Thirty years since the discovery of the P53 gene

Weizmann Institute scientists, pioneers in the study of the p53 cancer suppressor gene, are drawing a road map in the development of research into the factor involved in approximately half of human cancer cases

In 1979, the disco craze was at its peak, and the negotiations between Israel and Egypt ended in the first peace agreement with an Arab country. Cancer researchers at that time uncovered a series of evidences that certain genes promote the development of the disease. Some viruses, for example, insert their DNA into the host cell's genetic material, while others are able to "take over" the host cell's genes and activate them in an abnormal way that leads to cancer. In the same year, by chance, several research groups around the world identified a gene suspected of playing a central role in turning a healthy cell into a cancerous cell, following the penetration of cancer viruses.

Two young Israeli researchers working in the United States that year were interested in the new gene, called p53 (the number indicates the molecular weight of the protein produced by the gene. It has since been determined that its exact weight is 43.7, but the name remains). Prof. Moshe Oren then worked in the laboratory of Prof. Arnold Levin in Princeton - one of the laboratories that first published the discovery of p53. At the same time, Prof. Verda Rutter, who worked in the group of Nobel Laureate Prof. David Baltimore, identified the p53 in a cancer tumor, which was induced by another virus. Following the findings of the initial studies, scientists believed that p53 acts as an oncogene - that is, a gene that causes cancer. In the experiments carried out by Prof. Rutter in his laboratory in Baltimore, high levels of the p53 protein were found in many types of cancer cells - including cancer cells that do not originate from a viral infection - but it is almost never found in healthy cells.

Oren and Rutter returned to Israel in 1981, and in a short time established independent laboratories at the Weizmann Institute of Science, in the department that later became the Department of Molecular Biology of the Cell, and continued to research the gene that sparked their curiosity. At this point it was clear that it was necessary to clone the gene. This process required in those days, according to Prof. Oren, "a lot of improvisation, sophistication, and quite a bit of luck." Prof. Oren, who started his work at the institute in the laboratory of Prof. David Gavol, and continued to collaborate with Arnold Levin, was the first to clone the gene in 1983. Since then, Prof. Gavol joined the circle of p53 researchers, and made a significant contribution in the field. Prof. Rutter, following the work that began in the United States, developed new methods for detecting p53 in cells - methods that are currently in use in hundreds of laboratories around the world. In 1983, Prof. Rutter suggested that the protein could be used as a "tag" that allows cancer cells to be identified.

The two scientists say that they worked in an atmosphere of "friendly and constructive competition". In the first decade, p53 research went through several interesting upheavals. In some experiments it appeared to play a central role in the development of cancer, but in other experiments it was not associated with the induction of the cancer process. In addition, the findings that emerged from studies that used cloned p53 from different sources showed contradictions and inconsistencies. In 1989, when Prof. Oren, Prof. Rutter and other researchers in the world compared the different clones of p53, it was discovered that each version is slightly different from the others. It turned out that the gene that was identified and defined as an oncogene - that is, as a cancer promoter - is actually a mutant version of the original gene that plays a completely different role in the healthy cell.

It was later discovered that healthy p53, without mutations, not only does not promote cancer but on the contrary: it is a cancer suppressor gene, which prevents other "treacherous" genes from pushing the cell in the direction of cancerous transformation. Sir David Lane, one of the discoverers of p53, even dubbed it "the guardian of the genome". Equally significant were the findings that showed that mutant versions of p53 are found in about half of the cancers, and in many other cases its activity is disrupted. Following this, p53 research gained further momentum around the world, in an attempt to better understand the causes of cancer development. At the same time as raising awareness that a single gene might provide the answer to this mystery, scientists also began to understand how complex and changing the role of a single gene might be. To date, more than 50,000 scientific papers on p53 have been published, and the stream of new discoveries shows no signs of abating.

The researches of Prof. Oren and Prof. Rutter gradually focused, over the years, in two different directions: while Prof. Oren's research was concerned with understanding the role of natural, mutation-free p53 in the healthy cell, Prof. Rutter chose to study the various mutants in cancer cells. However, the collaboration between the two became tighter, and to date they have published 15 joint scientific articles (see box). Their pioneering work earned them many awards, and recently each of them was individually asked to contribute an article to a special issue of the journal Nature Reviews: Cancer, marking the 30th anniversary of the discovery of p53.

Was it worthwhile for the small Israeli research institute to support in the 80s two groups that were engaged in innovative research on a single gene? Prof. Oren and Prof. Rutter believe that the synergy between them created a nucleus around which a "critical mass" was gathered that placed the institute at the forefront of global p53 research. Today, the two scientists emphasize, there are about 20 research groups working at the institute whose work is related to p53. As of today, there is almost no scientist in the field of cancer whose research does not concern p53 in one way or another.

When to give up the vitamins

It is commonly assumed that vitamin D has anti-cancer properties. But can it be useful even when the person already has cancer? Clinical trials in patients treated with chemotherapy have not yet been able to answer this question. The latest collaboration between Prof. Oren and Prof. Rutter, in which the joint research student (at the time) Dr. Perry Stambolsky also participated, approached it from a different angle: experiments they performed indicated a connection between p53 and the molecular machines that carry out the cell's response to the vitamin D. A thorough examination revealed the mechanism of action of these machines, which function as a kind of "amplifier" for the activity of p53. This is a positive activity when the normal p53 works to suppress the cancer - in this case vitamin D will help fight the cancer. On the other hand, when the gene becomes an oncogene following a mutation, problems may arise. Prof. Oren: "Normal p53 prevents cancer, but when mutations occur in it, they 'get stuck in the wheels' of the machines that keep cancer at bay. In that case, vitamin D may "push" the sticks a little deeper." Prof. Rutter: "It may not be enough to determine whether a mutation has occurred in the p53 gene, but the exact nature of these mutations must also be known, before considering giving vitamin D as a medicine."