As I listened to the Nobelists describe their neuroscience research, I was struck by the realization that their individual genius could not have achieved such remarkable results without a synthesis of many basic and clinical sciences and plenty of international cooperation. I will return to this theme later.

Much has been written about the work of these men. The story of how their research has contributed to developing new drugs for the treatment of neurological and psychiatric diseases has been widely reported, but the significance of their basic discoveries will be more enduring. Was there anything left to say? I thought so, but I couldn’t find a way to start, until…

One morning at breakfast, while cutting into a juicy honeydew melon I noticed a tiny fruit fly (Drosophila) landing on the melon. Before I had time to brush it away, my hand was stayed by the thought of what a miracle it is that a creature 1/8^th of an inch in length is equipped with complex body structures, including a brain of 250,000 neurons (compared to our 100 billion or so) that is capable of behaviors similar to our own, including learning and memory. It is even more amazing that the molecular mechanisms involved in encoding memories are like those in other species, including humans and sea slugs, as discussed below. This makes it a useful and highly popular experimental animal for neuroscientists.

Another indication of how closely we’re related to Drosophila is the discovery that about 60 percent of its genes can be found in humans and 70% of the genes known to cause human malignancy have been found to exist in similar form in the fruit fly. No wonder this little relative is one of the most studied organisms in biology.

In appreciation for the contributions of this clan to the advancement of science, I allowed the little creature to eat its fill of my melon and to depart in peace.

FROM MOLECULES TO MEMORY: Consolidation of long term memory involves gene expression, new protein synthesis, and the growth, or pruning, of synaptic connections.

Another experimental animal is the sea slug (Aplysia californica), which has gained immortal fame from studies in the laboratory of psychiatrist- neuroscientist Eric Kandel, who used it for “the molecular biological analysis of learning and memory.” He chose the sea slug because of its large neurons and simple nervous system (about 20,000 nerve cells). It is a suitable model because it is comparatively easy to study and, like the fruit fly, the mechanisms involved are like those in humans. Kandel’s work is built on that of fellow Nobelists Carlsson, Greengard and others.

Space will permit only a brief and simplified description of the mechanisms that have been identified in long term facilitation, from signal transduction to long term memory. In most cases, neurotransmission involves the release of a chemical neurotransmitter by the presynaptic neuron. The neurotransmitter (in the following example, serotonin), packaged in vesicles, diffuses across the synaptic cleft and acts on a postsynaptic receptor to activate a cascade of intracellular events involving the second messenger molecule, cyclic adenosine monophosphate (cAMP), which in turn activates the cAMP dependent protein kinase A (PKA). Long term facilitation (lasting one or more days) involves the synthesis of new proteins. The switch for this is initiated by PKA, which triggers a chain of events leading to a regulatory protein called CREB. Through another series of steps, CREB-1 activates certain genes that encode proteins important for the growth of new synaptic connections and for the conversion of short-term memory to long-term memory.

The preceding outline describes the learning process that takes place when the gill withdrawal reflex of the slug is facilitated in association with noxious stimuli. The results of studies with this simple creature apply to the basic cellular mechanisms of learning and memory in other species, from fruit flies to humans.

Long Term Storage: As previously noted, memory is based on changes at the cellular level. Long term memory is represented in multiple regions throughout the nervous system. For example, semantic (factual) memory is distributed in the neocortex and implicit memory (motor skills etc) is stored in perceptual and motor circuits.

Before memories can be stored in any of the locations described above, they must be processed in the hippocampus. With sufficient damage to the hippocampus, most types of new memories cannot be stored, but old memories may remain intact.

GENES AND MENTAL ILLNESS: Mental illnesses of all types have a genetic component.

The human genome differs from that of other species, not so much in the number of genes as in the larger proportion of genes involved in regulating the structure and functions of the brain. It is estimated that in humans, over one third of the total genetic information encoded in DNA is expressed in brain cells-- more than in any other tissue in the body. According to Kandel, both hereditary and acquired illnesses have a genetic component. Hereditary illnesses result from the expression of altered genes or allelic variants which leads to the production of an abnormal protein, thereby giving rise to the disease state. An acquired illness (such as PTSD) involves the modulation of gene expression by environmental stimuli as a result of learning, leading to the transcription of a previously inactive gene. By this means an abnormal learning experience can also lead to the expression of a protein that gives rise to a mental disorder.

Kandel also states “Development, hormones, stress, drug addiction, alcoholism and learning are all factors that alter gene expression by modifying the binding of transcriptional regulatory proteins to each other and to the regulatory regions of genes. It is likely that at least some neurotic illnesses (or components of them) as well as various forms of drug addiction result from reversible defects in gene regulation…

The ongoing modification of synapses throughout life means that all behavior of an individual is produced by genetic and developmental mechanisms acting on the brain—that everything the brain produces, from the most private thoughts to the most public acts, should be understood as a biological process.” (1)

TERRORISM AND MENTAL ILLNESS: Terrifying experiences can cause defects in gene regulation that lead to mental disorder.

International terror reached a new level on September 11, 2001. One of the immediate consequences was an increased demand for psychiatric services. As noted earlier, many of these reactions to emotional trauma involve transcription of a previously inactive gene and expression of a protein-giving rise to the mental disorder. Kandel illustrates this fact with the example of PTSD. The mechanisms involved are similar to those described for the sea slug.

Both the use of medication and psychological approaches are biological treatments that may contribute to the reversal of learned defects in gene regulation. Although drugs are not a substitute for psychotherapy, they may enhance its effectiveness in appropriate cases by reducing symptoms and improving cognitive functions. Psychotherapy may also enhance drug effectiveness.

SCIENCE AND WORLD PEACE: Science synthesizes and unifies

We hear so much about the misuse of scientific technology for destructive purposes that we can easily overlook the fundamental unifying effects of scientific activities. The human genome project is a good example. This international effort has demonstrated that all humanity shares the same genome, with only insignificant variations. Awareness of this discovery can help to reduce the artificial boundaries that divide mankind. Genetic studies have also demonstrated the remarkable extent to which we are biologically related to all other creatures. This knowledge can help us appreciate the interdependence of all life forms and the need to conserve natural resources.

Science unites all mankind in a cooperative quest for scientific truth and human betterment. No other group of disciplines speaks the same language everywhere, or has verifiable and universally agreed upon standards.

The overlap between sciences is illustrated by the ability of Nobelists Francis Crick (genetics) and Gerald Edelman (immunology) to switch to neuroscience, in which they have rapidly become leading investigators.

The ACNP presentations by the Nobel Prize winners illustrated that neuroscience is a synthesis of neurology, psychiatry, cognitive neuropsychology, genetics, molecular biology, and much more. Rather than competing destructively, workers in each of these fields and in many nations share the benefits of cooperative enterprise. This has led to results that could not have been achieved by solitary efforts. It is a model for all competing political systems.

Alfred Nobel, who died in 1896, left most of his fortune to fund the prizes in his name. Since 1901, Nobel Prizes have been awarded to men and women of all continents and many races. Nobel intended his prizes to promote world understanding, cooperation and peace. It is appropriate that the sciences are well represented.

From the time they were first awarded, the Nobel Prizes for Science have illustrated the benefits of international interdependence. The modern era of neuroscience began over a century ago with Camillo Golgi, who discovered an improved method for microscopic visualization of the nervous system and with Ramon y Cajal, who used Golgi’s method to identify the neuron as the basic unit of the nervous system. (These achievements were forerunners of the visualization of the synapse with the use of the electron microscope in the 1950s.) Golgi, an Italian and Cajal, a Spaniard, shared the Nobel Prize in 1906 for their discoveries.

There is no better way to promote relationships with people from other nations or to improve the prospects for world peace than by cultivating the sciences and the international cooperation that goes with them.

1. Principles of Neuroscience, Kandel, E., Schwartz, JH; Jessell, T.M., Fourth Edition, McGraw Hill, 2000