[Congressional Record Volume 143, Number 159 (Wednesday, November 12, 1997)]
[Extensions of Remarks]
[Pages E2325-E2326]
From the Congressional Record Online through the Government Publishing Office [www.gpo.gov]




                CONGRESSIONAL BIOMEDICAL RESEARCH CAUCUS

                                 ______
                                 

                          HON. GEORGE W. GEKAS

                            of pennsylvania

                    in the house of representatives

                      Wednesday, November 12, 1997

  Mr. GEKAS. Mr. Speaker, on September 10, the Congressional Biomedical 
Research Caucus conducted its 57th briefing on the subject of the 
``University of Genes: The Bits of DNA That Make Us What We Are.'' Dr. 
H. Robert Horvitz, Howard Hughes Medical Institute investigator and 
professor of biology at MIT, and Dr. Philip Heiter, professor of 
medical genetics of the University of British Columbia, Vancouver, 
spoke about the similarity of genes across species and how this 
discovery assists in biomedical research.
  I was particularly pleased to have Dr. Horvitz participate because as 
a member of the Joint Steering Committee--a coalition of five basic 
biomedical research societies: the American Society for Cell Biology, 
the American Society for Biochemistry and Molecular Biology, the 
Biophysical Society, the Genetic Society of America, and the 
Association of Anatomists--he has played a significant role in 
supporting the caucus briefings.
  Congressman Joseph Kennedy of Massachusetts introduced Dr. Horvitz 
and was joined in attendance by myself, Congressman Steve Horn, 
Congressman Joel Hefley, and Congressman Tom Petri, as well as a room 
full of senior health staff.
  I believe our colleagues will find Dr. Horvitz's remarks useful.

        All Creatures Great and Small: The Universality of Genes


                            I. Introduction

       First, I would like to thank the organizers of this Caucus 
     for inviting Phil Heiter and me to talk with you today. The 
     title of this Caucus is ``All Creatures Great and Small: The 
     Universality of Genes.'' What we are going to discuss today 
     is one of the most striking discoveries in the history of 
     biomedical research: genes--the bits of DNA that make us what 
     we are--genes are so remarkably similar among different 
     organisms that we can study what they do in a microscopic 
     worm or in a yeast that is used to make beer to learn how 
     they work in us.


                               II. Genes

       Let me start with a few introductory remarks about genes. 
     Genes define hereditary traits. Each gene can exist in 
     different forms, and such variations in the forms of genes 
     result in variations in traits. Some such variations we 
     consider simply to be what make us different from one 
     another: for example, eye color and blood type are defined by 
     genes. Similarly, our sexual characteristics, whether we are 
     boys or girls, as David Page put it in an earlier Caucus, are 
     determined by our genes. Variations in other genes result in 
     variations in other traits: for example, dwarfism, deafness 
     and color blindness can be caused by variations in genes. 
     Variations in still other genes results in variations in our 
     traits that we label ``disease'': Huntington's Disease is 
     caused by one such gene; variations in other genes cause or 
     predispose one to cancer, cardiovascular disorders, asthma, 
     cystic fibrosis, premature aging, Alzheimer's Disease, bone 
     loss, and many, many other diseases.
       So, genes are important to us, and crucial to our health. 
     How can we learn about our genes, what they do, and how they 
     sometimes go wrong? One approach is to study our genes--human 
     genes--directly. Biologists do this. (I do this.) But the 
     study of human genes is in many ways very slow and 
     inefficient. Furthermore, some types of genetic studies are 
     simply impossible to do with people. For example, the classic 
     method of genetics is to cross individuals with different 
     gene variants (called mutation); this we cannot do with 
     people.


                           III. Universality

       Fortunately, biology has provided us with an approach that 
     is feasible: genes are strikingly conserved among organisms, 
     so we can study genes in experimental organisms and in this 
     way learn what genes do in us. Let me show you an example 
     from my own research. I study two organisms, human beings and 
     the nematode roundworm known as C. elegans. My focus in 
     humans is on Lou Gehrig's Disease, or ALS, the devastating 
     disease that killed Lou Gehrig, Jacob Javlts, David Niven, 
     and many others. Four years ago, with a team of 
     collaborators, we found a gene responsible for ALS, a gene 
     known as SOD1. SOD1 in humans is strikingly similar to SOD1 
     in my worm, as can be seen by the large number of boxed 
     identities in the sequence of the protein products of these 
     genes. Such similarity is seen in SOD1 in many organisms: the 
     gene in spinach is essentially the same as well. To 
     understand what SOD1 does, and how it goes wrong in ALS, one 
     can study the gene in whatever organism is best suited for a 
     particular line of inquiry, and SOD1 is now being studied in 
     worms, in brewer's yeast, in fruit flies and in mice in 
     attempts to understand how it causes ALS in humans. Let me 
     generalize from this example and show you more broadly the 
     degree to which genes are conserved among organisms.
       The next slide is from an article written by Phil Hieter, 
     our next speaker. This table shows a list of 84 human genetic 
     diseases, from A to Z (really from A to W: achondroplasia or 
     dwarfism is No. 2 on the list, while Wornor syndrome, which 
     results in premature aging, is 4 from the bottom). The 
     columns show matches (in color) with genes found in those 
     organisms commonly used for laboratory studies of genetics: 
     the mouse, the fruit fly, the nematode roundworm, brewer's 
     yeast, and the intestinal bacterium E. coli. What you can see 
     is that almost all of these human genes have a counterparts 
     in the mouse, that many do in the fruit fly and worm, and 
     that quite a few do in the yeast and bacterium. This table 
     underestimates the degree of similarity with mice, fruit 
     flies and roundworms, since many genes remain to be 
     characterized in these organisms and some will no doubt 
     provide additional matches. It is now clear that almost every 
     human gene has a mouse counterpart, that the majority have 
     fly and worm counterparts and that many have yeast 
     counterparts. These kinds of observations, coupled with 
     findings that genes that look similar act similarly, have led 
     to the use of experimental organisms as models for human 
     biology and human disease.


                             IV. Organisms

       If all organisms have similar genes, how do scientists 
     decide which organisms to study? The short answer is that 
     different organisms have different experimental advantages 
     and that by studying a variety of organisms biologists obtain 
     different types of data that together help us understand what 
     genes do. To provide some concrete examples of how studies of 
     these simple organisms are helping us to understand as well 
     to prevent and cure human disease, Phil Hieter and I will now 
     talk about work involving ``our'' organisms, the brewer's 
     yeast and the roundworm. The next slide summarizes my 
     perspective on using roundworms to study human disease, given 
     what we know about human genes and worm genes: ``Worms are 
     little people in disguise.'' So let me start with 
     the neurodegenerative disorders, such as Alzheimer's 
     Disease, and on cancer.


               V. Alzheimer's Disease and the Presenilins

       First, let's talk about Alzheimer's Disease. Some, but not 
     all, cases of Alzheimer's Disease are clearly genetic, i.e. 
     pass from parent to child. Most genetic or ``familial'' AD is 
     caused by changes in a single gene, known as PS-1, for 
     ``Presenilin gene number one.'' In 1995 this gene was 
     isolated biochemically. What does it do? How can we find out? 
     Simply having access to a gene is not enough to tell us what 
     it does unless it is sufficiently similar to a gene we 
     already know about.
       PS-1 is similar to four other known genes. One, called PS-
     2, is a second Alzheimer's gene isolated in 1995. The other 
     three are all in the roundworm C. elegans. How similar are 
     these worm genes to the human genes? In one experiment, 
     researchers at Columbia University in NYC showed that the 
     human PS-1 gene could work in the worm, substituting for one 
     of the worm genes it looked like. This finding says that the 
     human AD gene and the worm gene are functionally 
     interchangeable. They are very similar. Thus, figuring out 
     what the worm gene does should give us a very strong clue 
     about what the human gene does. Studying this worm gene is 
     now a important effort in both academia and the biotech 
     industry.


                     VI. Cancer and the Ras Pathway

       Let me turn now to cancer. Cancer, like familial AD, is 
     caused by variants in genes. The first human cancer gene was 
     identified in 1981. This gene was called Ras. Biomedical 
     researchers actively analyzed Ras and desperately wanted to 
     know what it does and, in particular, wanted to know the 
     pathway through which Ras acts. This concept of pathway is 
     key for the development of pharmaceuticals: if you can block 
     the action of a disease gene, either directly or indirectly, 
     i.e. either by acting directly on that gene or by acting 
     later in the gene pathway through which that gene acts, you 
     should be able to prevent the disease.
       What is the Ras genetic pathway? The answer emerged not 
     from studies of human Ras but from very basic and apparently 
     unrelated studies of animal development, in particular 
     studies of the development of a sexual organ of the roundworm 
     and of the eye of the fruit fly. It turned out that a gene 
     that controlled worm sexual development as well as a gene 
     that controlled fly eye development were both strikingly 
     similar to human Ras. The levels of identity were 
     approximately 80 percent. Furthermore, at the time it was 
     discovered that a Ras-like gene was involved there had been 
     very extensive studies of these processes; as a consequence 
     within a few years detailed gene pathways were

[[Page E2326]]

     completed. Together these studies, which were done in my 
     laboratory at MIT, at CalTech, and at Berkeley, revealed the 
     pathway of action of Ras. Now cancer biologists and drug 
     companies alike are using this knowledge of the Ras pathway 
     both for further studies of how Ras causes cancer in people 
     and for the development of drugs, drugs that can block the 
     various steps in the Ras pathway.


    VII. Programmed Cell Death, Neurodegenerative Disease and Cancer

       The third example I'll offer from worms relates both the 
     cancer and to neurodegenerative diseases, which include AD. 
     This example again is one in which studies of a basic 
     biological phenomenon in the roundworm have had a major 
     impact on our understanding of and approach to human disease. 
     The biology in this case involves a phenomenon called 
     ``programmed cell death.'' For many years, biologists assumed 
     that cells died because they were unhappy, i.e. because 
     somehow they had been injured. However, a variety of studies 
     revealed that many cells die during the normal course of 
     development. For example, as our brains form, as many as 85 
     percent of the nerve cells made at certain times and certain 
     parts of our brains die. Such death is a natural phenomenon 
     and for this reason is often referred to as ``Programmed Cell 
     Death.''
       Given that cell death is a natural aspect of development, 
     some years ago my colleagues and I reasoned that like other 
     aspects of development, PCD should be controlled by genes. We 
     sought such defined a 15-gene genetic pathway that controls 
     programmed cell death In the worm. It now appears that a 
     least some of these gene correspond to human genes that 
     caused disease. For example, we talked earlier about 
     neurodegenerative diseases, such as AD, Huntington's Disease, 
     Lou Gehrlg's Disease and Parkinson's Disease. Many 
     researchers believe that these diseases, which are 
     characterized by the death of nerve cells, are diseases in 
     which the normal process of PCD has gone amok. Specifically, 
     the normal pathway that causes cells to die by PCD during 
     development for some reason may be unleashed in nerve cells 
     that are not meant to die.
       How might we stop such deaths? By blocking the killer genes 
     responsible! And what are the killer genes? We have ID'd two 
     such genes in the worm, genes we call CED-3 and CED-4, for 
     ``cell-death abnormal.'' Given these worm genes, others have 
     gone on to find similar genes in humans that also act to 
     cause cell death. These genes have now become major drug 
     targets: many companies in the pharmaceutical industry are 
     attempting to block the action of these killer genes, with 
     the goal of preventing such neurodengenerative diseases.
       It turns out the genetic pathway for PCD we have defined is 
     relevant not only to neurodegenerative disease but also to 
     cancer.
       Let me explain. What is cancer? In brief, cancer reflects 
     an uncontrolled increase in cell number. How can you get such 
     an increase? One way is to make too many cells. This is 
     precisely what happens when the Ras gene, which we just 
     discussed, is mutated. However, it turns out there is another 
     way to make too many cells. The number of cells in our bodies 
     is really an equilibrium number. Cells are always being added 
     to our bodies, by the process of cell division, but cells are 
     also always being taken away, by the process of programmed 
     cell death. So, we can generate too many cells--as in 
     cancer--not only by too much cell division but also by too 
     little cell loss.
       How can we bet too little cell loss? One of the genes we 
     identified as controlling cell death in the worm is not a 
     killer gene but rather a protector gene--it protects cells 
     from dying by PCD. If a gene like this is too active, too 
     many cells would survive, and cancer would result. In fact, 
     there is a human cancer gene that is very similar to this 
     worm protector gene, so similar that the human gene can work 
     in worms to protect against worm cell death and to substitute 
     for the worm gene. Given such protector genes, how might one 
     prevent? Again, this is precisely the approach that is now 
     being taken in the pharmaceutical industry, and there is 
     great nope that by learning to control such protector genes 
     it will be possible to control certain cancers.


                           VIII. Conclusions

       Let me conclude very briefly by summarizing what I've said. 
     First, a gene is a gene is a gene. Genes in humans are 
     fundamentally no different from genes in other organisms and 
     are so similar in many ceases that a human gene can be put 
     into another organism and work just fine. Second, genes are 
     much easier to analyze in experimental organisms than in 
     people. In few years, the Human Genome Project, sponsored by 
     the NIH, will tell us what all of our genes look like. But 
     what do they do? To find out, we must study experimentally 
     tractable organisms. Third, time and time again truly basic 
     studies of genes in experimental organisms have proved 
     directly relevant to human diseases and disease genes, once 
     we knew what those human genes looked like. An investment in 
     such basic studies is an effective investment indeed, as it 
     means that knowledge will proceed at an enormous pace once a 
     human disease gene is identified. Finally, knowledge of what 
     the counterparts of human disease genes do in an experimental 
     organism can be directly used both in the understanding of 
     what that gene does in people and also in the application of 
     that knowledge to the development of a treatment of cure. I 
     thank you for your time.

     

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