News and Publications

Year In Review - 2000

Neurobiology

Gerald M. Edelman, M.D., Ph.D., Chairman

hile the Department of Neurobiology is small -- with a complement of 30 staff members -- its focus is the vast, and relatively uncharted terrain of the development of the vertebrate nervous system. Its scientists are particularly interested in the morphogenetic process -- the growth of a particular organ or part of the body -- as it applies to the interactions between functional groups of cells in the embryo, particularly as they change to form various tissue types within the central nervous system.

How does the nervous system wire itself? Is it controlled strictly by the genes? Can researchers create tools to manipulate gene expression more effectively? How does one begin with the single-dimensional genetic code at the embryonic stage and end up with a three-dimensional human being with billions of neurons working together to create thought, memory, and physical motion? The department continues to look for the answers to these fundamental questions by studying the links between genetic regulation and new ways of manipulating the processes that control such basic functions as cell division, cell movement and cell death. Working to find the answers are Drs. Bruce Cunningham, Kathryn Crossin, Frederick Jones, Vincent Mauro, Robin Meech, and several postdoctoral fellows.

Simply stated, DNA produces RNA messages, RNA messages serve as templates for protein synthesis, and proteins induce changes in cells to produce various organ and tissue types that make up an organism. These scientists are interested in uncovering fundamental mechanisms of the transcriptional process -- the way genetic information reproduces itself in RNA -- and the translational process -- the production of specific amino acid sequences (proteins) controlled by the genetic information in messenger RNA. RNA is created in the nucleus and exported out as messenger RNA and then, through the process of translation, expressed as proteins that cause changes in cell behavior. The control of these processes is much more complex and subtle than first anticipated.

Prime subjects for the research are cell adhesion molecules (CAMs), which were first discovered by the Edelman laboratory in 1978, and substrate adhesion molecules (SAMs). These two sets of proteins link cells together to form more complex tissue types and regulate cell proliferation, movement and differentiation. While humans share a majority of their genetic code with many other organisms, the real difference rests in the ability to switch certain genes on and off through various proteins, called transcriptional regulators. One of the group's major goals is to understand the influence of CAM and SAM binding on morphogenesis and gene expression, and how interaction with neural (N) CAMs and neural activity in general, may alter gene expression.

POTENTIAL APPLICATION IN GENE THERAPY AND BIOTECHNOLOGY

Recently, they expanded their study of regulation of gene expression caused by the interactions of messenger RNA and ribosomes, elements involved in protein synthesis that provide the translation machinery of the cell. Ribosomes recognize messenger RNA and their interactions lead to the synthesis of proteins. It was thought that the ribosome was recruited by the messenger RNA and scanned from one end to the other until the right starting sequence was reached. The work has shown that short sequences within the RNA messenger can also recruit the ribosome. When these short-recruiting sequences are linked together, a huge increase in protein expression results. This tremendous amplification of output may have potential application in gene therapy and biotechnology. Scientists also have shown that some messenger RNAs have other short sequences that regulate translation indirectly, that is, they seem to affect the efficiency of the ribosome recruitment sequences, acting as translational promoters or inhibitors.

Neural stem cells are the foundation of many other cells within the brain. Crossin discovered that by adding neural (N)-CAMs to rodent stem cells, the stem cells become transformed into neurons. Cellular therapy studies in other laboratories have begun to implant neural stem cells into the brains of mice with illnesses resembling Parkinson's disease, and have shown some limited success. The main problem has been that most of the implanted cells don't become neurons. In in vitro studies, when N-CAMs bind to rodent stem cells, a significant percentage -- as high as 90 percent -- become neurons. They are, in effect, biasing these stem cells toward differentiating into neurons, a bias that one day may point the way to novel treatments for a number of neurodegenerative diseases. Next year, the researchers have planned several in vivo experiments to implant these neuron-based stem cells into the brains of live rodents.

To date, research in the department has led to a deep reexamination of how all of these fundamental cellular processes are controlled and to the development of basic approaches to these processes that have practical significance. While the scientists are dedicated to basic research, the work with gene translation and transcription will have an impact on gene therapy and will allow fruitful clinical applications.