LiveWorld Transcripts

Bio Online presents

Dr. Joan Brugge, Dr. Peter Devreotes, Dr. Gary Firestone, and Dr. Allan C. Spradling
Molecular Biologists

December 8, 1999

Life Science pioneers and opinion leaders review significant recent advancements in molecular biology, contemplate future directions and address your questions.

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BioOnline: Welcome to Chat with Bio Online! Our discussion this evening with Life Science pioneers and opinion leaders will review significant recent advancements in molecular biology, contemplate future directions and address your questions.

Alan Kimmel: Good evening! I am Alan Kimmel, and I will be moderating our chat for the next hour. We will have the chance to interact with a panel of very distinguished, accomplished scientists. Molecular Biology at some level is a rather new discipline, with recombinant DNA technology, for example, stretching back only 25 years. We are only now just beginning to see its great rewards and enormous potential and promise. Thus, with the end of century and millennium quickly approaching, it is a most suitable time to review the role of molecular biology. Our panelists will discuss recent notable achievements and exchange thoughts about future expectations for progress. I hope each will have the opportunity in their discussion to relate some of their own interesting work. After some initial discussion, panelists will address questions from our audience participants. First, let me give you a bit about my background. I am Chief, Molecular Mechanisms of Development /Laboratory of Cellular and Developmental Biology at the National Institutes of Health in Bethesda, MD. Joining us tonight, we are fortunate to have: Dr. Joan Brugge, Professor in the Department of Cell Biology, at the Harvard Medical School, Boston, MA; Dr. Peter Devreotes, Professor in the Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD; Dr. Gary Firestone, Professor in the Department of Molecular and Cell Biology at the University of California at Berkeley; and Dr. Allan C. Spradling of the Department of Embryology, Carnegie Institution of Washington, and Professor of Biology, Johns Hopkins University, Baltimore, MD. Allan, you have been a technological innovator. Perhaps you can start by defining what molecular biology is, with a brief overview of some significant breakthroughs.

Dr. Allan C. Spradling: Molecular biology, in its broadest sense, is the view that we need to understand biology in terms of molecules and molecular processing. This is especially true of the large molecules in cells, particularly the protein molecules that are encoded by the cell's genes. So, in molecular biology we analyze a problem by determining which genes and the proteins they encode are important and responsible for ensuring that that aspect of the organism is able to carry out this function .

Alan Kimmel: Peter, one interest common to all of us is cell to cell communication, cell signaling, and cell interaction. Could you define these concepts and their significance for molecular biological research?

Dr. Peter Devreotes: Cells in the tissues throughout our body are constantly interacting with one another and their behavior depends on the signals and the types of communication that they get from each other. These signals are usually in the form of created chemicals such as hormones and neurotransmitters. (Neurotransmitters being chemicals and signals between nerve cells.) Some hormones in neurotransmitters that we could mention are insulin, estrogen, botamine. These are the signals that tell us to communicate with one another and, broadly speaking, this is what cell interaction is. All of the behavior of cells is dependent on the cues they receive from one another.

Alan Kimmel: Joan, there has been enormous success for targeting specific proteins for disease treatment. How do you view the potential for molecular biology in developing new therapeutics?

Dr. Joan Brugge: I think the major role that molecular biology is playing in the area of therapeutics is in the identification of proteins that are involved in human diseases, so molecular biology has contributed the technologies for mapping genes that are defective in human genetic diseases like Alzheimer's, Cystic Fibrosis, Neuro Fibromatosis and many others. However, in addition, through studies in cell biology and cellular signaling like that discussed by Peter, molecular biology advances have led to the identification of cellular proteins that are involved in processes that are associated with diseases like inflammation and program cell death These proteins either themselves can serve as therapies -- for instance, insulin, interferon, or growth hormone -- or intracellular proteins can serve as targets for the development of small molecule drugs that block the activity of these proteins and inhibit disease. Molecular biology is just beginning to be used in the design of small molecule drugs. This is through deriving the crystal structure of the disease protein either alone or in a complex with an inhibitor. In the future, this will be used more and more. So, the major challenge in the future is really going to be to exploit the information from sequencing the human genome for either therapeutic proteins or disease targets.

Alan Kimmel: Allan, your organism of interest is Drosophila, the fruit fly. The sequence of its genome is all but complete. What is the future for the 'Post-Genome' Era as we look to the completion of the Human Genome Project in two years?

Dr. Gary Firestone: I want to tie this into Peter and Joan's answer also. One use of molecular biology is to understand cell function, as Peter pointed out in discussing cell-cell interactions and that Joan pointed out in looking at structures of signing components. Once you know function, you can understand better about the dysfunction of cells, such as in the case of cancer cells where cancer cells are fairly small changes in the utilization or activity or production of normal gene products, so that molecular biology can be used to ask, "What's the difference in the overall expression pattern of a tumor cell versus a normal cell?" And once you know those differences you can then start discussing and figuring out the function of those particular genes. And so one of the approaches with therapeutics is to target those differences. So, for example, a cell that is defective in a particular gene can be manipulated to stop the growth of that tumor cell, thereby providing a normal-line genotype back to the cell that would be the goal. So, one of the very exciting new areas in molecular biology is to try to figure out what are the total gene expression changes in a tumor state and one approach to that is to use the relatively new DNA microarray technology. This technology allows a fairly complete analysis of all genes that change. As a result of the microarray analysis, in many instances, unanticipated changes in genes have been observed and therefore provide new targets for potential therapeutic for that particular cancer cell. This is a very exciting area. This relates to Allan's question about function of these proteins because many times you can't anticipate a biological function until you know the cellular context of what is produced and that its targets may be. This is what molecular biology will do. This is what is exciting about the new approach -- not just to uncover a gene, but also provide information perhaps on the function of genes.

Dr. Peter Devroetes: Gary is getting into an important challenge for the future -- understanding how all these gene products or proteins work together in order to carry out the functions of the cell. All of us have spent many, many years defining and finding all of these products and now with the Human Genome Project we will basically have a list of all of the components. There are perhaps 150,000 proteins in a cell. They all have to interact and work together, so it is sort of like a machine that has more parts than a 747. It all has to work together smoothly and you can fit about 1,000 of these machines on the head of a pin. So that is the challenge of the future -- to find out how these machines work, and microarray technology would be one way knowing how some of the parts change when we alter other parts.

Dr. Allan C. Spradling: There are these tens of thousands of genes. Today, we really only understand 1,000 or less in terms of their basic function and we don't today know which cells of the body all of these tens of thousands of genes are expressed in.So, the microarray technology will help us get a picture of where and when the body uses its genes. Since I've worked on the Drosophila genome project, I would like to mention another approach to understanding what genes do, which is the use of model organisms, such as the fruit fly, nematode of brewer's yeast, the mouse, and then make a mutation in each gene in these organisms and study what goes wrong. And because biology is very similar between different organisms, this approach, along with the knowledge of which cells use each gene, can make it possible to learn a lot about how the gene works and what it does. I think one also needs to combine, as Joan was mentioning, knowledge of the actual three-dimensional structure of the gene and its biochemical properties. Biologists try to put all of this diverse information together to come to an understanding of how genes work and we still have most of our work cut out for us in this task. The significance of using model systems emphasizes the importance of doing what we call basic research, as opposed to disease-directed research, because we often don't know what the answer is or how to phrase the question. So, I think it's a good time for the panelists to focus on the importance of basic research and how basic research in molecular biology has become critical for understanding and treatment of diseases.

Alan Kimmel: Dr. Spradling has already emphasized the model systems and I think the panelists perhaps can discuss the critical aspects of the general, basic research. Peter, again, has worked with a separate model system, and maybe he will speak about his own research and its influence on understanding the function of mammalian cells.

Dr. Peter Devroetes: In our work on dicyostelium, which are amoeba protozoan cells (and you can cite many examples), we look at a particular function in these cells, which is their ability to be attracted to chemicals -- chemical gradients -- and even though these cells are very simple, their behavior is very similar to that of cells of our own immune system, such as neutrocells and macrophages. Therefore, this is an example where a model can give you the general plan of how the proteins such as recepeptors and gene proteins and the set of bytoskeletons coordinate in order to move the cell in a particular direction. And this process is similar in amoeba and in white blood cells. There are many examples from other model systems as well, because as Allan Spradling had mentioned, biology is quite similar among all organisms.

Dr. Gary Firestone: Another excellent example of what Peter is talking about is that many of the signaling pathways that control the growth of a yeast cell or a fruit fly are virtually identical in their functional relationships to what is observed in human cells. Those are the pathways that in many cases are defective in cancer cells, so by studying what goes on in yeast and in fruit flies there is a direct functional relationship to what goes on in human cells.

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