Medical research; Virology

The following program is produced by the University of Michigan Broadcasting Service under a grant-in-aid from the National Educational Television and Radio Center in cooperation with the National Association of Educational Broadcasters. The Viruses, a program from the series Human Behavior, Social and Medical Research, produced by the University of Michigan Broadcasting Service. These programs have been developed from interviews with men and women who have the too often unglamorous job of basic research. Research in medicine, the physical sciences, social sciences, and the behavioral sciences. The people you will hear today are Dr. Jerome T. Siverton, head of the Department of Bacteriology and Immunology at the University of Minnesota, and Dr. John F. Enders of Harvard University's Medical School and the Children's Medical Center in Boston. And my name is Glenn Phillips.

So common has the word virus become of late in our every day vocabulary that we sometimes overlook its importance. A virus is very small. Thousands upon thousands would fit on the head of a common straight pin. If one should question their importance for medical research, these few facts may be of help. There are about 700 million virus infections in the United States in a single year. These include mubs, measles, chickenpox, influenza, and the old-fashioned common cold. Millions of manpower hours are lost because of virus infection, and millions more in school hours are lost by school children. We can see readily then that it does not take a computing machine to tell us of the suffering and manpower loss, resulting from these microscopic demons. Are they similar to bacteria, or are they something totally different? Dr. Jerome T. Civerton of the University of Minnesota tells us.

This question brings to mind a problem that used to bother us years ago, namely whether viruses were alive or not. Nowadays we do not find such a distinction important because we realize that all things living and non-living represent a hierarchy of organization. The complexity of this organization confers more and more capabilities on the organized entities. Bacteria, like ourselves, are what we call organisms. If we consider a very simple model of an organism, we see that it is an organization able to manufacture itself and its progeny according to definite plan. As an organism, it has an important ability to manufacture the plan itself, so we say it is self-reproducing. It converts raw materials into replicas of itself and incorporates in them instructions

for doing likewise. A bacterium or any other organism therefore contains instructions in the form of molecules of ribonuclate acid for pursuing its existence and for reproducing itself. A virus, on the other hand, consists of such instructions in molecular form wrapped up in apparatus that causes a virus to be delivered into a cell when the two meet. Once inside the cell, the viral molecular code instructs the cell to manufacture more viral code and to wrap it up into the necessary apparatus for its delivery. The cell does so at its own expense and hence suffers in the process. Viruses are packaged blueprints for subservience of cells.

Viruses are function to live and reproduce, viruses function only to reproduce. Viruses are, therefore, particles of nuclear protein totally dependent on cells to provide the machinery of reproduction. What about the connection between animal and plant viruses? I asked Dr. John Enders of Harvard University how the plant and animal virus is different. There is no fundamental difference that I know of between plant and animal viruses. As far as we know today, they are both composed of protein and nuclear acids. However, among the animal viruses, two sorts of nuclear acids have been distinguished. They are so-called ribonucleic acid viruses and the desoxyribonucleic acid viruses. The, while among the plant agents, as far as I know, they are all ribonucleic acid viruses.

As you know, the nuclear acids are the recent, a lot of recent work are the, and found to be the determinants of the genetic characters of all organisms as well as viruses. How many of these two complement each other as far as study is concerned? How many one relate to the other? You mean the plant and animal viruses? The amount of virus developing in an infected plant is very large compared with that found in most animal infections, therefore the plant, the viruses, provide a source of abundant

material for the chemist to analyze and from which he can obtain viruses in exceedingly pure condition. Still it remains paramount that the hope of virus research ultimately will lead to a complete cure of these diseases. What then are the principal research problems remaining? Dr. Sivartan enumerated these. The first is how to treat and prevent virus infection, and the second is to discover how viruses cause disease. We still do not know exactly how viruses destroy individual cells, and we do not know yet whether clinical disease may be attributed solely to effects on individual cells. In some instances, hypersensitivity, allergy, appears to play a role in animal virus disease.

Also, we do not know why some people are resistant to particular virus disease when their cells may be entirely susceptible in the test tube. Apart from these practical problems, there is one great fundamental problem still to be solved. That problem is how a virus causes a cell to cease its own beneficial activities and begin manufacturing parts for more virus. We know that this action is accomplished by the ribonoclake acid structure of the virus and that somehow it replaces a part of the analogous structure of the cell. But we do not know precisely how a cell is made subservient to virus. This problem is most important because the solution will not only tell us the basis of virus infection, but also tell us how a cell directs its own activities.

In this area, as in others, the study of viruses will make valuable contributions to our knowledge of biology and medicine in addition to its contribution to knowledge of viruses themselves. I was fortunate to see many interesting things in research laboratories during the period I visited these people. One was seeing a crystallization of a virus and I wondered why this was important to research. Dr. Enders explained it in this way. Well, it's important on the same general grounds, it's important to isolate in a pure form any biologically active compounds such as hormone or an enzyme because only when that is done can the precise chemistry of it be defined and when that is once done, there may be possibility of modifying the chemical structure of the virus at will in ways that we would like to

modify it, say in the direction of decreased virulence so that it might be used as a vaccine in the development of vaccines now which is consistent with living viruses like, well, the proposed living virus vaccine against polio, the development is largely empirical, it just under certain conditions, the change in virulence, the decrease in virulence may take place, but it doesn't always do so and we can't be predict with certainty that it will if the chemical structure viruses would thoroughly know why it might be possible to modify them for any degree of virulence that one wish.

Along these same lines I asked Dr. Sivitan how the study of physical and chemical properties of a virus might lead to therapy. That's a difficult question at the moment. I do not know of any preventive or therapeutic application of physical and chemical study of viruses. I have no doubt that Dr. Einstein felt similarly when he derived the relation between energy and matter which underlie the atom bomb. Virulologists, however, have many ideas how they might devise preventive or therapeutic applications if they knew enough about the physical and chemical properties of viruses. Among these are the possibility of manufacturing artificial viruses which, like vaccinate a virus, could be used to immunize people against disease producing viruses.

So ultimately, virulologists hope also eventually to discover an anti-metabolite, to interfere with the process of virus infection just as antibiotics now are used to interfere with bacterial infection. More practical aspects of physical and chemical study are already useful. The successful manufacture of the inactivated polio vaccine depended on determining the effect of chemical treatment of polio virus on its immunizing capacity and its infective capacity. I referred to viruses at the beginning as microscopic demons, but is it possible that there is a good virus as well as a bad virus? Dr. Sivitan told me, in reply, of course, there are many useful viruses. I am sure that you yourself bear the scar of one of the most useful of the viruses.

The vaccinate virus used to immunize you to smallpox. Vaccinate virus is quite distinct from the virus that causes smallpox, but is sufficiently related to be useful for immunization. You may remember also that the Australians employed a virus called mixomatosis to control the rabbits that rune pasture and hay meant for their sheep. A less familiar example is provided by the identification of many bacteria responsible for human disease by the use of bacterial viruses. These viruses, or bacterial phage, attack staff or coccy or other bacteria specifically. These viruses that can be used to trace the outbreaks of a specific viral infection. Another useful purpose is highly visionary, but perhaps possible many years hence. When defining a virus, I emphasized that it was essentially a set of instructions for

the operation of cellular processes. Now human genes also represent such instructions. Some viruses that attack bacteria can transfer portions of the genetic apparatus of cells from one cell to another during the course of infection. We know that a number of human diseases result because portions of the chromosome structure of cells are altered. Diabetes is a good example of this sort of disease. It is interesting to speculate, although I emphasize that the idea is pure speculation, that someday we might use viruses to transfer genetic information from cells in tissue culture into the cells of patients with diseases like diabetes. If we could do this, it might be possible to cure such diseases permanently. I should hasten to end that we know far too little about the process of transference

to foresee this sort of practical application in the very near future. So we can see that there are useful or good viruses, and that viruses at some future date may be applied beneficially. Unfortunately, the viruses still exist today in their present structure to wreak havoc on all mankind, through loss of work hours, school hours, and general discomfort, as any of us who have had a cold will attest. But are the diseases produced by viruses, ones of mortality or morbidity? Dr. Enders supplies this with that answer. Well, of course, again, it depends on the virus. In general, however, I would say that the morbidity is usually far greater than the mortality. There are a few exceptions to that, such as rabies, that if one actually develops rabies following

a bite of a mad animal, he's almost certain to die. Not in general, the mortality is low or moderate, and the morbidity high. And in many viral infections, the rule may be entirely independent, non-clinical infection, which is not recognized by the individual who has it or the physician. But nevertheless, the causes seem to become resistant or immunized. This is true, even in polio, where vast majority of people undergo an in-apparent infection

with a virus, the paralytic disease is really an exceptional event in the course of infection through the population. Viruses were scientifically unknown at the beginning of this century, but in those relatively few years, great advances have been made. I asked Dr. Enders what he felt were the greatest of these advances. Well, of course, historically, I suppose it really begins with, well, perhaps with an occupation against the smallpox that was introduced by Lady Mary Woodley Montague into England from the Near East in the early 18th century, which a person was anoculated with an actual smallpox virus, but by an unnatural root, and this, they usually resulted in a mild form of smallpox, which conferred protection against the subsequent exposure.

And in those days, the disease was so formidable that this procedure was widely used and acceptable. Of course, the real beginning perhaps of virologies with Jenna who discovered the vaccination against smallpox using a carpox vaccine of virus or vaccine of virus, which produces a trifling infection, but protects against smallpox. He was in an unfortunate position to demonstrate this protective action of vaccine because of the widespread use of the inoculation method.

He could challenge, as we say, the people whom he had vaccinated with the carpox by actually inoculating them with a smallpox virus and showing that they were protected. But then, of course, the next great advance was with Pasteur and the rabies, I would say. Of the very recent advances, I would perhaps put foremost the discovery by Geer and Shromb in Germany and Frankl Conratz, that the Bookly Virus Laboratory in California of the infectiveness of pure viral nucleic acid of the nucleic acid separated from all of, as well as they can

determine from all other constituents of the virus still shown to be capable of causing disease. And this means that this single, although very complex chemical compound, is in itself capable of initiating a multiplication of more of itself and the virus. This is a very important discovery. Not only from the viral point of view, but from the point of view of biology in general and the understanding of living processes of growth and reproduction and inheritance.

Research programs being conducted on the viruses are many and worldwide. To get some idea what things are important in research, I asked both Dr. Siverton and Dr. Enders to tell something of their current research, first Dr. Siverton. One of the research programs is concerned with viruses, particularly the Enteral viruses, which polio virus is one. This program is concerned with the mechanism of virus infection of mammalian cells, with improvements of methods for detection of these viruses, with study of the epidemiology of enduroviral diseases, and with the role of enduroviruses in congenital anomalies. A second program is concerned with biologic, genetic, physiological, and biochemical mechanisms

that determine the activity of the animal cells and their response to virus infection, including malignant alteration. A third program is concerned with the study of human normal tissue and tumor specimens obtained at operation biopsy to isolate cancer-causing viruses if present. The three programs and the training program are interlocking. We are studying destructive viruses, animal cell hosts, and tumor viruses at the same time because every advance in one area stimulates advances in the other. The research experience provided by the three programs is valuable to train more researchers, and this we believe is a function of the associated training program.

To mention briefly, three studies in my laboratory that have excited us most recently, two of my associates, Drs. McLaren and Holland, have succeeded in infecting normally immune cells, refractory cells, with an assortment of enduroviruses, including the virus apoiol myelitis, by using only the ribonucleic acid fraction of the virus' nuclear protein of the whole virus. Another associate, Dr. Brand, has been studying immunological differences in cells of different species origin. Dr. Claussen is studying the chromosome constitution of human cells of normal and malignant origin, first as means of identifying altered cells, and secondly as a possible means of recognizing the effect of tumor virus infection.

I mention these among the studies from our other associates, because as I mentioned earlier, we find them exciting. And now Dr. Enders tells us of his research at Boston. Well, we've been devoting a group of time, the last few years, to the study of the measles virus, specifically attempting to prepare a vaccine consisting of living attenuated measles of the virus that might be effective in preventing the disease. Measles is usually benign, and nobody worries much about it, but occasionally it's followed

by rather serious consequences. Finding some parts of the world, it is a real problem, where the sanitation is poor and medical treatment is not available, so that these complications, secondary bacterial infections will also develop cause a good deal of severe illness and even death, so we've been working on those practical reasons and also because it's an interesting biological problem. And now to conclude this program, I asked Dr. Siverton for his views on the future prospects for virology. I have already indicated what certainly will be future trends in fundamental virology. General trends I feel will be concerned with problems of cancer causation primarily.

We already are engaged extensively in research to see what viruses may be responsible for human malignant disease. This interest will be accompanied increasingly by study of non-destructive viruses. To find out how viruses could confer malignant potentialies on cells, virologists and biochemists will continue to concentrate on the process of virus synthesis by cells. Other currents in virology will continue. For example, I will cite three, first many new viruses of human disease have been added to the known list in the past five years, 50 or 75, and there is no indication that the list is complete. Secondly, production of vaccines will continue to be an important activity of virologists. Thirdly, an area deserving of continued and expansive expanded study is a possible role

of viruses in congenital anomalies. Research in this area is already being supported by the National Foundation. The trends will continue to be both theoretical and practical. If in ten years or so, you were to ask again what was the most important recent advance in virology, perhaps you might receive the answer that a virus had been completely synthesized chemically. Next week, you will hear Dr. C. Walton-Lilyhigh, Dr. Willis J. Potts, and Dr. John H. Gibbon-Junior, as they discuss surgery for heart disease, the first of three programs on this subject. From the next program from the series, Human Behavior, Social and Medical Research. The consultant for this program was Dr. Fred Davenport of the University of Michigan's

School of Public Health and Medical School. Flynn Phillips speaking, asking that you join us next week and thanking you for being with us at this time. This program has been produced by the University of Michigan Broadcasting Service, under a grant in aid from the National Educational Television and Radio Center in cooperation with the National Association of Educational Broadcasters. This is the NEB Radio Network.