"There is no national science"

Sergey Dobrynin

This year, Thomson Reuters, traditionally predicting future Nobel prize winners, once again unable to guess any of the laureate in the field of natural Sciences. However, getting into this very prestigious list, it means that the work of the scientist was the basis for many other studies were the impetus for the development of their research areas. Included in the list of Thomson Reuters researchers often become Nobel prize winners in one of the following seasons. In the latest forecast Agency got the only scientist of Russian origin, immunologist Alexander Rudensky, Ludwikowska the head of the center for cancer immunotherapy in the United States, Professor at Cornell University.

A week ago, ahead of the announcement of Nobel prize winners in medicine and physiology, Radio Liberty phoned Alexander Rudanskogo in new York and asked him why the immune system is not without control, how to use immunotherapy to treat cancer and the Russian scientists are different from the rest.

– You didn't expect that Thomson Reuters will put you in the number of candidates for the Nobel prize?

– Yes, it was unexpected. But I think that the Nobel prize this year will receive my former colleague Jim Allison, who was not included in the list, Thomson Reuters (Allison this year was not a Nobel laureate. – RS). His research in the field of immunology led to the transformation of cancer treatment. The first immunotherapeutic drug that entered the market and have now become the standard therapy for patients with melanoma, was developed on the basis of his studies of the mechanisms of activation of T-lymphocytes. On the basis of these developments was established drug small biotech company Меdorex, which bought the group Bristol-Myers Squibb. The drug was approved for use in 2011. Even if Jim will not receive a Nobel prize this year will probably be a winner in the near future.

– Now, when you were named among the contenders for the Nobel prize, many Russian media was tempted to call you a Russian scientist. Are you ready to agree with this description?

It would be more correct to say, an American, a Russian scientist. I went to the United States in 90th year as a senior researcher. Of course, the Russian education, Russian scientific culture had a big influence on me, but not less impact on me American academic environment.

– What do you think, if you were working in Russia, you could achieve the same academic success?

– I sure didn't. It's not so much technological and technical capabilities, the main thing in the environment and in the absence of administrative, bureaucratic and other barriers. But in fact, the national science does not exist. Can't be apart of Finnish science, or the Swiss science, or of Russian science. Only politicians use these terms, this is an implication of nationalism, a sense of belonging to a tribe or tribal mentality. This is a trivial argument, but science has no borders. It is important to research process involved the people who grew up in a different environment, which have different ways of thinking. When working together Chinese, Indians, Russians, Americans, Germans – everyone brings with them their cultural baggage, your language Luggage, which is very important, because language is fundamentally affects the way people think. Such confusion is an incredible source of creative impulse, it makes the science exciting venture, painted different national characters and languages.

– What is the most striking feature of Russian scientists in this palette?

– I don't know what it is, maybe it's the size of the country, the duration of the winter, increased cloudiness, but I would say that the peculiarity of Russian is to think about the global problems in isolation from reality, having no real opportunities to solve them. The technology of solving the problem is not their concern, you can look at the sky and solve the world's problems just like that, in principle. But there is also the opposite option when the sky does not look at all, and look at all sorts of devices and I think that when you put them in a big pile, then everything will be solved by itself. Of course, this is different extremes, and fear, both not working very well.

– Tell us a little about your work that gave Thomson Reuters Foundation to include you in the list of nominees for the Nobel prize. You are studying so-called T-regulatory cells and the role they play in the immune system? They limit excessive activity of the immune system?

– Yes, you can say so. Speaking at the simplest level – the immune system appeared to multicellular organisms are able to resist infection. Immune response, the immune response to an infection causes inflammation. Reaction of inflammation – adaptive, it is necessary to restore the function of the tissue or organ, disturbed, for some reason, as a result of infection, injury, stress, or lack of oxygen. But for this inflammatory response the body has to pay. Price is what the function of the inflamed tissue may be temporarily out of, and sometimes, this problem may become permanent. Therefore, in the body there are many mechanisms that can prevent or limit the inflammatory response, including those associated with the immune response to infection or self antigens, or the microorganisms that colonize the mucous surface or on the skin in humans. Here is one of such mechanisms in higher animals that have a system of acquired immunity, and are so-called regulatory T cells. Cells of the acquired immune system, T lymphocytes develop in a special gland, thymus. In the development process, they learn to distinguish between "foreign", that is, the potential targets of the immune system, from the proteins of the body's own, with someone else recognized against the background of "his" – in combination with defined their own proteins. But sometimes this recognition system, which, generally speaking, gives a great evolutionary advantages, faltering, which apparently can't be solved mechanisms themselves responding immune cells. And here the need for controllers, those regulatory T-cells, without them, the immune system can go into a state of uncontrolled activation. In the absence of regulatory cells have severe, even fatal, rapidly progressing systemic inflammatory autoimmune syndromes. For example, they develop in children who do not have a functional FOXP3 gene, which is responsible for the differentiation of regulatory T-cells. Boys with this genetic disease shortly after birth be in the clinic because they can't eat right, they develop diabetes, severe dermatitis, systemic inflammatory autoimmune disorder.

– Because without this gene in T-regulators?

– Yes, they are not formed. The same thing happens in mice, which have no FOXP3. In my lab, 13 years ago, was made FOXP3 knock-out mice died within 3-4 weeks after birth from the common autoimmune and inflammatory syndrome similar to that observed in humans. If you remove regulatory cells in perfectly healthy mice, the mice also die within two weeks. Regulatory cells is vital, although numerically it is a relatively small population, about 2 million cells, that is 5-10% of all T lymphocytes. And they control inflammation, autoimmune diseases, response to paternal antigens mothers response to metabolic inflammation and much more. Our recent work showed that, in addition, T-regulators there is another protective function, they not only provide anti-inflammatory effect, but also able to maintain the function of tissues and organs, producing growth factors that promote healing.

What is the history of the study of regulatory T-cells?

– The hypothesis of the existence of these cells was made 50 years ago, shortly after the opening of the functions of the thymus, the thymus gland. In the works of the early– mid-60s, it was shown that if the thymus is surgically removed from mice during the first three days of life, animals develop widespread autoimmune inflammation of various organs and tissues. It turned out that this inflammation is caused by immune cells, T-lymphocytes, and that the transfer of T-lymphocytes from mice in which the thymus has not been removed can prevent the development of these autoimmune inflammation and organ damage. In other words, among the T-lymphocytes produced in the thymus there are cells that can suppress autoimmune damage, they were called regulatory T-cells. The next task was to search for the molecular and cellular mechanisms of these cells. In fact, serious studies of regulatory cells began in the late 80s - mid 90s. In 1995, Shimon Sakaguchi identified a protein present on the surface of cells with this regulatory function, capable of suppressing autoimmune inflammation, and this allowed them to begin their research in earnest. Then 12 years ago, Shimon's laboratory, Fred Ramsdell's group and my laboratory showed that a protein called FOXP3 is a fundamental regulator of the differentiation of these cells, their development and function. This made it possible to study regulatory cells using modern molecular, genetic methods, to create experimental models to study their properties. We can say that there was an explosion in this area, regulatory cells were identified in humans, and over time, clinical applications of these studies were found. Today they are focused on the use of these cells for therapeutic purposes in the treatment of cancer, in the field of organ transplantation, bone marrow transplantation, in the treatment of a wide variety of autoimmune diseases, including diabetes, rheumatoid arthritis, multiple sclerosis. Today we know that regulatory cells control a variety of forms of inflammation, it has been shown that they are involved in ensuring the tolerance of the mother to the fetus and contribute to the development of the fetus. In short, now there is an understanding of how important these cells are in a variety of situations, including those in which, it would seem, immunity should not play a significant role, such as type 2 diabetes or obesity.

– How are T-regulators and cancerous tumors related? Do I understand correctly that cancer provokes an increase in the activity and number of regulatory cells, thereby reducing the immune response?– You are absolutely right.

In almost all forms of cancer, the number of regulatory cells increases. In many forms of cancer, a high number of T-regulators in tumors correlates with their aggressive development and is an indicator of a poor prognosis. However, the opposite situation also happens. In the early stages of cancer development, which is associated with an inflammatory response, for example, intestinal cancer, regulatory cells, on the contrary, can slow down the development of the disease by suppressing the inflammatory response. But at later stages, when cancer becomes independent of inflammation, regulatory cells, on the contrary, contribute to its development. This is a rather special case, in most tumors, an increased number of regulatory cells is indeed associated with a poor prognosis. Therefore, the possibilities of manipulating the number of regulatory cells are being studied now: their partial, and ideally complete removal in the tumor can contribute, if not to cure, then at least to a significant suppression of tumor growth and metastases.

– Can these cells be specifically removed in the tumor?– Currently there are no such methods, but we are trying to find a way to remove regulatory cells, if not only in tumors, then at least not systematically, not in the whole body, because systemic removal of regulatory cells can lead to significant inflammatory processes.

But, apparently, even temporary systemic removal of regulatory cells can have therapeutic benefits. Two years ago we published a paper in which we showed in a model on experimental animals that in the case of aggressive breast cancer caused by oncogenic mutation, temporary removal of regulatory cells leads to significant therapeutic effects, while this type of tumor, generally speaking, is not usually considered as a target for immunotherapeutic treatment, other methods of immune therapy they did not lead to any changes in the growth of the tumor. We believe that manipulation of regulatory cells, including their temporary systemic removal, can lead to positive therapeutic results, especially in combination with classical methods of treatment, local radiation, chemotherapy, and so on. Now I have a talented surgeon working in my laboratory who operates one day a week, and the rest of the time conducts research on experimental models of cancer in mice and clinical trials of the effectiveness of temporary removal of regulatory cells in cancer patients.

– It turns out that there is such a relationship: cancer provokes an increase in the number of T-regulators, but if their number is reduced, the likelihood of inflammation and autoimmune diseases increases.– Yes, it is.

Immunotherapeutic drugs, which are now being used in the clinic and which have transformed, for example, the field of treatment of metastatic melanoma, cause very significant immunological disorders. They have learned to cope with them, but they do not pass without a trace. Although the complications of immunotherapeutic treatment are much weaker than with classical treatment, such as chemotherapy.