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Pioneering Research in the p53 Gene
Drs. Varda Rotter and Moshe Oren

Weizmann Institute of Science

Back in the end of the 1970’s, as post-docs in the labs of David Baltimore at the Whitehead Institute, MIT (Varda Rotter) and of Arnold Levine at Princeton University (Moshe Oren), each of us started separately to study a new protein, which I eventually received the name p53. Upon preparing to return to Israel to start the next phase of our research careers, we both were determined to stick with p53 and reveal its secrets. At that time, hardly anything was known about p53, and some colleagues doubted that this obscure protein is worth at all pursuing. Nevertheless, we did not change our course, and each of us submitted a grant application to ICRF as our first move towards independence. Both our applications were approved. The grants were modest, but receiving them filled us with pride: after all, these were our first grants! And this was also a token of recognition, by anonymous experts, that what we were proposing to do was indeed worth pursuing. Since then, each of us has been leading an independent research team dedicated primarily to p53 research. We learned how to work simultaneously yet independently towards the same goals, sometimes in friendly competition and often in close collaboration and synergy. In retrospect, we believe that having two teams with common interests in the same institution was a valuable experience, which benefited both our own science and p53 research in general.

In the many years that have passed since we received our first ICRF grants, p53 has gone a very long way, and so have we. From an obscure gene, struggling for the attention of the cancer research community and drawing the active involvement of only a handful of researchers like ourselves, who stubbornly believed in its importance, p53 has  become the  king  of  tumor  suppressors.

Likewise the p53 protein, whose genetic information is encrypted within the p53 gene, has become arguably the most extensively studied protein on earth. This is because,

thanks to subsequent work in our labs as well as in several other research centers worldwide, it was realized that p53 is a potent tumor suppressor, whose activity serves as a main gatekeeper against cancer in practically each and every cell within our body. In fact, it is now believed that no cancer can develop as long as p53 is fully and properly functional, and that the road to cancer inevitably requires the elimination or at least perturbation of p53’s tumor suppressor activity. This is reflected by the fact that mutations, i.e. structural alterations, in the p53 gene are the most frequent single genetic change in human tumors. In fact, in some cancer types such as high- grade serous ovarian cancer – the most deadly form of ovarian cancer – the frequency of p53 mutations is close to 100%.

The realization that p53 is so important for preventing cancer, and is so frequently targeted by cancer, has understandably generated extensive interest in the p53 gene and protein.

From the early handful of stubborn researchers, the p53 research community has grown into thousands of scientists, working in many hundreds of laboratories and hospitals worldwide. Together, their massive efforts have led to elucidation of many of the secrets of p53, revealing that it serves as “guardian of our genome” to assure that our cells do not acquire undesirable changes in their genetic material that are essential for driving cancer. Moreover, thanks to work done first at the Weizmann Institute, it has been appreciated that p53 can force cancer cells to commit suicide (a process called “apoptosis” in professional language), thereby effectively eliminating them from the body. Moreover, again through work done in great part at the Weizmann, it has been realized that the cancer- associated mutations in p53 not only deprive it of its tumor suppressor activities, but actually confer on it as so-called gain-of-function, converting the mutant p53 into a cancer-promoting protein that renders the cancer cells more malignant. Much understanding has been obtained over the last two and a half decades with regard to how p53 operates, how it engages in intricate crosstalk with almost any process within the living cell to make sure that it is carried out properly and does not endanger the wellbeing of the cell and the body, and how it affects fundamental processes all the way from early embryonic stem cells to cell death and organismal aging. All throughout those years, our two labs have remained at the forefront of the p53 field, making the Weizmann Institute and Israel one of the foremost hubs of p53 research.

The extensive knowledge gained about p53 is now being increasingly mobilized towards developing innovative experimental cancer therapies, which aim to restore proper p53 functions to cancer cells that have lost them on their road to becoming malignant. These major efforts are shared by big pharma, biotech companies and academic institutions, including an ongoing collaboration between our two labs. It is our shared great dream to see in the not too far future how our early efforts to understand this puzzling and little-known molecule, which very few cared about, transform into therapies that offer new hopes and help to many cancer patients. When this happens, we will always remember that ICRF was there right from the beginning, to help us make our first step in this long journey.