Scientist’s discovery revives the dreams of 'magic bullet’

Press, 17 February 1984, Page 8

Scientist’s discovery revives the dreams of 'magic bullet’

By

DAVID SPURGEON

U.N.E.S.C.O. Features

A new strategy for conquering the major parasitic diseases of the developing world has emerged from the work of a British immunologist of Argentinian origin, Dr Cesar Milstein.

It brings closer to reality the production of vaccines for these diseases, which afflict hundreds of millions of people in the world’s poorest countries. Its potential benefits are not confined to these countries alone: they could extend also world-wide, for example in diagnosis and treatment of some types of cancer. In fact, the powerful therapeutic techniques resulting from Dr Milstein’s discoveries have led to a revival of the old medical dream, long fallen into disrepute, of “magic bullets” that could be aimed at individual disease-causing organisms to destroy them without harming the rest of the body.

Dr Milstein described some of these possibilities and the events that led up to them at U.N.E.S.C.O.’s Paris headquarters recently, when he received the Carlos J. Finlay Memorial Prize for his achievements. The prize, which consists of a silver medal and a cheque for $5OOO, was presented to Dr Milstein by U.N.E.S.C.O.’s Director General, Mr Amadou-Mahtar M’Bow. The prize, named after the Cuban microbiologist whose discoveries led to the conquest of yellow fever, is financed by the Cuban Government.

Dr Milstein was honoured for work carried out with colleagues at the Medical Research Council Laboratory of Molecular Biology, at Cambridge. They devised a technique for producing chemically pure antibodies, which are the body’s principal defence against agents of disease such as viruses. The antibodies are able to seek out the agents, identify and destroy them, without harming other cells aa more generalised treatments usually do. Furthermore, the method promises to permit the manufacture of

great quantities of such antibodies by means of genetic engineering techniques. So it could lead to treatments that are not only effective but inexpensive.

Before the Milstein method was developed, antibodies had been widely used in medical diagnosis to identify disease agents, but these antibodies were only obtainable in non-specific mixtures. That is, they would recognise all sorts of foreign substances in the body, from germs to chemicals taken in from the environment. In other words, one lock could be fitted by many different keys.

Immunologists had long dreamed of finding a way of obtaining antibodies so pure that they would be able to recognise just one particular antigen — a key that would fit just one lock. It was this that the Milstein method accomplished. Dr Milstein and his co-worker, G. Kohler, discovered the method by accident, as he describes it. They were trying to understand how it is possible for an organism to synthesise millions of different molecules in seemingly endless variety, as the body does antibodies. What was the genetic basis for this ability? How could cells do it?

In the course of their experiments, they discovered that, if they made hybrid cells from human cancer cells and cells from a mouse, the hybrids would produce only the specific kind of antibody they required. (Cancer cells were chosen because they reproduce indefinitely in a test tube, just as they do in the body). They were then able to clone these hybrids; that is reproduce successive generations with identi-

cal genetic characteristics which also produced only this specific antibody. These were dubbed “monoclonal antibodies,” and the process gave them a practically unlimited supply of the antibody. The medical implications of this discovery soon became apparent to Dr Milstein. Describing them in his speech accepting the Finlay Prize, he said:

“By developing a battery of monoclonal antibodies, then testing them one at a time to find out which of them is able to act in the expected manner, we can purify large amounts of that material. We can then study it and eventually develop — possibly by modern genetic engineering methods — ways of producing large amounts of that antigen without having to grow the parasite, and to isolate and purify from it the antigen to be used for vaccination.”

Dr Milstein gave as one example of the possible applications of these findings the identification of rotaviruses, which cause childhood diarrhoea, particularly prevalent in poor countries. Five hundred million children suffer from these diseases, and more than 20 million die from them annually. “In the past,” he said, “recognition of the presence of this virus required lengthy and expensive operations, and was only possible in highly sophisticated diagnostic laboratories. Recently, monoclonal antibodies have been developed and can be used for fast, simple, and cheap diagnosis of rotarival infections.”

The ideal situation, Dr Milstein said, would be to develop methods so cheap and easy to use that a country doctor could use them in

rural areas of developing countries. Doctors in such situations are often hampered by not knowing what is causing a particular case of diarrhoea, and thus cannot easily prescribe treatment.

Diagnosis of the causative agent would help them to provide appropriate treatment. Eventually a vaccine might be developed to prevent children from contracting the infection in the first place. Dr Milstein also spoke of possible applications in the control of other parasitic diseases. The major scources worldwide are malaria, schistosomiasis, onchocerchiasis, filariasis, trypanosomiasis and leprosy.

Malaria is the most important single disease in sub-Saharan Africa and one of the most significant elsewhere. A million children a year die from it and half those up to the age of three are affected by it.

Schistosomiasis, a water-borne disease carried by a snail, is found in Africa, Asia, South America, and the Caribbean. An estimated 200 million people are afflicted by it, with 600 million at risk.

Onchocerchiasis, which causes what is commonly known as “River blindness,” and is transmitted by a blackfly, is found in Africa and areas of Central and South America. It sometimes blinds as many as one-fifth of the people living in a single village.

By the beginning of this decade, according to a United Nations study, malaria was increasing and no safe drugs were available for treatment of onchocerchiasis on a community basis. The other parasitic diseases are also poorly controlled.

The biggest obstacle to the development of diagnostic tests and vaccines for these diseases, said Dr Milstein, stems from insufficient understanding of the strategy adopted by the parasite to circumvent the body’s natural immunological defenses.

The parasites exhibit many different antigenic structures, characterising different stages of their growth in the host. Not all of these are critical in providing immunity to infection, however. The most important are those involved in the early stages, but the early stages of the parasite cannot easily be grown in the laboratory. “The major difficulty in clafifying this situation in order to develop the necessary vaccines, therefore, is the identification of the specific antigen,” Dr Milstein said. And such identification is precisely what his method does best.

Dr Milstein made a strong plea for adequate funding of basic research during his presentation, noting that it was this kind of research that led to his discovery. He concluded his presentation with a story of Bernardo Houssay, the physiologist who was Latin America’s first Nobel Science Laureate, to illustrate his strong feelings about the need for support of basic research, even in developing countries.

Houssay, said Dr Milstein, was once asked by a journalist whether it was too much of a luxury for a country like Argentina to support basic research. Houssay replied: “Sir, we are an under-developed country. We cannot afford to be without basic science.”

A key for one lock

diseases

Uncontrolled