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Nobel Laureates Speak in Scientific American




Illustrations by Montse Bernal

The 61st Nobel Laureate Meeting in Lindau, Germany, is taking place from June 26 to July 1. At the event, about 20 past laureates in physiology or medicine will mingle with more than 550 young scientists. In honor of the meeting Scientific American has collected articles that Nobel Prize winners have published in the magazine recently as well as more than 60 years ago. You can find a number of excerpts from those articles in the June issue and enjoy others here. For ease of reading, we have not indicated deletions within these excerpts, some of which have been condensed considerably.

Compiled by Ferris Jabr

The Language of Bees, by August Krogh (1920 Nobelist)
Published August 1948

I propose in this article to describe the amazing experiments of Karl von Frisch on the ways in which bees convey information to their fellows.

His early experiments showed that bees must possess some means of communication, because when a rich source of food (he used concentrated sugar solution) is found by one bee, the food is soon visited by numerous other bees from the same hive. To find out how they communicated with one another, von Frisch constructed special hives containing only one honeycomb, which could be exposed to view through a glass plate. Watching through the glass, he discovered that bees returning from a rich source of food perform special movements, which he called dancing, on the vertical surface of the honeycomb. Von Frisch early distinguished between two types of dance: the circling dance (Rundtanz) and the wagging dance (Schwanzeltanz). In the latter a bee runs a certain distance in a straight line, wagging its abdomen very swiftly from side to side, and then makes a turn.

Von Frisch eventually conceived the idea that the type of dance did not signify the kind of food, as he had first thought, but had something to do with the distance of the feeding place. This hypothesis led to the following crucial experiment. He trained two groups of bees from the same hive to feed at separate places. One group, marked with a blue stain, was taught to visit a feeding place only a few meters from the hive; the other, marked red, was fed at a distance of 300 meters. To the experimenter's delight, it developed that all the blue bees made circling dances; the red, wagging dances. Then, in a series of steps, von Frisch moved the nearer feeding place farther and farther from the hive. At a distance between 50 and 100 meters away, the blue bees switched from a circling dance to wagging. Conversely, the red bees, when brought gradually closer to the hive, changed from wagging to circling in the 50- to 100-meter interval.

Thus, it was clear that the dance at least told the bees whether the distance exceeded a certain value. It was found, however, that the frequency of turns would give a fairly good indication of the distance. When the feeding place was 100 meters away, the bee made about 10 short turns in 15 seconds. To indicate a distance of 3,000 meters, it made only three long ones in the same time.

For my part I find it difficult to assume that such perfection and flexibility in behavior can be reached without some kind of mental processes going on in the small heads of the bees. Such processes may be, and probably are, very different from those taking place in the human brain. I would not venture to proclaim them as "thoughts" in the sense in which we use the word, but I do think that something is going on in the brain of the bee as well as in my own which cannot be reduced to the terms of matter and movement.

 

Life on Earth, by Alonso Ricardo and Jack W. Szostak (2009 Nobelist)
Published September 2009

Recent experiments suggest it would have been possible for genetic molecules similar to DNA or to its close relative RNA to form spontaneously. And because these molecules can curl up in different shapes and act as rudimentary catalysts, they may have become able to copy themselves—to reproduce—without the need for proteins.

This notion has inspired several experiments, both at our lab and at David Bartel's lab at the Massachusetts Institute of Technology, in which we "evolved" new ribozymes (an RNA molecule that can act as an enzyme). We started with trillions of random RNA sequences. Then we selected the ones that had catalytic properties, and we made copies of those. At each round of copying some of the new RNA strands underwent mutations that turned them into more efficient catalysts, and once again we singled those out for the next round of copying. By this directed evolution we were able to produce ribozymes that can catalyze the copying of relatively short strands of other RNAs, although they fall far short of being able to copy polymers with their own sequences into progeny RNAs.

Given the right building blocks, then, the formation of protocells does not seem that difficult: membranes self-assemble, genetic polymers self-assemble, and the two components can be brought together in a variety of ways, for example, if the membranes form around preexisting polymers. These sacs of water and RNA will also grow, absorb new molecules, compete for nutrients, and divide. But to become alive, they would also need to reproduce and evolve.

This process would not have started on its own, but it could have with a little help. Imagine, for example, a volcanic region on the otherwise cold surface of the early Earth. (At the time, the sun shone at only 70 percent of its current power.) There could be pools of cold water, perhaps partly covered by ice but kept liquid by hot rocks. The temperature differences would cause convection currents, so that every now and then protocells in the water would be exposed to a burst of heat as they passed near the hot rocks, but they would almost instantly cool down again as the heated water mixed with the bulk of the cold water. The sudden heating would cause a double helix to separate into single strands. Once back in the cool region, new double strands—copies of the original one—could form as the single strands acted as templates. As soon as the environment nudged protocells to start reproducing, evolution kicked in. In particular, at some point some of the RNA sequences mutated, becoming ribozymes that sped up the copying of RNA—thus adding a competitive advantage. Eventually ribozymes began to copy RNA without external help. With their astonishing versatility, proteins would have then taken over RNA's role in assisting genetic copying and metabolism. Later, the organisms would have "learned" to make DNA, gaining the advantage of possessing a more robust carrier of genetic information. At that point, the RNA world became the DNA world, and life as we know it began.

 

The Synthesis of DNA, by Arthur Kornberg (1959 Nobelist)
Published October 1968

My colleagues and I first undertook to synthesize nucleic acids outside the living cell, with the help of cellular enzymes, in 1954. A year earlier James Watson and Francis Crick had proposed their double-helix model of DNA, the nucleic acid that conveys genetic information from generation to generation in all organisms except certain viruses. We attained our goal within a year, but not until some months ago—14 years later—were we able to report a completely synthetic DNA, made with natural DNA as a template, that has the full biological activity of the native material.

It occurred to us in 1964 that the problem of synthesizing biologically active DNA might be solved by dealing with a simpler form of DNA that also has genetic activity. This is represented in viruses, such as ΦX174, whose DNA core is a single-strand loop. This "chromosome" not only is simpler in structure but also it is so small (about two microns in circumference) that it is fairly easy to extract without breakage.

In less than a year the test-tube synthesis of ΦX174 DNA was achieved. The steps can be summarized as follows. Template DNA was obtained from ΦX174 and labeled with tritium, the radioactive isotope of hydrogen. Tritium would thereafter provide a continuing label identifying the template. To the template were added DNA polymerase, a purified joining enzyme and a co-factor (diphosphopyridine nucleotide), together with A*, T*, G* and C* (nucleosides—containing a base (adenine, thymine, guanine or cytosine) joined to the sugar deoxyribose—linked to three phosphate groups). One of the nucleoside triphosphates was labeled with radioactive phosphorus. The radioactive phosphorus would thus provide a label for synthetic material analogous to the tritium label for the template. The interaction of the reagents then proceeded until the number of nucleotide units (consisting of a base, deoxyribose and a phosphate) polymerized was exactly equal to the number of nucleotides in the template DNA. This equality was readily determined by comparing the radioactivity from the tritium in the template with the radioactivity from the phosphorus in the nucleotides provided for synthesis.

Such comparison showed that the experiments had progressed to an extent adequate for the formation of complementary loops of synthetic DNA. Complementary loops were designated (–) to distinguish them from the template loop (+). We had to demonstrate that the synthetic (–) loops were really loops. Had the polymerase made a full turn around the template and had the two ends of the chain been united by the joining enzyme? Several physical measurements, including electron microscopy, assured us that our product was a closed loop coiled tightly around the virus-DNA template and that it was identical in size and other details with the replicative form of DNA that appears in the infected cells.

We tested our (–) loops by incubating them with E. coli cells whose walls had been removed by the action of the enzyme lysozyme. Infectivity is assayed by the ability of the virus to lyse, or dissolve, these cells when they are "plated" on a nutrient medium. Our synthetic loops showed almost exactly the same patterns of infectivity as their natural counterparts had. Their biological activity was now demonstrated.

The time is ripe for exploration of the factors that govern the initiation and rate of DNA synthesis in the intact cell and animal. Finally, there are now prospects of applying our knowledge of DNA structure and synthesis directly to human welfare. This is the realm of genetic engineering, and it is our collective responsibility to see that we exploit our great opportunities to improve the quality of human life.

Gradients That Organize Embryo Development, by Christiane Nüsslein-Volhard (1995 Nobelist)
Published August 1996

Bears mate in wintertime. The female then retires into a cave to give birth, after several months, to three or four youngsters. At the time of birth, these are shapeless balls of flesh, only the claws are developed. The mother licks them into shape.

This ancient theory, recounted by Pliny the Elder, is one of the many bizarre early attempts to explain one of life's greatest mysteries—how a nearly uniform egg cell develops into an animal with dozens of types of cells, each in its proper place.

About 100 years ago, experimental embryologists began to realize that developmental pathways need not be completely determined by the time the egg is formed. Slowly, an important idea emerged: the gradient hypothesis. The hypothesis, in essence, is that cells in a developing field respond to a special substance—a morphogen—the concentration of which gradually increases in a certain direction, forming a gradient. Different concentrations of the morphogen were postulated to cause different responses in cells.

The means of gradient formation remained elusive until recently, when researchers in several laboratories discovered gradients operating in the early embryo of the fruit fly, Drosophila. In all the pathways so far investigated, the final result is a gradient of morphogen that functions principally as a transcription factor, initiating or suppressing the transcription of one or more target genes in a concentration-dependent manner.

Some morphogenic gradients apparently yield but a single effect: If the concentration of a morphogen in a particular place is above a critical threshold, a target gene is activated; otherwise, it is not. In other cases, different concentrations of morphogen elicit different responses, and it is this type of gradient that is most important for providing an increase in the complexity of the developing organism.

Although each morphogenic gradient seems to control only a few targeted genes directly, interactions between co-factor molecules that can affect transcription can radically change responses to the gradients. These mechanisms of combinatorial regulation open the way to the formation of patterns of great complexity from an initially simple system.

Concentration dependence and combinatorial regulation together open up a versatile repertoire of pattern-forming mechanisms that can realize the designs encoded in genes.

Many more details remain to be discovered before we have a complete picture of how the Drosophila embryo develops. Yet I believe we have now uncovered some of the principal features. This accomplishment can illuminate much of zoology, because one great surprise of the past five years has been the discovery that very similar basic mechanisms, involving similar genes and transcription factors, operate in early development throughout the animal kingdom.

Basic research on good model systems has thus led to powerful insights that might one day help us understand human development. What these insights have already provided is a satisfying answer to one of the most profound questions in nature—how complexity arises from simplicity.

 

Oncogenes,by J. Michael Bishop (1989 Nobelist)
Published March 1982

In 1972 Dominique Stehelin, Harold E. Varmus and I set out to explore the "oncogene hypothesis" proposed by Robert J. Huebner and George J. Todaro of the National Cancer Institute. Seeking one mechanism to explain the induction of cancer by many different agents, Huebner and Todaro had suggested that retrovirus oncogenes are a part of the genetic baggage of all cells, perhaps acquired through viral infection early in evolution. (Retroviruses insert their genes into a host's DNA; oncogenes are genes that cause cancer when they behave abnormally.) The oncogenes would be innocuous as long as they remained quiescent. When stimulated into activity by a carcinogenic agent, however, they could convert cells to cancerous growth. We reasoned that if the hypothesis was correct, we might be able to find the src gene (the oncogene of the Rous sarcoma virus) in the DNA of normal cells.

On closer inspection, however, the gene we had discovered in vertebrates proved not to be a retrovirus gene at all. It is a cellular gene, which is now called c-src. The most compelling evidence for this conclusion came from the finding that the protein-encoding information of c-src is divided into several separate domains, called exons, by intervening regions known as introns. A split configuration of this kind is typical of animal cell genes but not of the genes of retroviruses. Apart from their introns, the versions of c-src found in fishes, birds and mammals are all closely related to the viral gene v-src and to one another. It appears the vertebrate src gene has survived long periods of evolution without major change, implying that it is important to the well-being of the species in which it persists.

Of 17 retrovirus oncogenes identified to date, 16 are known to have close relatives in the normal genomes of vertebrate species. To account for the remarkable similarity between retrovirus oncogenes and their normal cellular kin, most virologists have settled on the idea that retrovirus oncogenes are copies of cellular genes. It appears the oncogenes were added to preexistent retrovirus genomes at some time in the not too distant past.

What has been learned from oncogenes represents the first peep behind the curtain that for so long has obscured the mechanisms of cancer. In one respect the first look is unnerving, because the chemical mechanisms that seem to drive the cancer cell astray are not different in kind from mechanisms at work in the normal cell. This suggests that the design of rational therapeutic strategies may remain almost as vexing as it is today. It will be of no use to invent means for impeding the activities responsible for cancerous growth if the same activities are also required for the survival of normal cells.

However the saga of oncogenes concludes, it presents some lessons for everyone concerned with cancer research. The study of viruses far removed from human concerns has brought to light powerful tools for the study of human disease. Tumor virology has survived its failure to find abundant viral agents of human cancer. The issue now is not whether viruses cause human tumors (as perhaps they may, on occasion) but rather how much can be learned from tumor virology about the mechanisms by which human tumors arise.

 

The Brain, by David H. Hubel (1981 Nobelist)
Published September 1979

The brain is a tissue. It is a complicated, intricately woven tissue—like nothing else we know of in the universe—but it is composed of cells, as any tissue is. Their electrical and chemical signals can be detected, recorded and interpreted, and their chemicals can be identified; the connections that constitute the brain's woven feltwork can be mapped. In short, the brain can be studied, just as the kidney can.

In the past decade neuroanatomy has advanced at a higher rate, with more new and powerful techniques, than in the entire 50 years that preceded.

The latest in this series of advances is the deoxyglucose technique invented a few years ago by Louis Sokoloff of the National Institute of Mental Health. Glucose is the fuel for neurons, and the cells consume more glucose when they are active than when they are at rest. Radioactively labeled deoxyglucose is taken up by the cells as if it were glucose. For example, one can administer the chemical to a laboratory animal by vein and then stimulate the animal with a pattern of sound. Microscopic examination of the brain then reveals the various areas of the brain that are involved in hearing. Very recently a new technique called positron emission transverse tomography has been developed that makes it possible to detect from outside the skull the presence of deoxyglucose or other substances labeled with positron emission radioactive isotopes. This promising technique makes it possible to map active brain structures in a living laboratory animal or in a human being.

Applying all the available techniques, to work out in a rough and undetailed fashion the connections in a single structure, say, a part of the cerebral cortex or the cerebellum, may take one or two neuroanatomists five or 10 years. Accomplished neuroanatomists, a special breed of people, often compulsive and occasionally even semiparanoid, number only a few score in the entire world. Since the brain consists of hundreds of different structures, it is easy to see that an understanding of just the wiring of the brain is still many years away.

At the present stage, with a reasonable start in understanding the structure and working of individual cells, neurobiologists are in the position of a man who knows something about the physics of resistors, condensers and transistors, and who looks inside a television set. He cannot begin to understand how the machine works as a whole until he learns how the elements are wired together and until he has at least some idea of the purpose of the machine, of its subassemblies and of their interactions.

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