Will Russia be able to fit into the global genomics?
We will not give our bone to anyone
Galina Kostina, "Expert" No. 39-2014
Photo: Oleg Slepyan
Having read the human genome in 2001, geneticists around the world had the opportunity to conduct numerous studies to identify disease genes and approach methods of their treatment. Will Russia be able to fit into this trend?
Recently, Russian scientists have completed their part of the project as part of the international consortium for the study of cancer genomes. Our geneticists are participating in such a large-scale study for the first time in a long time. This means that we are able to carry out such complex work, as well as even more complex – with the genomes of ancient people and animals. But can we become on a par with the major genomic powers, joining the new era of genetics that opened after reading the human genome in 2001? We are talking about this with Academician of the Russian Academy of Sciences, Director of the Center "Bioengineering" of the Russian Academy of Sciences, Deputy Director of the RSC "Kurchatov Institute" Konstantin Scriabin and Head of the Laboratory of Genomic Analysis of the Center "Bioengineering" of the Russian Academy of Sciences Egor Prokhorchuk.
About diseases– I heard that you recently completed work related to the genome of kidney cancer.
Why did you study this particular type of cancer? What are the results of this work?
Konstantin Scriabin: This is a great work of the International Cancer Genome Consortium established in 2007. Its purpose is to describe genetic, epigenetic changes in tumors of 50 types of cancer. It is supposed to sequence 25 thousand genomes of tumors.
All types are distributed among groups from different countries. Many works are done by Americans. We participated in a group of several European countries, including France, Great Britain, Sweden, Czech Republic, Romania, Latvia. But only in two countries sequencing was carried out – here and in France.
We were tasked with cataloging mutations. To do this, it was necessary to collect many samples of a specific type of kidney cancer, sequence them and understand how they differ from healthy ones.
We looked at renal carcinoma, the proportion of which in kidney tumors is approximately 85 percent. It begins asymptomatically and is generally poorly treated. Therefore, it is very important to find new markers for the diagnosis and creation of new drugs.
– How many mutations have been detected?
Egor Prokhorchuk: About 30 mutations have been identified. A gene has been identified that mutates in 50-60 percent of cases of kidney carcinoma. The frequency of mutations in other genes was also revealed.
Epigenetic mechanisms have been identified when the work of a gene changes not because of a mutation, but because it has stopped working due to methylation. Projects on some types of cancer have already been done, more than 70 more works are in the process.
– Can participation in this consortium be considered important in terms of recognition of our genetics in the world?
KS: This is really important. We have shown that we are capable of doing such work. It's a kind of reputation.
E. P.: Maybe the restoration of reputation. At one time, we had to do part of the work in the Human Genome project. But they didn't. Because the collapse of the Union and all subsequent events began, when there was no time for genetics. China, which jumped into this project literally on the running board of the train, made about one percent of the genome and after that became considered one of the genomic powers, although at the time of the start of the project they were not yet able to conduct such research.
– The Human Genome project, the results of which were published in 2001, caused unprecedented euphoria: they say, everything has been solved, now they will begin to treat. And then came the disappointment. What is the reason for this?
K. S.: Undoubtedly, the Human Genome project can be called a triumph of our science. Individual genes have been studied before. In the nineties, one gene was found – and immediately an article in Nature. It was an event. And the publication of the complete human genome removed this problem. Many thought that some practical results would follow immediately after reading the genome. But scientists, having received a book with three billion letters-nucleotides, were not really ready to say what was behind this huge information, and even more so could not immediately use it for practical purposes. It was necessary to find out which genes were associated with which diseases. We knew about most of the monogenic diseases associated with mutations in one gene even before this project, but they are only a small and rare part of the diseases. The complete human genome has increased the overall progress of genomics at times. It has become a matrix on which scientists superimpose other genomes to find out the causes of many diseases.
E. P.: Now, taking this book of three billion letters, you can find out how many "typos" or genomic changes there are in it. Comparison with the complete genome allows you not to miss anything. Previously, we only knew individual paragraphs of the book, and maybe we didn't see the main thing. By analyzing the genes of a hundred sick people, we can find out what distinguishes them from healthy people. But how to interpret it? We will find a thousand differences, but we do not always know what the typos found are responsible for – for the disease or for the fact that the patient is blonde and the healthy one is brown-haired. Or the patient is Chinese, and the healthy one is African.
– But something in this thousand differences will be responsible for the disease?
E. P.: Of course, and it is important to find out. Then you need to take a thousand patients with one disease, sequence their genomes and compare them with healthy ones. And it will be possible to identify which "typos", or mutations, most often coincide in these patients and may be responsible for the development of the disease. Actually, we did such work on the genome of kidney cancer.
– How many diseases associated with gene errors can already be diagnosed?
E. P.: About a hundred monogenic diseases. And it's not easy with polygenics yet. Alzheimer's disease associated with a single gene is only one percent of cases of this disease. Many cancers are multifactorial diseases. Now thousands of laboratories are looking for the origins of polygenic diseases. It's a very difficult job to understand which genes are associated with them.
K. S.: Since a lot of scientists are working on this, I think that in the next ten years the genomes of many oncological and other polygenic diseases will be decoded.
– An ordinary person will immediately think that these diseases can be treated after that. But, probably, the nearest practical application is diagnostics, and as for gene therapy, is it not the near future?
KS: That's right. An absolutely stunning example is the non–invasive diagnosis of Down's disease in the fetus in the womb. Back in the 1970s, scientists found out that fetal cells can circulate in the blood of a pregnant woman. And they can be caught and diagnosed. But this became possible only after the genomic revolution.
– What do you call a revolution – cheaper sequencing?
K. S.: Cheaper, faster sequencing, computer data processing.
– And why were you interested in Down in the first place?
KS: As you know, humanity is aging, and women are increasingly giving birth after thirty. And it turned out that after thirty, the risk of having a child with Down's disease increases dramatically.
– Nature has not provided that women will first make a career, and then give birth.
KS: That's right, you need to give birth after twenty.
E. P.: At the mature age of the mother, one sick child is born for 800 healthy ones, after forty years – ten times more often. So that's a problem. The risks are greatly increasing. When my wife was pregnant with her third child, after biochemical tests, she was told that the child was at risk for Down. Biochemistry gives a very inaccurate forecast – about one in ten. This means that nine women have to make a painful decision about what to do next. There is such an invasive procedure – you need to extract the cells directly from the mother's womb. But this procedure is traumatic and unsafe, the child may die. I did the genetic analysis myself and said that my wife was fine.
K. S.: More than 400 thousand such studies have already been done in America, there are a lot of them in China, and they are doing it in Europe. In the US, this will soon become a routine screening program for pregnant women. In Russia, a couple of laboratories are also doing it, including the company "Genoanalytika", for which we developed the technology.
– What do you mean, developed? I heard that this is American technology? I thought ours worked under licenses.
E. P.: We have our own technology, the Europeans have their own, the Chinese have their own. We used a general principle. Besides, you can't always buy everything. Or the conditions are unacceptable.
– They said that soon the child will be born and immediately receive a genetic passport. It turns out that he will receive it already in the womb?
E. P.: This is really important. Currently, such large genome errors associated with trisomies are being watched, when chromosomes are incorrectly divided and a child has three chromosomes instead of two. These are Down's disease, Edwards syndrome and Patau syndrome. With the increase in the "resolving" ability of technologies, scientists will deal with smaller mutations, and we will be able to obtain the genome of a child already in the tenth week of pregnancy. Actually, such work has already been done for a lot of money. It was important for parents to know for sure if there were any serious illnesses while there was an opportunity not to carry a child.
KS: And many more want to know the sex of the child at an early stage. By the way, when China began to do an analysis for Down's disease, as a side information, it was possible to find out information about the child's gender. But the Chinese government has banned the disclosure of this information to parents. This is generally one of the unresolved ethical issues of genetic research. Others will also arise: will such information become available to the employer or the policyholder? You are now paying with a credit card in a restaurant, and the manager at the bank can easily find out where you are, how much you spent and what you ate. And what will happen when you give your passport with genetic information?
– And it will be the same as with the cards. If they don't learn how to protect better, then genomic databases about any person will be sold on the market.
K. S.: Seriously, genetic research will help not only to identify various diseases, but also to decisively change the diagnosis, as well as the selection of medicines for a particular person. Now these are single tests, for example, to determine the dose of warfarin prescribed after cardiovascular surgery. It dilutes the blood. The dose is different for each person, if you give something in the middle, you can cause either bleeding or thrombosis. Now a lot of work is being done on cancer – how to choose the right drugs for a particular patient. Genomic data will be a real revolution in medicine, which will be personalized and predictive.
E. P.: Naturally, genome data alone is not enough for a doctor. This does not negate traditional analyses and other data that will be collected much better and faster than now. Google has launched a five-year project involving 200 volunteers. Their iPhones read many parameters: pressure, pulse, cardiograms, information is also added there, what I ate, how much I slept, when I was worried, and so on. And then computers will process all this and find out the connection of genetics and external factors with the human condition and diseases. This is the future of medicine.
– What about gene therapy?
KS: It's too early. It has been tried since the early nineties. But there are three main unresolved problems: the delivery of the right gene, its integration into the right place, whether the gene will work there and how well. It seems to me that rather the therapy of genetic defects will be solved through cellular technologies. In this sense, the technology of induced pluripotent cells, from which the necessary cells or even organs with the correct genome can be cultured, seems to be the most promising.
About bulls– Various projects have been and are being carried out in your laboratory.
I've heard about the genome of the Russian man, about the genomes of ancient people, about the mammoth and about bulls…
K. S.: Yes, animal husbandry is not the strongest side of our agriculture. Breeding work was largely nullified. We are now mainly buying bulls abroad. And we need to understand whether he is a good manufacturer. Without genetics, we need to wait until the bull grows up, until he gets married, until his daughter starts giving milk. It's a long time.
– And what, do the milk yields depend heavily on the father?
E. P.: What's so surprising about that? People have a lot of things depending on their dad. A bull can produce thousands of spermodoses in its lifetime, and a cow, no matter how good it is, can produce from two to four calves. If the father is good, then even with a weak mother, the quality of the herd can be significantly changed on an industrial scale. Dad is a manufacturer. And an index is assigned to it. If you take genetic information from him, you can say whether he will be a good producer or there is nothing to spend on him for food, you need to give it to meat.
– But this has been done in the West for a long time.
E. P.: Well, yes. It was only when animal husbandry in Western countries moved to a new genetic level, in the early nineties, that you know what happened here. So we have to start from scratch. We want to make a genomic index for the whole of Russia so that we do not depend, as now, on the West.
– Are you sequencing the complete genome of bulls?
E.P.: No. We are looking at 55 thousand specific DNA sites, the totality of which will tell us what milk yields, milk fat content, and so on are possible. A certain algorithm outputs the index of a particular bull. Now we are collecting statistics. And then the companies that sell sperm doses of bulls will focus on their genetic index. And there will be no need to keep a herd of animals with unknown virtues.
About the mammoth– And why a mammoth?
E. P.: But it's interesting, what is the genome of an animal that lived 40-50 thousand years ago!
– I read that back in 2006, the mitochondrial DNA of a mammoth was sequenced in the USA by our compatriot Evgeny Rogaev, and a little later nuclear DNA was sequenced in Canada and Pennsylvania. What is our contribution?
E. P.: That's right. However, we could not pass by this mammoth, which was found on the Chroma River on the Yamal Peninsula, because of its amazing preservation. It is extremely difficult to work with ancient DNA, and the quality of the material is crucial here.
– Americans and Canadians managed to decipher about 70 percent of the mammoth nuclear genome.
E. P.: And it looks like we will decipher everything. And with good quality.
– And what can be learned from what you have read?
E. P.: For example, how mammoth genes differ from elephant genes. It is known that mammoths had a good adaptation to a cold climate and a slow metabolism, unlike modern southern elephants. In the future – while I'm fantasizing – it will be possible to create the necessary proteins.
About the genomes of Russian and ancient man– A few years ago you sequenced the genome of a Russian person…
KS: Maybe we shouldn't talk about him, especially now?
– Why not and why especially now?
K. S.: Because speculation begins: for example, how the genome of a Russian differs from the genome of a Ukrainian. Here Egor was asked provocative questions on one TV channel like "There must be genetic differences between freedom-loving Ukrainians and slavish Russians?". We have sequenced the genome of one person so far. Of course, this is very little to say about Russian identity. A lot of research is needed. We found out that the genome of the Russian almost does not differ from the genomes of our Slavic brothers and from many Europeans too. We have not found any noticeable Tatar-Mongol influences, contrary to the well-established opinion that a lot of things are mixed up in us because of the centuries-old Tatar-Mongol yoke. Ideally, it would be nice for us to make a genetic map of the country. There are already genomes of Yakuts, Buryats, Khants, Old Believers. This is information, in particular, to understand the susceptibility of different ethnic groups to various diseases, medicines, and food. So far, there is too little such information. Well, you probably know such examples that the best "digestion" of alcohol by Russians, unlike Asians, depends on genes. Or the digestibility of milk, unlike the inhabitants of the Mediterranean, in whose traditions there was no consumption of milk.
E. P.: Knowledge of genomes can be important for those groups of people who live apart and practice closely related interbreeding. There may be a high concentration of monogenic diseases.
– As an example, Ashkenazi Jews are often cited, who even seem to have to take special tests before giving birth to a child. I also heard that there are such problems in our villages in the Caucasus.
E. P.: Yes, we sequenced the genomes of one family of 18 people and found two important mutations in them. All family members had them in different combinations. Therefore, children often died there. And since there are only two large families in the village, about fifty people each, they marry each other. In a good way, you need to do a test for these mutations, otherwise they will have to do in vitro fertilization and then choose a non-mutant from the embryos.
K. S.: Scientists are interested in whether different peoples have any distinctive genes that make it possible to resist infections. For example, it was found out that Pomors and Icelanders have genes that allow them to practically not perceive HIV.
– What can be found out by analyzing the genomes of ancient people?
KS: A lot of things. This is generally an extensive topic. In short: migration paths, who came from where and what happened next. Isn't it amazing that American Indians have Altaic roots? Or that the Basque language is very similar to Adyghe? How did people from the Caucasus end up in Spain? Except with Jason and the golden Fleece.
We made an analysis of the bones of the Maikop and Novosvobodnenskaya cultures that lived six thousand years ago on the same patch in the region of Adygea. And it turned out that some came from Europe, and others from Near Asia. And before that, there were only guesses.
– Why are you interested in the Maikop culture, and not something closer, "poslavyaniste"?
E. P.: It all depends on contacts with archaeologists. One of our employees is familiar with the famous St. Petersburg archaeologist Alexey Rezepkin. The archaeologist, based on his knowledge of the types of burials and artifacts, developed the hypothesis that different cultures converged on this patch – one Central European, and the other Near–Asian. And he asked if it was possible to test it at the genetic level. And we checked. And confirmed his guesses.
In Russia, actually, there are a lot of excavations, but we are not looking at genomes, but foreign laboratories.
- why?
E. P.: All the most significant works, for example on the Denisov man, were made abroad. At that time, our country did not yet have the potential for such research. And now, by inertia, archaeologists are turning to Western laboratories. The analysis of ancient DNA is a very complex process both technologically and in the sense of mathematical processing. It also requires high qualifications and experience, which we are just starting to acquire. And we would like to carry out such an analysis within the country as we gain this experience. This is primarily our question, our history. And now we got one bone – and we are glad.
About the elite– Somehow it seems that we get some pieces.
Are we the last ones everywhere? Why is that? What are we missing? It seems that your laboratory at the Kurchatov Institute was recognized as the largest in Europe?
E. P.: Our participation in the cancer project has shown that the niche "genes – health" is highly competitive. We cannot compete in modern conditions with the Americans, the British or the Chinese. Reagents are more expensive, the delivery time of anything is months, problems with customs, with equipment. We don't have an engineer who will support one sequencer. In niches where time decides everything, we lose. Whoever did it first, skimmed the cream. If we put ten groups, we will come last, not because we are fools or do not know how to do something. This is how our life is arranged. Therefore, we try to choose those areas where competition is minimal, where only we own unique material. Here we got a unique bone, and we will not give it to anyone and can safely deal with it.
– But we still have other well-known laboratories and scientists. Why not cooperate, not take significant projects, the same historical or on diseases that are important in our country? After all, the Chinese have created the largest genomic center, and at first almost without funding from the state?
E. P.: This is the right question And the right topics. Apparently, our elite has not yet matured, does not understand that this is the future. There is no firm will. In addition, we have quite disparate laboratories, research groups often with conflicting departmental, academic or personal interests. This is a very painful question.
KS: I keep repeating that a country that has genetic information and understands it will rule the world. There are powerful centers in America, Europe, and China. They accumulate this information. They will use it.
– But maybe in the conditions of globalization (true, now faith in it is greatly shaken) it is not so important to own this information, there is a lot of open data?
E. P.: Compare this with the possession of information on nuclear energy. Only countries that know the technology have the ability to make such energy. So it is with genetics. We will buy everything.
K. S.: Besides, the medicine that will be made in Europe may not work on the Buryats. This is also possible. What can I say! The world is moving towards bioeconomics. This information is needed for medicine, for agriculture, for the forestry industry. All fine chemistry can be replaced by bio. I'm not talking about the fact that without developing this area, we will lose new generations in it. As one of our scientists bitterly jokes, the horror will not be when we stop publishing in Nature, but when we stop understanding what is written there.
Portal "Eternal youth" http://vechnayamolodost.ru22.09.2014