26 August 2014

A team to fight cancer

Galina Kostina, "Expert" No. 35-2014

A talented biologist teamed up with a talented mathematician. Then they were joined by a talented programmer-organizer-a business angel. And a little later – a talented venture investor. As a result, an almost utopian idea – to treat cancer better – has turned into a fully working system that, taking as a basis data on a specific tumor, in virtual mode examines data about it lengthwise and across, presenting the profile of the tumor. Then the system selects from the list of targeted drugs those drugs that will be most effective for the patient. Moreover, it does not just issue one drug, but ranks them according to the degree of effectiveness.

The system is already being tested in several Russian cancer clinics. It has no analogues in the world yet. And no one is looming on the horizon, although it is known what forces and sums are working in the field of global oncology. Large companies were already interested in the development, jingling money. But our company is still increasing its capitalization.

Looking at this team, you are imbued not only with optimism, but also with pride. After all, there are talents in the fatherland, because we can not only shoe a flea, but get ahead in the world peloton, and even find our own investors.

If you add a biologist with a mathematicianAnton Buzdin began to be interested in living beings from the age of six.

He adored the program "In the World of Animals", which led him to the biological circle. Of course, the family atmosphere also affected. Dad is a famous physicist, mom is a graduate of Phys Tech, family friends are a match. There were many biophysicists among them who liked to talk about the most fashionable field – molecular biology. Anton understood from these conversations that molecular biology is the coolest part of the science that he fell in love with from early childhood. So there was no hesitation with the choice of profession. The last year of school – intensive work with tutors, and now he is already a student of the biology faculty of Moscow State University. Moreover, the department of molecular Biology, which was considered almost the best in the faculty. Interestingly, the strongest influence on him at first was not even famous teachers, but classmates. "They were all so super serious, so purposeful, so eager to make great discoveries in science," says Anton. – Well, I, accordingly, joined this stream." After graduating from Moscow State University, Buzdin entered the graduate school of the Institute of Bioorganic Chemistry named after M. M. Shemyakin and Yu. A. Ovchinnikov, where he got into the laboratory of Evgeny Davidovich Sverdlov, whom he calls great and mighty.

In the laboratory, Anton took up a very interesting topic: how we differ from monkeys at the genetic level. I laughed: probably not so much. "How to say it," Anton grinned. A chimpanzee can keep three tasks in his head, and we have seven, they climb trees better, but we control our emotions better, read books and are generally much smarter. The laboratory has found a number of mobile elements – such DNA sequences that can be randomly embedded in genes and sometimes significantly change their work. So, one of these mobile elements, consisting, by the way, of viral fragments that the human genome is stuffed with, has embedded itself into one of the genes active in our hypocampus. Thus, he strengthened the work of the gene responsible for controlling emotions and thought processes. So, it is likely that viruses that have long inhabited our DNA have helped us become homo sapiens.

Two new families of mobile elements were discovered in the laboratory, and these works were cited in international publications. Anton defended his PhD first, and in 2008 – his doctorate, after which he received his laboratory, which continued research in the field of the human genome. Along the way, along with fundamental works, he decided to engage in the field that can bring fundamental discoveries closer to medicine. Scientists began to study the features of the genome associated with the development of cancer. I was surprised: thousands of groups around the world, plus large corporations, are engaged in research in the field of oncology. Does it make sense to get into this marathon? "There is," Anton smiled, "everyone was engaged, but not like us. We had experimental techniques that allowed us to study this area in a different way. However, it was a few years ago, when genome sequencing was an expensive pleasure. Now that sequencing and microchipping, which make it possible to quickly study and compare DNA fragments, have become significantly cheaper, all earlier techniques have been discarded, including ours. Nevertheless, we have not lost the advantage, because we have started using huge amounts of data, while most other researchers choose, as it seems to them, the most significant pieces, and discard everything else." In fact, no one really knows what is more significant and what is not. Let's remember that until quite recently, most of our DNA was considered "garbage". And then it turned out that there are a large number of regulatory elements that control the genome.

For many teams working in oncology, processing large amounts of data still remains a stumbling block. "Five years ago, at one of the conferences, I was lucky enough to meet with a wonderful biophysicist-mathematician from the Burnazyan Biophysical Center – Nikolai Borisov," Anton says. Buzdin made his report on the comparison of chimpanzees and humans. Borisov and his – about modeling the cellular signal that leads to cell division. Everyone received their prize for the report, and at the buffet they exchanged business cards and agreed to meet.

"We decided to unite when Anton showed me data on the analysis of gene expression of several cancer patients treated at the Herzen Institute," says Nikolai Borisov. – He asked my opinion on how to extract from all this a practical result that doctors could apply. And then at the same time we made the same assumption: now the expression level of a small number of genes involved in the development of cancer is being determined, and this is a very narrow view of the problem." Our scientists decided to take a global approach.

What is going on in a cancer cell anyway? "The cell does not become cancerous instantly," explains Anton Buzdin. – The accumulation of mutations can go on for years. The totality of all processes in the cell changes all the time and eventually leads to the fact that the cell turns into a cancerous one. In parallel, there are processes of influence on the changing cell by the immune system. It's a huge tangle of interactions." It turned out that in a cancer cell, compared with a normal one, about 10 thousand genes work differently. But mutations in these genes do not necessarily reflect the current state of the cancer cell. Let's say there was some kind of initiating mutation that played an important role at a certain stage, but then the process continued, other changes became important. If you target the initiating mutation and try to block it, therapy may be useless. "Therefore, we are not even studying genome mutations, but the transcriptome of a cancer cell – the totality of all synthesized molecules: proteins, mRNA, non–coding RNA," Anton continues. "It is these data that show the real current processes in the cell."

Nikolai Borisov has long been tormented by the idea of why even so-called targeted drugs may not achieve the goal and what can be done about it. "Signaling pathways in a cell are basically protein–protein interactions," he says. – Eventually these interactions reach the nucleus and cause the cell to divide. But the signal paths are not so straightforward, they are highly branched. And even if it seems to us that we have blocked one interaction, the signal can go along another branch." Therefore, even targeted drugs that seem to act on a specific target may not always be effective: "Do you understand that these drugs, firstly, are very expensive, and secondly, take up precious time and even harm: the patient undergoes a course with one drug, then another, a third, and the drugs-they are toxic."

Our scientists decided to create the most detailed picture of the tumor. To do this, it was necessary to include in the system the expression data of almost 10 thousand genes involved in cancer (7 thousand are included so far) from a huge number of samples, about 300 known signaling pathways also involved in cancer, and about 300 metabolic pathways (for example, biosynthesis or decomposition of substances inside the cell). And all this wealth of data had to be "multiplied" and quantified in order, for example, to know which signaling pathways in a particular case are strengthened, which are weakened and how much. Then it is possible to get an idea, of course, not quite complete, but quite voluminous, about what is happening in the cell at the elementary level. "This level is elementary enough to describe the situation in detail," says Anton, "but at the same time it is too large–scale to be understood by the human brain." Borisov was able to create an algorithm that reduces all this huge amount of data to understandable information. No one could do it before him. The result of these calculations may suggest which target or targets should be affected first. With the help of this system, it is also possible to assess how successful the therapy used is.

Moreover, the system has another value. "The fact is that sequencing and microchipping methods, although progressing, are still imperfect," says Anton Buzdin. – The data of these two methods for one object may differ significantly. We bring them together and sort of remove the noise and errors of these methods."

Programmer, innovation manager, angelIn general, when the general concept became clear to Buzdin and Borisov, it also became clear that more money was needed for its implementation than they invested themselves in the process.

And then another character of this story appeared on the horizon – Alex Zhavoronkov. "We were introduced by a mutual friend, a scientist," says Buzdin. – He told Alex that we have an interesting project, and we – that Alex is a unique person, what we need."

Zhavoronkov, in turn, says that such unique people as Buzdin and Borisov can be counted on the fingers in the world, even though they do not yet have the titles of Nobel laureates. "They did a great thing, but at that time it was not a software product," says Zhavoronkov. – Anton at first asked me to just evaluate the idea: they say, one large Western pharmaceutical company wants to buy the development for 100 thousand dollars. Help me talk to them. I replied, let me see the project, I'll sleep with him, as they say." Alex read the materials and barely waited until morning. And in the morning I told Buzdin that it was by no means impossible to sell it now. "And where can I get money for development?" Anton asked. "I'll give it to you first," Alex replied, "and then we'll look for someone bigger."

Why Alex, not Alexander, why unique and where did he come from? He was born in Riga, his father is a military man, his mother is an engineer. He studied well, and his parents sent him to study in Canada. In the mid-1990s, everyone who had the slightest financial opportunity exported children to study abroad. Alex entered Queen's University in Kingston for two majors at once. One is computer science. The second is a business school. Alex as a child did not dream of becoming a computer scientist and businessman, but dreamed of being a doctor or a scientist. "I was about eight years old when I was lying in the grass at the dacha in the evening and looking at the stars. Then everyone dreamed of becoming astronauts, and I thought that astronauts were too pretentious, and risky," says Alex. "I was thinking that we live too little to fly far into space, and I decided that I would become a medic solving this problem." However, opportunistic considerations defeated the childhood dream. AI-ti is something that was in great demand at that time. After graduation, Zhavoronkov got into a company that developed computer chips for telecommunications networks. He became a product marketing engineer - he developed a chip and sold it. Salary is super, bonuses are super. When the dot–com bubble began to collapse, Alex was lured away by another computer graphics development company. After a while, he headed the department dealing with Central and Eastern Europe, and invested the money he earned in shares of Chinese IT companies. His colleagues mostly had fun playing golf in their free time, while Alex decided to work out for himself. He entered the master's program at the American Johns Hopkins University. And at the same time to the graduate school of Moscow State University. He was returning to his childhood dreams. And also followed the new conjuncture – now all the most interesting things began to happen in biotech. At the American University, he took up the problems of longevity, in the Russian – the biophysics of amino acids. While studying for an American master's degree, Zhavoronkov traveled to at least twenty laboratories dealing with aging, then got a job at a company organizing biological conferences in the United States. Became one of the directors. Working at the company, according to Alex, allowed him to get acquainted with a huge number of scientists, whom in other circumstances he would hardly have approached: "You have no idea how many contacts are in my mobile phone. Eight thousand. And in the database – one million six hundred!" Then Alex went to work for a company that was engaged in a specific project – the development of antioxidants. Invested in it. Then he sold it together with other shareholders. Along the way, I met some wonderful scientists again. I invested in another company where our compatriot Mikhail Shchepinov promoted his project related to aging. "Through Mikhail, I met one wonderful scientist and technology entrepreneur, Charles Kantor,– says Zhavoronkov. – He's fantastic. A sea of ideas, a sea of projects, has been nominated for the Nobel Prize more than once. I learned a lot from him. He took me to one of his companies, Sequen, and offered to make a little “daughter” in Russia who would be engaged in early non-invasive prenatal diagnostics. By isolating DNA from the peripheral blood of the mother, a test can be done to determine whether there is no risk of Down-type diseases." Alex Zhavoronkov created such a laboratory at the new Federal Research and Clinical Center for Pediatric Hematology, Oncology and Immunology named after him. Dima Rogachev. At the same time, Alex himself invested in part of the equipment and staff.

It was at this center that Alex met Anton Buzdin. And invested the remaining funds in his project. "I realized that gold was in front of me,– says Alex. – Anton had a great idea and developments, Nikolai was able to do something that no one in the world could do: he found a fine line between too complex and simple methods for processing arrays of information. Then we held several meetings and thought that the best way to bring this science to the clinic is through personalized medicine. It is necessary to develop a software medical platform that will be able to examine a specific tumor and give recommendations to the doctor. And the faster we make a ready-made clinical product, the faster we will move forward."

"And Anton believed you right away? I ask Alex. – You never know who will want to attach themselves to a promising development, besides not allowing it to be sold to a well-known company." Alex was not offended by the question: "Well, I already had a good reputation here. And not only here. Besides, Anton saw that I was just fired up with this job and ready to join the team."

"And who is Alex in the company – a business angel?" - I ask Anton already. "Maybe an angel,– Anton replied thoughtfully. – But not only. He's also a scientist, he's also a programmer. Plus the organizer. So he is a scientist, a manager and an angel."

Progressive investor, philanthropistAnton, Nikolai and Alex created the company "First Oncological Research and Consulting Center" (PONCC).

By the way, we have received the status of a resident of Skolkovo. Alex's investments were used to accumulate more material. Working in the mode of clinical research with three cancer centers, the company also provides services to private patients. But, as in the classics of the innovative company genre, there comes a time when you need to move on to the next stage of development, from a pilot product to a commercial one.

About a year ago, another important person appeared in the team – venture investor Dmitry Kaminsky. First Dmitry met Alex. And for the first time, it seemed to Kaminsky too complicated. He knows so much, and gushes with unfamiliar terms and other information. It cannot be said that Dmitry did not understand anything about biotechnology at all. You could say he was getting close to them. Actually, he has a computer education and he was an IT specialist, then he was engaged in analytics in the banking sector. But Dmitry is also one of those active young people who are interested in many things. And at first futurologists and fans of artificial intelligence carried him away. But, as it turned out a little later, he was still more attracted to the sciences of life. He began to develop his horizons in this direction. And those who begin to develop in this direction are involved in an absolutely incredible complexity, sophistication and at the same time simplicity of the world of the device of all living things. At the same time, Dmitry initially believed that only large rich corporations were engaged in great things like cancer research. And it turned out that the researchers of the great are literally at hand, in their homeland, and they do not work in any megacorporations. After the first acquaintance with Alex, Dmitry decided to get better at it. "I have assembled a team of students, postgraduates of MIPT and MSU, engaged in bioinformatics and programming," Kaminsky says. – I asked to monitor trends, scientists, the market in the field of biotech. They started making regular reports to me. I needed to learn quickly to understand the idea of the guys – Anton, Nikolai and Alex. I only guessed that it was something interesting and unusual and at the same time promising." Gradually, Dmitry began to speak the same language with the team members. He was preparing to join the team.

Anton Buzdin, Dmitry Kaminsky and Alex Zhavoronkov – team against cancer
Photo: Oleg Core

"I was an investor in the traditional sphere, working with stable assets – securities, real estate, and so on," says Dmitry. – But I realized that the most interesting thing right now is the biotech boom. Besides, these are just humanly interesting and high matters." At the beginning of the year, Dmitry created a venture investment fund Deep Knowledge Ventures with a residence permit in Hong Kong. "I thought it was a very favorable place. There is a huge concentration of scientists and extremely rich people who are inclined not only to traditional, but also to progressive investments. There is strong legislation and powerful financial institutions," Kaminsky explains. Having created the fund, Dmitry began to cooperate with the English analytical agency Aging Analytics Agency, which monitors all companies, from large to tiny startups dealing with the problems of aging and longevity. This agency once created a robot that "parses" the Internet, raking out everything from it that concerns the topic of interest. The robot's name is Whitel (VITAL – Validating Investment Tool for Advancing Life Sciences). He parses and puts all the information on the shelves with his algorithms. Dmitry's Foundation received one White for running in test mode. Everyone wins – the foundation receives important information, while at the same time teaching the robot with its daily requests, which will then be taken into account by the robot developers. "They expect that after our upgrade they will be able to create a version of Whitel 2.0, which will monitor all biomedicine in general," says Dmitry. The encyclopedic and all-seeing Whitel, looking for even tiny startups, helped Kaminsky make investments in several promising companies and startups, including Hong Kong-based Pathway Pharmaceuticals, which deals with personalized medicine in the field of oncology. And then Pathway invested in Buzdin's PONCC. Now Anton is one of the directors of Pathway, supervising his project. Along the way, Kaminsky, as a philanthropist, helped create the Center for Biogerontology and Regenerative Medicine in Moscow, which is headed by a young promising scientist Andrey Garaza. The Center actively cooperates with laboratories at MIPT and the Children's Cancer Center, developing new methods of treating oncological diseases and combating aging. Dmitry also helped to create a Fund to support promising biotechnologies, which will include many scientists and progressive entrepreneurs. "I will try my best to persuade investors to progress,– says Dmitry. "Society should evaluate them not by the number of palaces, yachts and football clubs, but by the benefits they bring to science, in particular medicine and, accordingly, to people."

It is planned that by the end of 2015, the Deep Knowledge Ventures fund, to which Dmitry Kaminsky invited several influential partners from China and Russia, will invest more than $ 100 million in projects related to increasing productive longevity and combating age-dependent diseases. So far, the fund has managed to attract about 30 million. Part of the money goes to buy shares of large companies, part goes to startups, and part goes to Pathway. The amount that Kaminsky invests in the PONCC project, in his opinion, is enough for the company to develop dynamically: adequately support scientists, develop research information, register patents, and publish in well-known scientific publications. "With a high probability, this company can achieve such capitalization in one and a half to two years that large strategic investors will see," says Dmitry. – And they see starting from about $100 million. The second way is to enter the IPO."

And another trump cardI ask Anton Buzdin: and what, in fact, will you sell – a company or a flash drive with a program?

"We have a software product and a small research center that provides customized solutions based on the program. We are not planning to sell the program itself yet, we will sell a license for use. The program itself will be in our center – in remote access." In order for any clinic in the world to obtain such a license, the product must be approved by the relevant authorities, for example, the FDA. But for this, probably, you will need a strategic investor already. While the company is moving gradually. The study concerns kidney cancer, and the product will be certified according to this nosology first in Russia. Now doctors are cooperating with the PONCC in the mode of clinical research. Naturally, they cannot make only those prescriptions that the program offers them, since drugs for a certain type of cancer are prescribed in an approved protocol. But doctors correlate their appointments with the program ones and make their comments. However, in an extreme case, they can prescribe a medicine that is not specified in the protocol and agree with the program. Anton tells one case. The patient underwent all possible types of therapy specified in the protocol. Nothing helped. The forecast is clear without words. And in this case, the doctor can suggest any measures that the patient or his family will agree with. The program, having examined the tumor profile of this patient, proposed a targeted drug that has never been used for this purpose at all. The doctor decided to prescribe it. The patient became much better. "It took quite a bit of time to make optimistic forecasts, but this clear improvement was obvious to everyone," Anton continues.

Scientists are developing another very promising application for their program – the search for new targets in a cancerous tumor, as well as the selection or prediction of new drugs for cancer and other age-dependent diseases.

Portal "Eternal youth" http://vechnayamolodost.ru26.08.2014

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