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• Dr. Albert Bruce Sabin (born 1906) ( "After completing his medical training, [Dr. Robert Merritt Chanock (born 1924)] did a fellowship Cincinnati's Children's Hospital, where he worked under [Dr. Albert Bruce Sabin (born 1906)], who called Chanock his "star scientific son." " ... [HK00A0][GDrive] )

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https://www.nytimes.com/1981/01/13/science/imaginative-researcher-wages-30-year-war-against-viruses.html?searchResultPosition=4

1981-01-13-nytimes-imaginative-researcher-wages-30-year-war-against-viruses.pdf

IMAGINATIVE RESEARCHER WAGES 30-YEAR WAR AGAINST VIRUSES

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By Harold M. Schmeck Jr.

• Jan. 13, 1981

THE human population is a hunting ground for viruses that stalk every man, woman and child throughout life. Only a few persons ever turn the tables to pursue, capture and defeat these universal predators. Among those few is Dr. Robert M. Chanock of the National Institutes of Health, a specialist in virus research for 30 years. His team at the National Institute of Allergy and Infectious Diseases, a unit of the N.I.H., continues to score victories and broaden the scope of human knowledge of virus infections. Their formula; a blend of imagination, scientific creativity and much persistent hard work.

''Our motto is: do whatever we have to do to solve a problem,'' says Dr. Chanock. Today his main research role is that of director, collector of talented staff, catalyst of ideas, polisher of the many scientific papers his team puts out. Colleagues say he is equipped for his role by a voracious appetite for reading The Scientific Mind One in a series of articles that will appear from time to time on the creative process in science. everything in his field, a sharp, retentive mind, rigor in compiling airtight scientific evidence, persistence and infectious enthusiasm. He appears to be one of those scientists for whom the research is the whole game, who needs no flamboyance.

''He is very low-key when you talk to him, but very clear,'' said Dr. John Seal, deputy director of the institute. ''People don't come away from talking to Bob with much doubt about what they've heard.''

A visitor is likely to come away with a clear perception of another trait - modesty. When pressed for details of his own work, Dr. Chanock strays soon into enthusiastic accounts of what his colleages are doing - the immune electron microscopy work of Dr. Albert Kapikian, Dr. Ching Juh Lai's skill in what laymen call genesplicing; the ingenuity of Drs. Richard Wyatt and Harry Greenberg in persuading viruses to grow in laboratory cultures. Dr. Chanock cites many examples from his group and from collaborators elsewhere in a rapid stream of narrative that makes it all clear - and exciting. Press him again for his own contributions and again the tapestry broadens quickly to show the contributions of everyone else.

Confronted with this trait, Dr. Chanock explains that there is a reason - collaboration is the lifeblood of modern virus research, which necessarily covers a huge panorama of science, from studies of the molecules of heredity to the disease history of human populations. It takes many different skills. To his colleagues and former mentors, however, Dr. Chanock's role appears crucial.

''He is my star scientific son,'' said Dr. Albert Sabin, one of the great figures in modern virus research. ''He is a brilliant leader,'' said a colleague at the N.I.H. Early in his career, Dr. Chanock discovered the first virus known to cause croup, the illness of paroxysmal coughing in young children. Later his group proved, against the scientific dogma of the time, that some organisms of the strange group called mycoplasma are important causes of human pneumonia. A Beginning in Science

Dr. Chanock, a tall, gray-haired man of medium build, has a passion for classical music as well as science. He trained as a pediatrician at the University of Chicago, worked for several years under Dr. Sabin, and chose early to pursue the unknown viruses that assaulted the lungs and air passages of babies and young children. Waves of illness every year brought many infants, blue of skin, gasping and coughing, to hospitals whenever and wherever the epidemics struck.

The group Dr. Chanock directs at the institute was the first to capture on film the image of a virus called the Norwalk agent. The feat led them to link it unmistakably with what laymen call ''intestinal flu.'' They developed the first effective vaccine against adenoviruses, a major cause of illness among military recruits. It was licensed last year after a decade of research.

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Recently the team succeeded in growing in the laboratory two other viruses, called rota viruses, that are probably among the most important causes of human infection and death. Every year, from fall through early spring, rota viruses invariably cause epidemics of diarrhea in the world's great urban centers, including New York. In tropical regions, the epidemics simply continue year after year. Public health experts estimate they cause five to 10 million deaths a year, most of the victims children.

Discoveries like these do not come easily. Finding viruses is sometimes difficult, requiring inspired guesswork as to what tissues should be searched, how and with what special techniques the search should be done. Sometimes the finding of viruses is all too easy, but identifying a given virus with a specific disease is another matter. Once found, some viruses seem almost impossible to grow in the laboratory for research and vaccine development. Each step in the research has its own difficulties and pitfalls. Credit to Former Colleagues

Dr. Chanock, a believer in the apprentice system of training in science, credits much of his research style to Dr. Sabin and to Dr. Robert Huebner of the National Cancer Institute.

''In a sense Bob Huebner and Albert Sabin are more responsible for the things I have done than I am,'' Dr. Chanock told a recent visitor to his laboratory. From Dr. Sabin he learned the discipline of being rigorous in evidence and proof. Dr. Huebner showed him vistas of creative imagination in how to attack a problem in any or all of the ways that might bring a solution.

He also inherited from Dr. Huebner an office in Building 7 on the N.I.H. campus in Bethesda that had long been crammed with Dr. Huebner's papers, reports and journals. Today it is so filled with similar material, collected by Dr. Chanock in the same style, that the scientist sometimes seems in danger of being crowded out of his own chair.

Dr. Chanock's group has had many successes and some bitter disappointments. They found the first human virus of a family called respiratory syncytial viruses that are among the major threats to the lives of young children. They tried to make a killed virus vaccine. It was a tragic failure, actually making some of the children's virus attacks worse. The reasons, unpredictable at the time, are now believed to be quirks of the interaction between the killed virus and the person's immunological defenses. The research team tried to develop a live virus vaccine, so far without success.

Their attack on the adenoviruses, on the other hand, was a dramatic success. In its later stages, the effort was a collaboration with specialists at Walter Reed Army Medical Center. Recruits are given the vaccine - one tablet taken by mouth - at the start of training or whenever an epidemic threatens. Few if any of the young men and women entering the services realize what coughs and fevers and debility their single gulps prevent. Organ Cultures a Turning Point

The discovery that slices of human intestine and other organs could be maintained as living, functioning tissues in laboratory flasks brought a key turning point to the team's research, Dr. Kapikian said, because of a brilliant insight by Dr. Chanock. The socalled ''organ cultures'' were perfected initially for study of respiratory viruses, the main concern of the team at that time. Some respiratory viruses that do their damage in the lungs and bronchial passages grow first in the intestine.

But the availability of intestinal slices growing in the laboratory gave a new way of studying viruses that cause disease in the digestive tract, Dr. Kapikian said. He noted that Dr. Chanock saw this and launched the laboratory into major efforts on gastroenteritis viruses. This field has given the team their successes against the Norwalk agent and rota virus.

Within the past year, the research group at the institute has succeeded in growing in the laboratory both of the known types of rota virus that infect humans. Their success opens the possibility, for the first time, of developing a vaccine. No one can say how the current work, just now turning toward the possibility of a vaccine, will turn out. Conceivably, the rota virus work could lead to disappointment, as did the vaccine against respiratory syncytial virus.

It could also lead to a success as clear as that against the adenoviruses, but with far broader implications for public health. The answer may come soon from a red brick building in Bethesda, crammed from basement to roof with equipment, books and journals, scientific reports, enzymes, virus specimens and some of the most creative minds in modern biological science.

1984 (April 29) - NYTimes : "THE NEW AGE OF VACCINES"

By Harold M. Schmeck

• April 29, 1984

https://www.nytimes.com/1984/04/29/magazine/the-new-age-of-vaccines.html?searchResultPosition=9

1984-04-29-nytimes-the-new-age-of-vaccines.pdf

OURTEEN LITTLE PLASTIC dishes, pink because of the nutrients in them, lay on a stainless-steel sheet on the laboratory bench. There were tiny white pockmarks in the gelatinous culture medium. ''Each of the white marks is a clone started from a single virus particle,'' said Dr. Bernard Moss of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., pointing to one of the dishes.

He was talking about vaccinia viruses, possibly descendants of those used by Edward Jenner almost 200 years ago to protect humans against smallpox. Dr. Jenner's was the world's first and most successful vaccine. But these 20th century specimens have possibilities that he could never have imagined. They have been genetically engineered to protect people not only against smallpox, but also against totally different viruses that were unknown until recent years. These rebuilt viruses represent the cutting edge of a new vaccine strategy against disease, one of several ideas that could have profound effects on public health in the years to come.

VACCINES ARE AMONG THE MOST POtent weapons ever devised against infectious diseases. Yet many grim plagues of humans and animals remain beyond their reach. In the United States, herpes viruses cause illness in millions of people. Many of the infections are transmitted through sexual intercourse, and a number of them may contribute to cancer. There is no vaccine.

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In some regions of the third world one baby in every four dies before its first birthday. Diarrhea from viruses and bacteria and the devastating effects of parasite diseases such as malaria are important factors in these deaths. The infections conspire with malnutrition to end millions of lives almost before they have begun. (Paradoxically, this toll in babies' lives only aggravates overpopulation, the world's greatest public health problem. Couples who want a family and know their babies are likely to die are not enthusiasts for family planning.)

In Asia, some 200 million people have liver disease caused by the hepatitis B virus and act as carriers to spread it to others. Many children are infected within their first few months of life. The liver infections almost certainly help produce liver cancer. In large areas of southern China and Southeast Asia, liver cancer is the leading cause of cancer deaths.

Vaccines might prevent much of this illness and death, but today they are either lacking altogether or far too expensive for the third world to use. In recent years, in fact, vaccines seemed to have been coming to the end of their long, fruitful road. Vaccine makers were getting out of the business. There seemed to be few new ideas on the horizon. The swine flu program of 1976, in which more than 40 million Americans were immunized against a virus that never appeared, gave vaccines an undeserved bad name.

Now the outlook is dramatically different. Experts foresee greatly improved vaccines against flu, cholera and several other diseases. Public health experts hope that worldwide diseases like malaria and hepatitis B may be conquered. New vaccines are envisioned for some infections that may be linked to cancer.

MANKIND IS NOW ON THE THRESHOLD OF A new era in the technology of vaccine development and production,'' said Drs. G. C. Schild and Fakhry Assaad of the World Health Organization. Their optimism stems from several new strategies, each made possible by discoveries in the esoteric science of molecular biology, particularly the techniques of recombinant DNA technology known as ''gene splicing.'' Scientists know how to read the messages encoded in genes. They can take genes apart, add new parts to the message and fabricate totally artificial genes.

In one of the new strategies, genes of flu viruses have been reassembled to make a new virus which, though harmless, has a surface identical to that of the flu virus that causes illness. The virus works by a kind of benevolent trickery. The human immune system reacts defensively against its surface, and immunity is stimulated without illness.

Every flu virus has eight genes, each physically separate from the others. In the new vaccine, six come from a harmless laboratory version of the virus. The other two, which give the virus its surface profile, are borrowed from one that causes disease. (See diagram on page 83.) Until the present, such manipulations of virus structure could be done only by indirect and imperfect means. Now, the genes themselves are known quantities that can be manipulated almost at will. Scientists reported just a few weeks ago that viruses with reassorted genes can protect against influenza.

Unlike the flu vaccines in current use, the new one is made from live, rather than inactivated, viruses and is introduced into the human body by nose drops rather than by injection. The nose-drop method is much more convenient for the patient and, researchers have found, also gives a better quality of immunity against flu. The report of this advance, published in the British scientific journal The Lancet, was by Dr. Mary Lou Clements, University of Maryland., Dr. Robert F. Betts, University of Rochester, and Dr. Brian R. Murphy, National Institute of Allergy and Infectious Diseases.

Another vaccine strategy, developed largely at the Research Institute of Scripps Clinic in California, uses totally synthetic

VACCINE JUMP Page 81 & 82 vaccines made from artificial chemicals. A short string of chemicals is put together in the laboratory in such a way that it simulates a portion of a virus. A person's immune defense system is tricked by this substance into thinking it has encountered a whole virus and builds immunity to it. It is as if, looking at a photograph, you recognize your Uncle George, even though only an eyebrow, eye and part of a nose are visible. In the same way, the immune system can recognize, say, a hepatitis virus when it ''sees'' only a corner, an elbow, of a molecule that ordinarily protrudes from the virus surface.

A third revolutionary strategy is that of bringing vaccinia virus, the virus that protects against smallpox, out of retirement and giving it a whole new career - indeed a new set of careers - by fitting it up with new genes and giving it identities the vaccinia virus never had before.

In a fourth strategy, scientists using the gene-splicing techniques have made it possible to grow in harmless bacteria large quantities of substances that can be used as the active ingredients of vaccines.

These and other new strategies are startling. Nothing like any of them has ever been possible before. The work with the vaccinia virus, for one, is in concept as strange as the idea of sprouting the wings of sparrows on laboratory mice. Each of the new ideas has generated controversy. Each has its enthusiasts and its doubters. There are some people who oppose many of the new strategies simply because they involve recombinant DNA techniques. Some opponents object to all aspects of gene-splicing work, either as improper interference with the course of natural life on earth or because they fear a new source of environmental pollution in the products of this powerful biotechnology.

Among the new ideas for vaccine development, that of bringing vaccinia virus out of retirement is perhaps the strangest and the most controversial. But some scientists believe it may also be among the most promising. The idea has an element of poetic justice, too, because vaccinia was the first and, by long odds, the most successful vaccine ever made.

Vaccination began almost 200 years ago because Dr. Jenner noticed that people who milked cows often had a mild infection called cowpox, and that these same people were almost all immune to smallpox. So he infected patients with material from cowpox sores. In those days, no one realized that the two diseases were caused by different viruses. No one really knew what a virus was. But Jenner's inspiration worked, and the modern era of vaccination was born. (The word vaccine came from the Latin for cow.)

For almost a century, the vaccine against smallpox was the only vaccine in existence. Like many developments in medicine, it started out in fierce controversy. Cartoons in the British press showed people with the horned heads of cows growing out of their arms after vaccination. Epidemics of smallpox continued even after the controversy abated.

What might have been the final chapter of vaccinia's use ended in 1977 when a 10- year effort, marshaled worldwide by the World Health Organization in Geneva, succeeded in eradicating smallpox. Today, although the United States' armed forces require vaccination in some circumstances, as do those of the Soviet Union and perhaps a few others, routine vaccination of civilians is a thing of the past.

Dr. Moss and his colleagues at the infectious diseases institute and another research team led by Dr. Enzo Paoletti of the New York State Department of Health have, independently of each other, redesigned the vaccinia virus to produce an entirely new breed of live-virus vaccine. Laboratory animals were innoculated with the new vaccines, exposed to germs and then monitored to see if they resisted disease. In this way, retooled vaccinia viruses have already been used to protect mice against herpes viruses, chimpanzees against hepatitis B and hamsters against flu viruses. And this is only the beginning.

All of these seemingly bizarre feats depend on modern knowledge of what a virus is and how it causes disease.

Viruses occupy a strange niche on the borderline of life. Unable to move by themselves, metabolize foods or even reproduce without help, they seem lifeless. Some viruses have actually been reduced to the form of crystals.

But once a virus invades a living cell it can reproduce. This happens because viruses are really little more than packaged genes, itinerant sets of instructions drifting about in the world until they find living cells to inhabit. Once they find such a home, their genetic instructions can be carried out.

Each virus consists of a core of nucleic acid, either DNA or RNA, surrounded by a coat of protein. (Living cells, of course, contain both these nucleic acids. DNA, deoxyribonucleic acid, is the active substance of the genes of all living things. It carries the blueprints of heredity in every microbe, plant and creature. RNA, ribonucleic acid, translates those instructions into action. It controls the manufacture of the substances each cell needs.) When a virus encounters a living cell it attaches itself and inserts its nucleic acid. Infection has begun.

The cell accepts the foreign genetic instructions and manufactures a whole new crop of virus particles identical to the original. Usually, when the new crop of viruses has been made, the cell dies and the new virus particles emerge to infect other cells. The effects that humans recognize as symptoms are the results of cell damage and the reactions of the body's immune defense system to the assault.

But, while the nucleic acid does the subversion inside the living cell, it is the virus's surface coat of protein that gives it its identity so far as the body's immune defenses are concerned. The structure of this coat also determines what cells a virus can penetrate. Only if the surface of the virus has something on it that matches a part of a cell's surface - like a key fitting its lock - can the virus invade and infect. The body's immune defenses recognize the viral surface shapes and make defensive antibodies that match those shapes.

The whole art of vaccine design is really a matter of exploiting the crucial shapes. In conventional vaccines against virus diseases, this is done either by killing viruses and putting them whole into the vaccine or by choosing a harmless variant of a live virus.

Conventional flu vaccines and the original Salk vaccine against polio are examples of killed-virus vaccines. They can be highly effective but do not often give long- term immunity.

Live virus vaccines, such as the Sabin polio vaccine, are made of viruses that have undergone mutations - genetic changes - that render them harmless without altering the surface characteristics that make them ''immunogenic,'' that is, capable of eliciting an immune response.

The attempts to use redesigned vaccinia virus for new vaccines are based on the strategy of placing within it genes from other viruses. When the resultant hybrid virus reproduces, it will carry a trait of another germ on its surface but will have no increased potential for causing disease. Vaccinia virus is one of the largest viruses known, and its inner core of DNA contains enough material for at least 100, perhaps 200 genes. If molecular biologists can add a message to the DNA of vaccinia so that it carries instructions for making not only all of its own necessary parts, but also a key surface protein of another virus, then each new crop of vaccinia virus particles will have a dual identity. The human body will respond by making protective antibodies not only against the original virus, the one that protects against smallpox, but also against the one whose identifying substance has been added - one causing herpes, say.

Dr. Paoletti of the Albany group estimates there is room in the vaccinia virus DNA for insertion of at least a dozen foreign genes. These could transform the vaccinia virus into a multipurpose vaccine that might protect, for example, against hepatitis, herpes and, conceivably, even important nonvirus diseases such as gonorrhea and malaria.

Some public health experts who helped drive smallpox out of existence are enthusiastic about this new role for vaccinia, which can be given almost anywhere, cheaply, efficiently and effectively. For many diseases that plague the third world, it seems ideal.

But there is controversy about the possible new uses of vaccinia. The virus itself is not totally harmless. About one in 100,000 people who receive the vaccine have serious reactions, which can include encephalitis. If the alternative is smallpox, the risk is worth taking, but no one would advise giving this virus for less than urgent reasons.

Dr. Maurice R. Hilleman of the drug company Merck Sharp & Dohme notes that vaccinia is a live virus and suggests that manipulating its genes in the laboratory might have unexpected dangerous effects. Dr. Hilleman, an urbane but bluntly outspoken scientist and one of the world's leading experts in vaccine research, favors a different use of gene-splicing techniques to produce a vaccine that would be completely harmless.

Again, the idea boils down to a matter of shapes. Scientists find a gene that represents the instruction code for making a protein of the virus

VACCINE JUMP PAGES 84 & 86-87 surface. They put that gene into bacteria or yeast capable of putting the gene's instructions to work. The microbes produce the protein, which can then be harvested for use as a vaccine. In theory, the product ought to be totally harmless because it contains nothing but the surface protein.

Under Dr. Hilleman's direction Merck has already produced a safe, effective vaccine against the hepatitis B virus. It has been on the market for more than a year under the trade name Heptavax-B and is already widely used in the United States to protect hospital workers and others who are at high risk of infection with the virus. Since hepatitis B may be a key factor in the cause of liver cancer, particularly in Asia, a vaccine against the disease could also turn out to be the world's first effective anticancer vaccine.

But no one expects that Heptavax-B will solve the world's 200 million cases of liver infection. The way the vaccine is produced explains why. To date no one has found a practical way of growing the hepatitis B virus in the laboratory. The vaccine makers solved this problem by letting natural infections do the job for them. When the virus grows in its human victims it makes a large excess of a substance that makes up part of the surface of the virus particle. It is known as the hepatitis B surface antigen. Clumps of it circulate in the hepatitis patient's blood as tiny particles.

To make the vaccine, these particles are harvested from blood donated by persons who are infected carriers of the virus. The particles are extracted from the donor's blood and are purified to eliminate all trace of the virus itself and everything else that might be harmful. The harvested particles become the vaccine.

But it takes nearly a year to make a batch of the vaccine, and a series of three shots costs about $100. Although considered safe and effective, the vaccine is too expensive for the regions of the world where it is needed most.

Some extraordinary talents of the gene splicers may be coming to the rescue, however. In January, Dr. Hilleman's group at Merck published a report in the scientific journal Nature saying they had grown the hepatitis B surface antigen in cells of brewer's yeast, harvested the particles - they looked just like the particles found in human blood plasma - and used this material to innoculate chimpanzees and protect them against the dangerous liver infection. ''This is the first example of a vaccine produced from recombinant cells which was effective against a human viral infection,'' they wrote in the report.

The vaccine project has been a collaboration between the team at Merck and scientists led by Dr. William Rutter of the University of California, San Francisco, and Dr. Pablo Valenzuela of Chiron, a biotechnology firm in California. Dr. Valenzuela is a specialist in adapting yeast cells to gene-splicing technology. Hepatitis vaccines produced through similar genetic-engineering techniques are being developed by several other companies here and abroad. The international company Biogen has also protected chimpanzees in tests of another hepatitis vaccine.

Hepatitis B is only one among many important possibilities for such genetically engineered vaccines. They are called ''subunit vaccines'' because they consist not of whole viruses, but of carefully selected pieces of the virus, usually proteins of the particle's surface. Such vaccines would be easy to produce and would be safer than any conventional vaccine, because there would be no virus in them at all.

Among these vaccines, applications to veterinary medicine have run ahead of those for human medicine. Cetus Corp. in California and Norden Laboratories in Nebraska have already marketed jointly a vaccine against scours, a widespread diarrheal disease of pigs and calves. Genentech, of South San Francisco, one of the most successful American gene-splicing companies, has collaborated with the United States Depart ment of Agriculture in an effort to develop a subunit vaccine against foot-and-mouth disease, one of the most devastating virus diseases of livestock throughout the world.

But subunit vaccines do not always give strong immunity. Nobody yet knows exactly why, but it may be, again, a matter of shapes. Within the tight architectural constraints of the virus's surface, a protein may take a different conformation than it would when free and separate. Perhaps this makes a difference in the way the body's immune defense system ''sees'' the invader.

Among the new strategies of vaccine design is work that makes maximum use of the shapes of certain proteins. The idea was pioneered by Dr. Richard A. Lerner of the Research Institute of the Scripps Clinic in La Jolla, Calif., and by Dr. Eckard Wimmer of the State University of New York, Stony Brook. The logic is quite simple: if the body's immune defense system makes antibodies against invading viruses on the basis of parts of the shapes their surfaces present, why bother with the virus itself or even with its products? Why not just mimic the key shapes?

There were many who thought this idea did not have a prayer of working. Although proteins are really nothing more than long chains of amino acids, the components come together in intricate forms. Would it ever be possible to learn just which portions of such a form could be used to suggest the whole thing? Dr. Lerner and his colleagues started a few years ago with the influenza virus.

Dr. Ian A. Wilson and Dr. Don C. Wiley of Harvard with Dr. J. J. Skehel of Britain's National Institute for Medical Research in London, pursuing research aimed at discovering how flu viruses cause infections, had already worked out the three-dimensional structure of a key protein of the flu virus surface. This is a protein called a hemagglutinin. It forms spikes that stick out of the roughly spherical surface of the virus. A human exposed to flu will make antibodies against it. The spikes are also important because they enable the virus to stick to a living cell and begin the process of invasion.

Analysis of the structure of the hemagglutinin molecule showed what portions of the protein were on its surface. This provided hints of what portion might be used to elicit antibodies. But the whole protein consists of hundreds of amino acids and it was not at all clear that any short strings of eight to a dozen or so would stimulate immunity.

To test the idea, Dr. Lerner's team used the known structural and genetic blueprints to make 20 different short chains of amino acids that corresponded to about three-quarters of the protein's total. They attached each of these to a large carrier protein and tested each in rabbits to see if the animals would make antibodies. To their delight, the scientists found that 17 of the 20 reacted with the whole virus.

''In other words,'' said Dr. Lerner, ''a short string from almost any region of a viral protein can elicit an antibody that will recognize the entire protein.''

The main requirement seems to be the selection of a piece that would be on the outside of an intricately folded protein.

Knowing this rule, the scientists have used a computer to determine which portions of a protein are likely to be on the surface and are therefore good candidates for making a synthetic vaccine.

There are also certain tricks of the trade that make it possible to do it without the computer. Such is the sophistication of today's molecular biology that a scientist can simply look at the DNA code of instructions for making any protein and make a shrewd guess as to which parts of the protein are likely to lie on its surface.

Dr. Lerner and his team have made synthetic mimics of viruses that cause several important human diseases, including flu and hepatitis. Unlike all the virus vaccines made during the past two centuries, these have nothing in them that were ever part of any virus. They are artificial concoctions made from ordinary off-the- shelf chemicals. Yet they can make the body think it has encountered a natural, disease- causing virus.

Collaborating with the group on the West Coast, Dr. Robert Purcell and his colleagues at the National Institute of Allergy and Infectious Diseases have protected chimpanzees against hepatitis by using an artificial string of 27 amino acids that mimics just part of a surface protein of the hepatitis virus.

While the Genentech-United States Department of Agriculture group was putting together a foot-and-mouth-disease vaccine using the more conventional techniques of gene splicing, Dr. Lerner's group, collaborating with British animal disease experts, was assembling their own off- the-shelf synthetic vaccine against the same disease. It has already been successful in experiments in protecting animals against foot-and- mouth disease.

So far as human disease is concerned, though, there is a serious drawback to synthetic vaccines. The short strings of amino acids are too small by themselves to produce much immune response. That is why Dr. Lerner and his group at Scripps tied them to larger proteins in the original experiments. To be effective they all seem to need something called an adjuvant, a substance that sharply accentuates the immune response. Unfortunately, today's most powerful known adjuvants are too corrosive for use in humans. They cause sores and abcesses at the point of injection. One of the current needs of the field is a new and better adjuvant that can be used in vaccines for humans.

The new techniques of biology allow vaccine designers to do things with precision that they used to do almost blindly, and to discover causes that had always been obscure.

To make a live virus vaccine, for example, it has been necessary to take a virus known to produce disease and grow it in the laboratory until the vaccine makers get at least one strain that has become harmless. Dr. Edwin D. Kilbourne of Mount Sinai School of Medicine says this is much like animal husbandry. The research workers grow a virus in the laboratory under abnormal conditions of temperature or in cells to which the virus is not accustomed, knowing that mutants, arising spontaneously, will grow if they can profit from the conditions. These same mutants, however, will be at a disadvantage when they try to multiply in the human body. They might, therefore, make safe and effective vaccines.

Today, that somewhat hit-or- miss process can be streamlined. A virus's traits can be changed deliberately by deleting small, precisely known pieces of its DNA or RNA. In short, today mutations can be made to order.

In a recent conversation, Dr. Robert M. Chanock, a virus expert at the National Institutes of Health in Bethesda, Md., cited some recent work at the Centers for Disease Control in Atlanta. He noted that some rare cases of paralytic polio arise from taking the polio vaccine. These cases, he said, seem linked much more often to the polio virus known as type 3 than to either of the other types that go into the vaccine. Until recently no one had any idea why this was true. Close study of the genetic material of the polio virus by scientists in England now offers an explanation. The vaccine virus of type 3 differs from the disease- causing ''wild type'' virus by mutational changes in only 10 of the thousands of molecular subunits in the virus's DNA or RNA. In type 1, the mutations total five times as many. The case with type 2 has not yet been checked, but the numbers arrived at so far explain why it is easier for type 3 to revert to the wild type. An important lesson from this, according to Dr. Chanock, is that the techniques of modern biology offer better ways of modifying viruses and other causes of disease to make much better and safer vaccines. It is a matter of specific mutations made to order.

One of the newest and most promising examples of this kind of genetic manipulation comes from the Center for Vaccine Development, University of Maryland School of Medicine, Baltimore. A team led by Dr. Myron M. Levine and Dr. James B. Kaper has done genetic surgery on the bacteria that cause cholera. They have produced something they hope will become a new, more effective, vaccine against that disease.

''Despite nearly a century of effort, a satisfactory cholera vaccine is not yet a reality,'' Dr. Levine and his colleagues reported this month in Bio/ Technology.

They have developed something better by finding those genes of the cholera germ that are the keys to its production of cholera toxin, the poison through which the bacteria do their harm. The scientists then used gene-splicing techniques to make a specific laboratory- designed mutation. They constructed a new gene that was missing most of its parts. Cholera bacteria that are modified in this way stimulate immunity to cholera but do not produce the dangerous toxin. Again, it is a matter of benevolent trickery. These genetically engineered microbes have already protected human volunteers against the disease. They represent, in the scientists' view, ''the beginning of a new generation of cholera vaccines.''

Dr. Chanock is among those scientists who see a new era ahead in which vaccines may do things for world health that were unimaginable just a decade ago. The most sophisticated talents of modern biology will be needed to bring them to fruition, but, ultimately, they all stem from the inspiration Dr. Jenner had two centuries ago when he foresaw the end of smallpox, a disease that had maimed and killed millions from the dawn of history but does so no longer.

https://www.nytimes.com/1994/02/15/science/a-novel-genetic-therapy-holds-promise-in-treating-pneumonia.html?searchResultPosition=3

1994-02-15-nytimes-a-novel-genetic-therapy-holds-promise-in-treating-pneumonia.pdf

A Novel Genetic Therapy Holds Promise in Treating Pneumonia

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By Lawrence K. Altman

• Feb. 15, 1994

A novel immune therapy has cured a respiratory viral infection in mice, and a scientific report issued today says it holds great promise for treating the most common cause of pneumonia in infants and young children.

Experiments to prove the therapy's effectiveness in humans have yet to be done. But in a report in The Proceedings of the National Academy of Sciences, the authors said success with the animal experiments "may signal the beginning of an era of immunotherapy" for many serious human viral infections, including influenza.

The virus targeted by the new therapy, respiratory syncytial virus, or R.S.V., takes a heavy toll on people throughout the world. The infection causes an estimated one million deaths a year worldwide, principally in developing countries.

In the United States, R.S.V. is the chief cause of early childhood viral pneumonia and bronchiolitis and leads to the admission of 90,000 children to hospitals each year. The infection often requires intensive respiratory care, including use of mechanical ventilators.

The new therapy can be likened to a targeted missile in which a genetically engineered immune substance is introduced directly into the lungs. The immune substance, known as Fab, is a tailor-made piece of a human antibody. Antibodies are the proteins that defend against the invasion of viruses and other microbes.

Last year in a preliminary report the scientists said they were "astonished" by how effective the Fabs were in the animal experiments. The Fabs are part of a broader area of research interest in the use of human viral antibodies to prevent and treat many viral infections. Targeting Specific Viruses

Gamma globulins, which contain groups of antibodies, have long been used to treat certain infections such as hepatitis A. But only a small proportion of gamma globulins are specific for particular antigens, the foreign substances that stimulate the immune system to produce antibodies.

With new techniques, scientists have developed more specific antibodies, known as monoclonal antibodies, that can be directed against certain antigens in viruses. Scientists are using monoclonal Fabs, which are tiny pieces of immune substances in the blood called immunoglobulins, to identify the number, relationship and relative importance of protective antigenic sites on the surface of many viruses to determine how the human immune system "sees" them.

In the experiments, the researchers cured the infection in mice by introducing small amounts of Fabs directly into their lungs. The research was carried out by scientists at the National Institute of Allergy and Infectious Diseases, a Federal agency in Bethesda, Md., and at the Scripps Research Institute in La Jolla, Calif.

"This is the first time that a study has demonstrated the successful use of recombinant Fabs in a therapy for a viral infection in an animal," Dr. Dennis R. Burton, one of the authors from Scripps said in a news release issued by the Federal institute in Bethesda.

Although the research represents a significant advance, there is no assurance that what works in animals will work in humans.

The virus's chief targets are children 2 years old and under. About half of the infections occur before age 1, with the peak age being about 2 months, and re-infection is common among children, Dr. Robert M. Chanock, the head of the National Institute of Allergy and Infectious Diseases team, said in an interview. Decadelong Effort

R.S.V. can also cause serious illness in adults with birth defects affecting the heart and those whose immune systems are impaired, for example, as a result of AIDS or treatment to prevent rejection of transplanted organs.

Dr. Chanock said that for a decade his team has been working on ways to use antibodies to prevent and treat R.S.V. Studies have shown that injections of large amounts of human gamma globulin, which contains antibodies for R.S.V., protect infants and children at high risk for the infection for short periods.

Dr. Chanock's team found that the therapy could be made several thousand times stronger by introducing Fabs against R.S.V. into the lungs after mice were anesthetized in the laboratory. No resistant strains could be detected after such therapy, the scientists reported.

Dr. Chanock said that delivering Fabs is safer than injecting whole antibodies and that Fab therapy offers several additional potential advantages.

One is that because Fabs can be produced in bacteria by recombinant genetic-engineering techniques, such fragments are easier and cheaper to produce than whole antibodies.

Another advantage is that use of Fabs instead of the whole immunologlobulin molecules from which they are derived reduced the amount of protein in a therapeutic dose. The point is important, Dr. Chanock said, because only a limited amount of protein can be delivered safely to the lungs. Obstacles to Human Research

Nevertheless, the researchers must overcome several hurdles before they can attempt to test Fab therapy in humans.

Relatively small amounts of Fabs are needed for the mice experiments, and Dr. Chanock said the Scripps researchers could make the material in their laboratories. But he said much larger amounts will be needed for the next step in the research: experiments in larger animals such as monkeys and chimpanzees.

Another hurdle is to develop techniques to deliver the Fabs as an aerosol for eventual human use against R.S.V. Dr. Chanock said he could not estimate when human trials can begin to test Fabs.

He said his team is pursuing a different line of research, meanwhile, to develop a vaccine against R.S.V.

2010 (Aug 04) - NYTimes : "Dr. Robert M. Chanock, Prominent Virologist, Dies at 86"

By Lawrence K. Altman

Aug. 4, 2010

https://www.nytimes.com/2010/08/05/health/05chanock.html

2010-08-05-nytimes-robert-m-chanock.pdf

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