Saga of the sarcoma

The publishing house “Alpina publisher” has published a book of Virology Karin Melling “Viruses: friends rather than enemies.” “Pravmir” print Chapter “the Saga of Kaposi” about how scientists have shown a connection of viruses and cancer.

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Elusive infection

Peyton rouse, the scientist who discovered oncogenic virus, give up. As well as Galileo Galilei, who lied to the court of the Inquisition, and to save a life, abandoned their studies, rouse under pressure from colleagues stopped cancer research. They were unable to replicate his findings, and instead to solve the problem, rouse just didn’t take!

Karin Melling. Photo: moelling.ch

About 100 years ago it was established that cancer can be transmitted, like all infectious diseases in chickens. One day a farmer brought him to Rockefeller University (new York) chicken with a large tumor. The farmer feared that infected the rest of the chickens.

Rouse, an experienced pathologist, was diagnosed with sarcoma. He isolated the tumor, homogenized cells, filtered them and introduced the virus to healthy chickens. There is a new tumor. This result is consistent with the first postulate of Robert Koch, formulated in about 1880, according to which the standalone agent is considered to be the causative agent of the disease, if it excites the same disease from which was isolated for the first time.

Rouse spoke of a “filterable agent”, not the virus. He published the results in 1911. Similar results for leukemia were obtained and published by William Ellermann and Olaf Bang. But the problem was that nobody has been able to reproduce the results obtained by Routh.

At that time nobody knew about genetic resistance to viruses and cancer. His opponents used different resistant tumor agent chickens. Today, it is simple and clear. Routh was not lucky, he lost sight of the main thing.

Those chickens

Eighty years later the same thing happened to me. I didn’t know about the problem faced by rouse. What a shame! I tried to grow the virus leukemia in chickens, in order to isolate it in large quantities for isolation and study of reverse transcriptase.

For several months I was successful in this project. However, after my lab moved from the max Planck Society (tübingen) in the Robert Koch Institute (Berlin), I have no longer anything to happen. Chickens simply were not ill, and the virus to replicate without success.

Being desperate, I ordered Chicks from the original supplier — poultry farm near tübingen, although it was associated with a complicated transfer of several thousand day-old Chicks to Berlin flight PanAm, because at that time West Berlin was in the middle of the former East Germany. In the body of the chickens from the previous provider, the virus has earned.

Chickens contracted the virus (called virus myeloblastosis birds, PMF), and received a huge amount of virus. Many years later began the study of HIV. And then we first not without surprise, I realized that there are people that are resistant to this virus.

15% of Europeans do not become infected with HIV because of genetic resistance, because they have a defective receptor for the introduction of the virus into the cell (CCR5delta32).

Rouse and his colleagues simply did not think that used the “wrong” Chicks. Perhaps this knowledge would not help Routh, as if to take into account such exceptions, his conception was not accurate. But he gave up! He did not understand the significance of his observations for migration of the tumor in animals!

“Dad virus”

However, later he was recognized as the “father of oncogenic viruses” and open the first oncogenic virus was named in his honor by the rous sarcoma virus (HRV). In 1966, 55 years after its discovery, rouse was awarded the Nobel prize. He was 87 years old. He was nominated for the Nobel prize in 40 years, but in that time it has been awarded.

Peyton Rouse

He developed a method of growing the virus in chorioallantoic membranes of chicken eggs (like a small air bubble). It’s hard to believe, but according to the old-fashioned way we still use to get millions of doses of vaccine against influenza virus. The same method we used for verification of the alleged case of smallpox in the 1970s. Then the Robert Koch Institute (Berlin) with special tool we have opened the shell, was placed to a suspicious sample, closed the shell, and incubated the eggs to grow virus — in such a nourishing environment he grew up incredibly fast!

The viral protein v-Src multifunctional. Single multifunctional molecule involved at several stages of tumour formation. V-Src is shorter the same cellular protein C-Src in seven of 536 amino acids. This change may seem small, but viruses are always looking for simple solutions and a small decrease in the number of amino acids has enormous consequences — the loss of binding to the inner side of the cell surface, resulting in uncontrolled cell growth and cancer development.

The loss of even a single acid on the end has serious consequences — the behavior of cells acquires the metastatic character.

Upon discovering this phenomenon, we were so surprised — it was very hard to believe — that began to analyze it. We explained that the loss of the ability of the protein to contact a tumor suppressor that has serious consequences, leading to loss of control over intercellular interactions, resulting in cells there is a possibility to change their location, causing metastases. The next surprise was the fact that such a tiny loss of one amino acid caused a change of nearly one hundred other cellular functions. (We showed this by examining the expression profile of metastatic cells. In more detail this procedure is described in the Chapter on “-amikam”.)

Viral promoter (long terminal or LTR sequences) intensificare fusion protein v-Src. This leads to overexpression of the oncogene, which is a dangerous dose-dependent effect. Viral promoters generally regulate the replication of the virus inside the cell, avoiding the change in the function of cells, the so-called “selfish behavior” of viruses. Such viral promoters are the most powerful properties known in biology, is increased expression of viral genes, which leads to a severe overdose oncogene, “promotora” the development of cancer. It is favorite tools for gene expression in all biomolecular laboratories.

Cancer everywhere?

John Mike Bishop

In San Francisco in the 1970’s, John Mike Bishop and his assistant postdoctoral fellow Harold Varmus used the Src protein as a model for cancer research. They tried to find out the origin of this virus and found it everywhere — from flies to elephants, in normal cells, absolutely free of cancer. It was mysterious and seemed to imply a system error. They withdrew their article that was already accepted for publication and materials which have already started to circulate at the Institute of Virology of the max Planck Society (tübingen).

The problem was that the methods used did not allow to distinguish a normal gene from the Src oncogene: a slightly shorter version of this gene (oncogene) looked the same.

John Mike Bishop and Harold Varmus have solved this problem and in 1989 received the Nobel prize for his work.

I attended their celebration in a laboratory in cold spring Harbor. Michael was in a tuxedo and was holding a manuscript is usually to discuss she was never he needed. Varmus (who, as I recall, came to all the events held in Europe, on the bike and was so wet, soaking wet) looked more energetic the majority of the attendees!

They both came to my laboratory in the max Planck Society (Berlin) and asked about wild boars on the territory of the hunting castle Grunewald mentioned in the guide — I never asked such questions. Peter Vogt from Los Angeles, which supplied the rous sarcoma virus, also contributed to the study. In addition, the Berliner Peter Duesberg with Steve Martin (currently both working in Berkeley) conducted an important experiment that showed that genetically modified inactivated Src does not cause tumor development.

It was the last tangible proof that Peter Duesberg — the devil’s advocate and have always maintained a point of view opposite to the view of the scientific community (always reminded of Mephistopheles from “Faust” by Goethe). He has been right, but he was wrong when he rejected the idea that HIV is cause of AIDS. I remember how he spoke to several hundred students during a panel discussion at the University. Humboldt in Berlin. I thought this view is dangerous and misleading. They arranged a scientific debate, never come to a common opinion, but always remained friends.

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