external respiratory organ, is partially covered by the mantle shelf, which contains the thin residual shell. When either the mantle shelf or anal siphon, a fleshy continuation of the mantle shelf, is gently touched, the siphon contracts and the gill withdraws into the cavity under the mantle shelf.
We can now propose a simplified circuit diagram to illustrate the locus and mechanism of the various plastic changes that accompany habituation and dishabituation of the gill-withdrawal reflex. Repetitive stimulation of sensory receptors leads to habituation by producing a plastic change at the synapse between the sensory neuron and the motor neuron. Stimulation of the head leads to dishabituation by producing heterosynaptic facilitation at the same synapse.
It would seem that cellular approaches directed toward working out the wiring diagram of behavioral responses can now be applied to more complex learning processes.
The Problem of Consciousness
By Francis Crick
(1962 Nobelist) and Christof Koch
Published in September 1992
Some psychologists feel that any satisfactory theory [of consciousness] should try to explain as many aspects as possible. We thought it wiser to begin with the particular aspect of consciousness that is likely to yield most easily. We selected the mammalian visual system. We have postulated that when we clearly see something, there must be neurons actively firing that stand for what we see.
How can we discover the neurons whose firing symbolizes a particular percept? William T. Newsome and his colleagues at Stanford University have done a series of brilliant experiments on neurons in cortical area MT of the macaque’s brain. By studying a neuron in area MT, we may discover that it responds best to very specific visual features having to do with motion. A neuron, for instance, might fire strongly in response to the movement of a bar in a particular place in the visual field, but only when the bar is oriented at a certain angle, moving in one of the two directions perpendicular to its length within a certain range of speed. Such experiments do not, however, show decisively that the firing of such neurons is the exact neural correlate of the percept. The correlate could be only a subset of the neurons being activated or the firing of neurons in another part of the visual hierarchy that are strongly influenced by the neurons activated in area MT.
The key issue is how the brain forms its global representations from visual signals. If attention is crucial for visual awareness, the brain could form representations by attending to just one object at a time, rapidly moving from one to the next. For example, neurons representing all the different aspects of the attended object could all fire together very rapidly for a short period, possibly in rapid bursts. This fast, simultaneous firing might not only excite neurons that symbolized the implications of that object but also temporarily strengthen the relevant synapses so that this particular [firing pattern] could be quickly recalled—a form of short-term memory.