Genetics

Chairman's Overview

Bruce Beutler, M.D.

Biology is unique among the natural sciences for many reasons, not least because living things are constructed according to a blueprint that is largely open to our inspection. This blueprint is the genome, and although many gaps remain in our understanding of its language, we can at least read the genome to deduce the primary structure of most of the proteins that an organism can synthesize.

This is only a beginning, of course. Most would agree that even the most complex clock built by humans is far simpler than the simplest eukaryotic cell. Yet having an inventory of all of the gears, levers and springs in a clock would not tell a naïve observer how the clock works to keep time. If biologists studied enormously complex clocks with millions of component parts, and if they were presented with a bag loaded with these parts in no particular order, they might have a difficult time in assembling them.

But in reality, biologists can do certain things that the would-be clockmaker cannot. Their first tool in understanding the workings of a living organism is genetics. Genetics is not merely the science of heredity but the science of exceptions. Exceptions to the norm teach us an enormous amount in biology. Here I refer to the process by which geneticists dissect complex phenomena, first splitting them into phenotypes, and then finding out the most fundamental cause of the phenotypes they have created: the precise mutational change that was responsible.

In practice, one comes to the genetic approach with questions about a particular phenomenon. Rather than making guesses about how the phenomenon “works,” the phenomenon is probed by introducing mutations into the host germline at random using the chemical mutagen N-ethyl-N-nitrosourea. When individuals with abnormal phenotypes are detected, the mutation that causes the abnormality can be tracked down by positional cloning. This process can be repeated until one knows approximately how many proteins are required for the phenomenon to occur as it normally does, and until many or most of these proteins have been found.

During its first year of existence, the Department of Genetics at TSRI has used genetics in the mouse to study an enormously complex phenomenon: how the mammalian host defends itself from infection. There are many aspects to host resistance, which might be seen as the reciprocal of host susceptibility. For any aspect of immune defense we wish to study, however broadly or narrowly defined, an appropriate genetic screen can be devised. One might ask: how many genes are required for a mouse to defend itself against a specific viral pathogen, mouse cytomegalovirus (MCMV)? The answer appears to be: a minimum of 300, and very likely a thousand or so. To date, 48 mutations that disrupt defense have been created, and 26 of them found. The others will likely be found in the near future. How many genes can be mutated to give exaggerated resistance to this same virus? Perhaps a similar number; 7 mutations that will do so are now under study, and it is possible that some of these will point to important new targets for anti-viral therapy.

Mutations that cause susceptibility to a virus can affect many different processes. We require specific proteins to sense the virus, signal its presence to other cells, and activate those cells to make them eliminate the virus before it spreads out of control. Other proteins allow us to tolerate the immune response itself, and without them, we would surely die from trivial infections. Examples have been found in each category. The screen for virus susceptibility is therefore extremely broad. Other screens target immune phenomena that are much more tightly defined. How does the antibody response to an infectious agent get started? How do NK cells, antigen presenting cells, or cytotoxic T cells become activated? And how do these cells differentiate in the first place to assume their proper roles in the immune system? Genetics can tell us, and we have begin to understand each process in turn.

Genetics creates phenotypes in all realms of biological function, and even when certain phenomena are not kept under surveillance, some declare themselves so loudly that we simply can’t ignore them. During the past year, a mutation called mask was identified in our laboratory. Mask makes mice lose truncal but not facial hair, and also makes them develop iron deficiency anemia. In collaboration with the laboratory of Professor Ernest Beutler (MEM), we deduced that mask disrupts a specific proteolytic enzyme, and further deduced that this protease is required to detect iron deficiency and respond appropriately to correct it. Now that a foothold has been gained, the biochemical basis of iron homeostasis may be understood as never before.

Another bizarre phenotype was add: so named because affected mice are wildly hyperkinetic. They are also deaf, and show a defect of vestibular function. The add mutation was also tracked down by Dr. Xin Du, a Staff Scientist in the Department of Genetics. She found the add phenotype to be a fundamentally new inherited disease, stemming from a mutation in a gene that had not previously been annotated. This gene encodes a new form of the enzyme catecholamine-O-methytransferase (which we have named COMT2). In collaboration with the laboratories of Professors George Kube (Committee on the Neurobiology of Addictive Disorders) and Uli Mueller (Department of Cell Biology), we have examined the mechanism of the phenotype, and have found that the new enzyme is required for hair cells in the inner ear to function properly. Not only mice, but humans lacking COMT2, develop profound deafness. COMT2 may also be required for normal cerebral function. Interestingly, mutations of the classical COMT enzyme (now called COMT1) have been associated with schizophrenia in humans. It is possible that combining mutations of both COMT isoforms will create an authentic mouse model of this disease, while neither mutation alone suffices to do so. We also anticipate that certain cases of deafness and vestibular disease in humans will result from mutations of the COMT2 gene.

Still other strange phenotypes in our collection include Possum (the mice appear to “play dead” when handled gently), and abnormalities of coat color, metabolism, and development. Finding such mutations becomes progressively easier with the technological advances in DNA sequencing. But understanding them mechanistically remains difficult. Obviously, a multidisciplinary approach to mutations is essential, for they touch on almost every field one might imagine.   For that reason, we have begun to display all mutations on a special website, where scientists from Scripps and from around the world can learn about them, offer their insight, and initiate collaborations. This website, maintained and constantly expanded by Eva Marie Moresco and Nora Smart, can be viewed at:

http://mutagenetix.scripps.edu

As stated at the beginning of this Overview, many gaps remain in our understanding of the genome. Epigenetic control of gene expression is one example. Why is a liver cell so different than a brain cell though both possess exactly the same genetic content? The genes are differently expressed, and are programmed to maintain a certain level of expression through mysterious processes that operate during development. The rules for epigenetic silencing or activation of genes have only been defined in the most limited way, and are partly embodied in the structure and behavior of chromosomes: visible bodies within the cell nucleus that are composed of both DNA and protein, and contain most of the genes we have.

A new member of the Department of Genetics faculty, Eros Lazzarini Denchi will soon join us from Rockefeller University. Denchi is an expert in the biology of chromosomes, with a distinguished reputation in the study of telomeres: the ends of chromosomes, which must be shielded with specific proteins (collectively termed “shelterin”) lest they trigger a catastrophic DNA damage response. He is seeking to understand precisely how this response comes about. His work in the Department will add great strength in an area of fundamental importance to genetics.

The Department of Genetics continues to seek outstanding new faculty, and will further expand during the coming year. It is my intention that it will remain a tightly integrated group of scientists, each with strong collegial ties to other members of the Department and to TSRI as a whole, and committed to exploring biological questions at their most fundamental level.

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