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.