About the most interesting areas of research in biology
Bioinformatician Mikhail Gelfand – about bacterial communities, individual cells and studies of the ancient genome
Together with At the Skolkovo Institute of Science and Technology, we filmed the course "The War of Bacteria", dedicated to the evolution of the resistance of bacteria and viruses and the development of drugs to combat them. In this article, the head of the master's program "Biotechnology" Mikhail Gelfand talks about the most interesting areas of research in biology, Western experience and modern scientific centers in Russia.
I conduct research at the Bioinformatics Educational and Scientific Center of the Institute of Information Transmission Problems of the Russian Academy of Sciences. In my laboratory, we are engaged in computer analysis of the genome, studying bacterial communities and the evolution of bacterial genomes.
It turns out that we can tell a lot about a bacterium by knowing only its genome. For example, if there is a protein with an unknown function, it is very difficult to understand experimentally what it does. It is even worse when there is a function, but it is not clear which protein performs it. It can be very difficult to find out by experimental methods, but if you have a specific prediction made using computer analysis, then you can check it directly. And these approaches are very effective.
Another area of research is the evolution of bacterial genomes. We are studying fundamental issues. For example, we are trying to understand what kind of bacteria is. It is approximately clear to us what a mammal species is, but it is completely unclear what a bacterial species is. About mammals, we can say that humans and chimpanzees are closer relatives than humans and monkeys, and a whale and a hippopotamus are closer relatives than a hippopotamus and a cow. The fact is that most of the genome in mammals is inherited from their ancestors directly, but with bacteria everything is not so: they often have genes transferred from one species to another. This raises an interesting question about whether the evolution of bacteria can be represented by a phylogenetic tree. Without understanding the evolution of bacteria, it is impossible to come up with a strategy to combat them. Not realizing that bacteria evolve very quickly, humanity has been using antibiotics incorrectly. Now we are dealing with bacteria that are resistant to existing antibiotics.
In addition, we study bacterial communities. In this case, not one specific genome is considered, but the genomes of all bacteria present in the community. If we go beyond bacterial genomics, then a lot of work is being done to study how DNA works in human cells. There are many interesting problems in this area, which ultimately boil down to the question of why the genome in all cells is the same, but the tissues are different and how different types of cells are obtained during development. The answer is that different genes work in different cells. And what genes work in a cell determines its individuality. An even more difficult question is why the structure and functional state of DNA change, although its sequence remains the same. In the genomics of bacteria, we have a certain scientific program, and we follow it with more or less success. And in the science of the structure and function of the DNA of eukaryotes (organisms whose cells have a nucleus), our work is largely opportunistic – it all depends on the experimenters who bring interesting data.
About achievements in biology
Modern biology is not about discoveries and achievements. Nobel prizes in physiology or medicine are losing their meaning before our eyes, because out of a large number of people who do the same thing, the committee increasingly chooses a random person. There is no such thing in other sciences. This is because modern biology is a collective science. Progress in it is continuous and gradual. Very rarely there are obvious breakthroughs. But there are beautiful examples. For example, CRISPR/Cas systems are a really cool new thing. The authors, of course, will be given the Nobel Prize. And the same question will arise: to whom to give? After all, the first hypothesis about how it should be arranged arose as a result of genome analysis by Evgeny Kunin and his colleagues. Then different groups of microbiologists showed how it works in living bacteria. And other scientists have figured out how to use these systems in genetic engineering. It is impossible to understand who is the main fellow.
Biology is not the science of tank breakthroughs, but the science of positional battles. Therefore, the question of achievements is difficult. Either they are always there, or they are never there – depends on how you look at it. I think that the share of what is understood in biology is decreasing all the time due to the fact that the proportion of things about which we understand that they are, but do not understand at all how they work, is growing disproportionately fast. There is a well-known aporia about the fact that Achilles will never catch up with the turtle. It's the same here, only the turtle runs faster than Achilles.
About genetic noise
We know the structure of DNA, the structure of the genome, the functional state of the genome of an average cell, but not a specific one. But even cells of the same type are all different. And it's interesting to find out how it works with the colossal noise level that exists in all molecular genetic systems. If we create a more efficient system in terms of noise control, it may turn out that we will spend more energy on this control. In Jordan Ellenberg's book "How not to Make Mistakes" there is such an idea that if your government does not spend a single dollar on nonsense, then it spends too much money not to spend a single dollar on nonsense. That is, control is actually expensive. The same is true in biology: the ratio of noise and control is a big and beautiful problem. It is clear that excessive control is evolutionarily unprofitable. Perhaps it is easier to ignore this noise than to endure it every time. If it is not very harmful, why invent a special mechanism to get rid of it? And on the other hand, any genomic garbage is a source of evolutionary innovation.
There is a subtle semantic difference between the English words trash and junk: trash is garbage that goes to the trash, and junk is what you have lying around in the garage and may need from time to time. For example, an old bike is junk. You can suddenly extract some useful detail from it. And it turns out that evolution works the same way: a fairly noticeable part of evolutionary innovations are old fragments of mechanisms that were once comprehended, then turned into junk, and then adapted to a new business. I wonder how it turned out as a result of random rearrangements and the selection that affected them.
About individual cell research
Now it is interesting to observe three areas of research in biology: the analysis of individual cells and the differences between them; the ratio of noise and function; and the last – the same question, but in evolutionary refraction. Individual cells are interesting to observe from the point of view of embryology. If we observe cells during embryonic development, when they are already beginning to acquire differences, we can trace how the cells gradually understand what functions they will perform.
The second area is cancer. It is known that tumors are extremely heterogeneous. There are a lot of works in which cancer and normal cells of the same tissue were compared and looked at what had changed. But they considered an average cancer cell, and the cells are very different. They gradually gain genomic breakdowns, become more and more malignant, endlessly divide, then some of them acquire the ability to "float away", attach themselves to another place and start dividing there, giving metastases. If you look at the genomes of individual cells, you can reconstruct the evolution of cancer (cancer is an evolutionary disease) and see the strongest competition between tumor cells. From the point of view of cancer, individual cells are individuals, and we are an external environment for them. Studies show that cells that have the potential to become a source of metastases may be present almost from the very beginning, they are not young. This is a fundamental thing to understand when choosing a chemotherapy strategy.
The third area for the study of individual cells is immunology, and more specifically, the individuality of lymphocytes. The fourth is the study of the individuality of neurons, which is carried out within the framework of neuroscience. There is a very beautiful thing there. It would be naive to assume that neurons in one area of the brain had one precursor cell, which then divided and from which this area grew. In this case, the genealogical tree of neurons should correlate well with their geographical proximity in the brain, but it turns out that nothing like that. It is possible to determine the genomes of individual neurons and trace the history of somatic mutations during cell division. We will see that even if the brain region is local and homogeneous, it is formed by cells from very different lines that diverged even when these cells were not neurons at all.
If you think about it, it turns out that this is very correct engineering, because if each area of the brain is a descendant of one cell, then if this cell is damaged in the embryo, this area of the brain will not develop at all. And if the region is formed by the descendants of a large number of different cells that have acquired a functional identity already at a relatively late stage, then this will not happen.
About ancient genome research
Very interesting research concerns ancient DNA, because it develops our understanding of history. The standard question is: who were the native speakers of the Indo-European language?
We know archaeological cultures around that time, but now we can look at the genomes of these people, see gene variants characteristic of different archaeological cultures, and trace how people moved across Eurasia. On the other hand, we can trace the relationship between modern humans and Neanderthals, we now know that there was another independent branch – the Denisovans, and there are large Denisov pieces in the genomes of the inhabitants of Indonesia, New Guinea, Australia. We can look at the process of domestication of livestock. All this is interesting not only from the point of view of biology, but also from the perspective of understanding history and culture.
About scientific centers in Russia
The problem of Russia is that there were great Soviet physics and great Soviet mathematics – amazing schools of world significance. Sometimes it is said that these sciences originated from the military field, but this is not true, although it allowed them to exist.
And the great Soviet biology did not have such a roof, so it did not exist since 1948. There were only some very good scientists, and, in general, it remained that way for decades. When scientists began to leave abroad en masse, the situation worsened. This is bad news. And the good news is that, nevertheless, now there are still several laboratories that do world-class science.
To observe science, it is necessary to look not at the level of centers, but at specific people. Geographically strong people can be in different places. An interesting situation is brewing at the Skolkovo Institute of Science and Technology (Skoltech): it was the biological direction of Skoltech that managed to gather very strong people, and if it works properly, it will be very good. There are successful laboratories in St. Petersburg and Novosibirsk, and then - Krasnoyarsk, Ufa, Tomsk, Kazan.
About the Western experience
I am a big supporter of building science in Russia according to Western principles – with a competitive system, expertise. But there are two aspects. The first one is quite banal: there cannot be a wonderfully constructed system of science in a country that does not function entirely as it should. The second aspect is that it is necessary to adopt principles, not mechanisms, because the mechanisms should be different every time. Russian science, for example, has a colossal, historically formed and very wrong gap between research and education. There were research and educational institutes. With rare exceptions like Novosibirsk Akademgorodok, these were two different worlds. Any attempt to build modern science and education should take into account and overcome this historical background. There should be a very good strategy and a long planning horizon, and this is what is missing at all.
To some extent, Skoltech inspires hope, because this is a new education in the open field. There is a hope that many of the problems will not start there, and it will be possible to get rid of the oddities that arose in it at the very beginning.
There is a Higher School of Economics, which has a very strong mathematical faculty – apparently, the best in Russia now. There is also an interesting computer science faculty there. The physics department opens, that is, there is an expansion into the field of natural sciences, which is very good, because it will set a certain bar. After all, natural sciences are good because they understand the quality criteria.
From time to time there are reasonable initiatives at St. Petersburg State University, although the degree of insanity there is very high. The European University in St. Petersburg is wonderful. I am by no means a humanitarian, but I am interested in what they do there.
About the future of Skoltech graduates
Our goal is to prepare such graduates who will be able to join world–class laboratories. In addition, they will be able to work in biotech and pharmaceutical companies. We are trying to make sure that the level of professional training allows it. And the third area where they can work is modern healthcare. Modern medicine increasingly requires an understanding of biology, in particular evolutionary biology. Generally speaking, where modern, technological, highly detailed medicine appears, there should be a very powerful biological basis – both doctors and people who work with doctors.
Finally, there are pharmaceutical startups in some countries. Many medicines are invented not by big pharmaceutical companies, but by people from universities. They develop a drug or technology to some advanced state, and then sell it to a large pharmaceutical company. This is a fairly standard business model, but it does not work in Russia for obvious reasons.
Portal "Eternal youth" http://vechnayamolodost.ru
20.03.2017