These selections are our tribute to the scientists who are convening in Germany this summer for the 64th Lindau Nobel Laureate Meeting, at which some 600 up-and-coming young researchers will exchange fi ndings and ideas with 38 prize winners in physiology or medicine.

Biochemistry

Physiology

By Edgar Douglas Adrian
Published: September 1950
Nobel: 1932

The aim of physiology is to describe the events that take place in the body and incidentally to help the doctor by doing so. But what events, and in what terms shall it describe them? About this there has been, during the past half-century, a change of view. Today it is generally agreed that although physiology is concerned with living processes, it must in the end bring its descriptions within the framework of physics and chemistry.

In the 19th century physiology could be less ambitious. There was so much to find out about the structure and large-scale activities of the various organs without attempting to measure the physical and chemical changes in them, for which there were, in any case, few methods of exact measurement available. That early phase is now over. The general organization of the body has been cleared of its more obvious problems. Physiologists have borrowed many new techniques from the exact sciences, and their interest is shifting in the direction of biophysics and biochemistry.

Muscle Research

By Albert Szent-Györgyi
Published: June 1949
Nobel: 1937

Muscle is a machine, and in any machine we must deal with two elements. One is the energy-yielding reaction, such as the expansion of steam in a steam engine, the burning of fuel in an internal combustion engine, or the flow of current in an electric motor. These elementary reactions can accomplish useful work only if they take place within a specific structure, be it a cylinder and a pistol or a coil and a rotor. So in a muscle we must also look for both the energy-yielding reaction and the meaningful structure.

The energy-yielding reaction is a chemical change which takes place among molecules, and its study belongs to the realm of biochemistry. The structure is the domain of the anatomist, working with his knife, microscope or electron microscope. Both paths of inquiry are most exciting. We can expect to find that the basic energy-yielding reaction is identical, at least in principle, in all living forms. Muscle research can thus take us to the very foundation of life. Its structure, although specialized, can likewise reveal the fundamental principles of biomolecular architecture. In this light muscle ceases to be a special problem. The study of its function merges with the study of all life, and for such study muscle is a wonderful and unique material.

Neuroscience

Brain Mechanisms of Vision

By David H. Hubel and Torsten N. Wiesel
Published: September 1979
Nobel: 1981

The cerebral cortex, a highly folded plate of neural tissue about two millimeters thick, is an outermost crust wrapped over the top of, and to some extent tuckedunder, the cerebral hemispheres. In this article we hope to sketch the present state of knowledge of one subdivision of the cortex: the primary visual cortex, the most elementary of the cortical regions concerned with vision.

We can best begin by tracing the visual path in a primate from the retina to the cortex. The output from each eye is conveyed to the brain by about a million nerve fibers bundled together in the optic nerve. These fibers are the axons of the ganglion cells of the retina. A large fraction of the optic-nerve fibers pass uninterrupted to two nests of cells deep in the brain called the lateral geniculate nuclei, where they make synapses. The lateral geniculate cells in turn send their axons directly to the primary visual cortex.

To examine the workings of this visual pathway our strategy since the late 1950s has been (in principle) simple. Beginning, say, with the fibers of the optic nerve, we record with microelectrodes from a single nerve fiber and try to find out how we can most effectively influence the firing by stimulating the retina with light. For this one can use patterns of light of every conceivable size, shape and color, bright on a dark background or the reverse, and stationary or moving. Working in this way, one finds that both a retinal ganglion cell and a geniculate cell respond best to a roughly circular spot of light of a particular size in a particular part of the visual field.

The first of the two major transformations accomplished by the visual cortex is the rearrangement of incoming information so that most of its cells respond not to spots of light but to specifically oriented line segments. There is a wide variety of cell types in the cortex, some simpler and some more complex in their response properties, and one soon gains an impression of a kind of hierarchy, with simpler cells feeding more complex ones. A typical cell responds only when light falls in a particular part of the visual world. The best response is obtained when a line that has just the right tilt is flashed in the region or, in some cells, is swept across the region. The most effective orientation varies from cell to cell and is usually defined sharply enough so that a change of 10 or 20 degrees clockwise or counterclockwise reduces the response markedly or abolishes it. (It is hard to convey the precision of this discrimination. If 10 to 20 degrees sounds like a wide range, one should remember that the angle between 12 o'clock and one o'clock is 30 degrees.)

There was a time, not so long ago, when one looked at the millions of neurons in the various layers of the cortex and wondered if anyone would ever have any idea of their function. For the visual cortex the answer seems now to be known in broad outline: Particular stimuli turn neurons on or off; groups of neurons do indeed perform particular transformations. It seems reasonable to think that if the secrets of a few regions such as this one can be unlocked, other regions will also in time give up their secrets.

The Molecular Logic of Smell

By Richard Axel
Published: October 1995
Nobel: 2004

The basic anatomy of the nose and olfactory system has been understood for some time. In mammals, for example, the initial detection of odors takes place at the posterior of the nose, in the small region known as the olfactory epithelium. A scanning electron micrograph of the area reveals two interesting types of cells. In this region, millions of neurons, the signaling cells of sensory systems, provide a direct physical connection between the external world and the brain. From one end of each neuron, hairlike sensors called cilia extend outward and are in direct contact with the air. At the other end of the cell, a fiber known as an axon runs into the brain. In addition, the olfactory epithelium contains neuronal stem cells, which generate olfactory neurons throughout the life of the organism. Unlike most neurons, which die and are never replaced, the olfactory sensory neurons are continually regenerated.

When an animal inhales odorous molecules, these structures bind to specialized proteins, known as receptor proteins, that extend from the cilia. The binding of odors to these receptors initiates an electrical signal that travels along the axons to the olfactory bulb, which is located in the front of the brain, right behind the nose itself. The olfactory bulb serves as the first relay station for processing olfactory information in the brain; the bulb connects the nose with the olfactory cortex, which then projects to higher sensory centers in the cerebral cortex, the area of the brain that controls thoughts and behaviors. Somewhere in this arrangement lies an intricate logic that the brain uses to identify the odor detected in the nose, distinguish it from others, and trigger an emotional or behavioral response.

To probe the organization of the brain, my co-workers and I began where an odor is first physically perceived—at the odor receptor proteins. Instead of examining odor receptors directly, Linda Buck, then a postdoctoral fellow in my laboratory, and I set out to find the genes encoding odor receptors. Genes provide the template for proteins, the molecules that carry out the functions of cells.

Using the technique of gene cloning, we were able to isolate the genes encoding the odor receptors. This family of receptor genes exhibited several properties that suited it to its role in odor recognition. First, the genes encoded proteins that fall squarely within a previously described group of receptors that pass through the cell membrane of the neuron seven times; these receptors activate signaling proteins known as G proteins. Early studies by Doron Lancet of the Weizmann Institute of Science and Randall R. Reed of the Johns Hopkins School of Medicine have established that odor receptors, too, use G proteins to initiate the cascade of events resulting in the transmission of an electrical impulse along the olfactory sensory axon. Second, the genes encoding the odor receptor proteins are active only in olfactory neurons. Although nearly every cell of the body carries a copy of every gene, many genes are expressed only in specialized cells.

Finally, a broad range of odor receptor genes appears to mirror the striking range of odors. By examining DNA from a variety of mammals, including humans, we determined that around 1,000 genes encode 1,000 different odor receptors. (Each type of receptor is expressed in thousands of neurons.) Given that mammalian DNA probably contains around 100,000 genes, this finding indicates that 1 percent of all our genes are devoted to the detection of odors, making this the largest gene family thus far identified in mammals. The enormous amount of genetic information devoted to smell perhaps reflects the significance of this sensory system for the survival and reproduction of most mammalian species.

The Biological Basis of Learning and Individuality

By Eric R. Kandel and Robert D. Hawkins
Published: September 1992
Nobel: 2000 (Kandel)

Elementary aspects of the neuronal mechanisms important for several different types of learning can now be studied on the cellular and even on the molecular level. Researchers agree that [some] forms of learning and memory require a conscious record. These types of learning are commonly called declarative or explicit. Those forms of learning that do not utilize conscious participation are referred to as nondeclarative or implicit.

Explicit learning is fast and may take place after only one training trial. It often involves association of simultaneous stimuli and permits storage of information about a single event that happens in a particular time and place; it therefore affords a sense of familiarity about previous events. In contrast, implicit learning is slow and accumulates through repetition over many trials. It often involves association of sequential stimuli and permits storage of information about predictive relations between events. Implicit learning is expressed primarily by improved performance on certain tasks without the subject being able to describe just what has been learned, and it involves memory systems that do not draw on the contents of the general knowledge of the individual.

The existence of two distinct forms of learning has caused the reductionists among neurobiologists to ask whether there is a representation on the cellular level for each of these two types of learning process. Canadian psychologist Donald O. Hebb boldly suggested that associative learning could be produced by a simple cellular mechanism. He proposed that associations could be formed by coincident neural activity: “When an axon of cell A ... excite[s] cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficacy, as one of the cells firing B, is increased.” According to Hebb's learning rule, coincident activity in the presynaptic and postsynaptic neurons is critical for strengthening the connection between them (a so-called pre-post associative mechanism).

Ladislav Tauc and one of us (Kandel) proposed a second associative learning rule in 1963 while working at the Institute Marey in Paris on the nervous system of the marine snail Aplysia. They found that the synaptic connection between two neurons could be strengthened without activity of the postsynaptic cell when a third neuron acts on the presynaptic neuron. The third neuron, called a modulatory neuron, enhances transmitter release from the terminals of the presynaptic neuron. They suggested that this mechanism could take on associative properties if the electrical impulses known as action potentials in the presynaptic cell were coincident with action potentials in the modulatory neuron (a pre-modulatory associative mechanism).

Subsequently, we and our colleagues found experimental confirmation. We observed the pre-modulatory associative mechanism in Aplysia, where it contributes to classical conditioning, an implicit form of learning. Then, in 1986, Holger J. A. Wigström and Bengt E. W. Gustafsson, working at the University of Göteborg, found that the pre-post associative mechanism occurs in the hippocampus, where it is utilized in types of synaptic change that are important for spatial learning, an explicit form of learning.

Immunology

The Immune System

By Niels Kaj Jerne
Published: July 1973
Nobel: 1984

The immune system is comparable in the complexity of its functions to the nervous system. Both systems are diffuse organs that are dispersed trough most of the tissues of the body. In man the immune system weighs about two pounds. It consists of about a trillion cells called lymphocytes and about 100 million trillion molecules called antibodies that are produced and secreted by the lymphocytes. The special capability of the immune system is pattern recognition, and its assignment is to patrol the body and guard its identity.

The cells and molecules of the immune system reach most tissues through the bloodstream, entering the tissues by penetrating the walls of the capillaries. After moving about, they make their way to a return vascular system of their own, the lymphatic system. The tree of lymphatic vessels collects lymphocytes and antibodies, along with other cells and molecules and the interstitial fluid that bathes all the body's tissues, and pours its contents back into the bloodstream by joining the subclavian veins behind the collarbone.

Lymphocytes are found in high concentrations in the lymph nodes, way stations along the lymphatic vessels, and at the sites where they are manufactured and processed: the bone marrow, the thymus and the spleen. The immune system is subject to continuous decay and renewal. During the few moments it took you to read this far, your body produced 10 million new lymphocytes and a million billion new antibody molecules. This might not be so astonishing if all these antibody molecules were identical. They are not. Millions of different molecules are required to cope with the task of pattern recognition, just as millions of different keys are required to fit millions of different locks. The specific patterns that are recognized by antibody molecules are epitopes: patches on the surface of large molecules such as proteins, polysaccharides and nucleic acids. Molecules that display epitopes are called antigens. It is hardly possible to name a large molecule that is not an antigen.

The immune system and the nervous system are unique among the organs of the body in their ability to respond adequately to an enormous variety of signals. Both systems display dichotomies: their cells can both receive and transmit signals, and the signals can be either excitatory or inhibitory.

The nerve cells, or neurons, are in fixed positions in the brain, the spinal cord and the ganglia, and their long processes, the axons, connect them to form a network. The ability of the axon of one neuron to form synapses with the correct set of other neurons must require something akin to epitope recognition. Lymphocytes are 100 times more numerous than nerve cells and, unlike nerve cells, they move about freely. They too interact, however, either by direct encounters or through the antibody molecules they release. These elements can recognize as well as be recognized, and in so doing they too form a network. As in the case of the nervous system, the modulation of the network by foreign signals represents its adaptation to the outside world. Both systems thereby learn from experience and build up a memory, a memory that is sustained by reinforcement but cannot be transmitted to the next generation. These striking analogies in the expression of the two systems may result from similarities in the sets of genes that encode their structure and that control their development and function.

Skin Transplants

By Peter B. Medawar
Published: April 1957
Nobel Prize: 1960

Plainly the reaction against a graft is an immunological one; i.e., a reaction of the same general kind as that provoked in the body by foreign proteins, foreign red blood cells, or bacteria. This is easily demonstrated by experiments. After a mouse has received and rejected a transplant from another mouse, it will destroy a second graft from the same donor more than twice as rapidly, and in a way which shows that it has been immunologically forearmed. This heightened sensitivity is conferred upon a mouse even when it merely receives an injection of lymph node cells from a mouse that has rejected a graft.

In most immunological reactions the body employs antibodies as the destroying agent—e.g., in attacking foreign proteins, germs and so on. Antibodies are formed in response to a homograft (a transplant between different animals of the same species), but there are reasons to doubt that these are normally the instruments of the reaction against such a graft. Paradoxically enough, a high concentration of circulating antibodies seems if anything to weaken the reaction: it allows the graft to enjoy a certain extra lease of life.

The actual agents of attack on the graft seem to be not antibodies but cells produced by the lymph glands. Some skillfully designed experiments by G. H. Algire, J. M. Weaver and R. T. Prehn at the National Cancer Institute certainly do point in that direction.

In one experiment they enclosed a homograft in a porous capsule before planting it in a mouse which had been sensitized by an earlier homograft from the same donor. When the pores of the capsule were large enough to let cells through, the mouse destroyed the graft. But when the experimenters used membranes with pores so fine that they kept out cells and let through only fluid, the graft survived.

The hypothesis that the action against a graft is carried out by cells explains why grafts in the cornea are mercifully exempted from attack. The cornea has no blood vessels; consequently blood-borne cells cannot reach the graft.

In the brain, on the other hand, the converse of this situation obtains: the brain lacks a lymphatic drainage system, so that any antigens released by a graft there may not be able to travel to centers where they can stir up an immunological response. This probably explains why homografts can often be transplanted successfully into the brain.