The age of gene surgery is coming
Alexander Telishev, "Russian Planet"
The famous Russian-American biologist Konstantin Severinov gave a lecture yesterday at the ZIL Cultural Center, in which he told the public about how the development of gene technologies over the past century has affected the appearance of medicine, and expressed his opinion on how they will change in the future. According to him, society should not be afraid of transgenic products and genetic medical research, as they have already saved thousands and millions of lives and in the near future, which he calls the "century of gene surgery", they will affect our lives even more.
Konstantin Severinov is one of a small group of Russian scientists who returned to Russia in the mid-2000s after gaining recognition and fame abroad. Today he is simultaneously a professor at Rutgers University in New Jersey, a professor at Skoltech and an employee of the Institute of Molecular Genetics of the Russian Academy of Sciences. He has over 200 publications in leading scientific journals, including such prestigious ones as Nature and PNAS. Severinov, together with Dmitry Livanov and Konstantin Sonin, is considered today one of the ideologists of the reform of the Russian Academy of Sciences carried out in 2013 and the transformation of the Academy into a "club of scientists".
The scientist began his story with a statement that many people do not understand how deeply rooted and how widely used various genetic technologies are in medicine today. "This is, of course, a very subjective view of how medicine and biology developed, but I decided to tell you about technologies that have already affected the lives of hundreds of thousands and millions of people. We are all beneficiaries of these discoveries and innovations, and many people just don't realize that this is really the case."
To understand how much medicine and the entire economy of the planet as a whole today relies on genetics and molecular biology, we need, as Severinov emphasizes, to turn our eyes to the past: at the end of the XVIII – beginning of the XIX century, vaccines were discovered – the first means to combat infections invented by man.
"The vaccination technology itself is extremely simple – a weakened form of the causative agent of the disease is introduced into the body, which is harmless in itself, but at the same time it helps our immune system to find ways to deal with a real threat. The immune response develops naturally – this is what nature has given us, what we have received in the course of evolution, since parasites have always surrounded us, and we have developed a way to fight them," explains Severinov.
Konstantin Severinov. Source: sk.ru
According to Severinov, doctors and biologists quickly faced a problem – it is not always possible to find a weakened form of the pathogen that would be suitable for vaccination. For example, scientists at the beginning of the XX century have been searching for ways to combat the polio virus for a long time and unsuccessfully. The problem was that this pathogen reproduces extremely poorly outside the human body, which is why scientists could not get enough of the virus to pull out its molecular "teeth" and test the safety of such a vaccine without resorting to human experiments.
"Two people – American Jonas Salk and our compatriot Mikhail Chumakov – have found a way to get a very large amount of the virus. Such vaccines were not perfect and had the most serious and even irreversible side effects, but they allowed a person to continue his existence and not die," the scientist continues.
The second serious problem that scientists developing vaccines quickly faced is that many viruses and bacteria change very quickly. For example, as Severinov explains, new strains of the influenza virus appear every year, and scientists constantly have to guess how the pathogen will change in the next season to get a vaccine. According to him, such predictions cannot be made without a deep understanding of how the virus genome works and how its genes change, which remains an unsolved task for molecular biologists.
There is also an alternative way to fight pathogenic bacteria – antibiotics. They were invented much later, at the end of the first third of the last century, when the British biologist Alexander Fleming accidentally discovered penicillin. After antibiotics began to be widely used in medical practice, it became clear to scientists that they are not a panacea – it turned out that microbes very quickly acquire resistance to them. Penicillin, as Severinov emphasizes, is ignored today by about 95% of bacterial strains living in hospitals and affecting patients whose immunity is weakened by operations or other diseases.
"What are the trends with the development of antibiotics? Unfortunately, they are not the most pleasant – the golden age of antibiotics has passed, and since the 90s of the last century, we have not been able to discover a single new antibiotic, but bacteria are becoming more and more immune to drugs. In the current century, a paradoxical situation may arise – diseases that we considered trivial and easily suppressed with antibiotics in the XX century may become a serious problem for doctors in the near future. Just walking around and digging under a bush is pointless – you won't find new antibiotics in nature," the Russian biologist noted.
According to him, there is still a way out of this stalemate for vaccines and antibiotics, and it lies precisely in what has been discovered and created over the past 50 years in the field of molecular biology.
"We are all made up of cells, and we are all the embodiment of the genetic information that is recorded in our DNA. It doesn't just have your name, but it has everything else. DNA can be represented as a kind of text consisting of words-genes. It is due to them that boys and girls are born in humans, and kittens in cats. In total, our genome contains about 30 thousand such "words", each of which contains instructions for the assembly of proteins that are responsible for muscle movements, eye work, for the digestion of food and for all other processes in the body. If there is a typo in this word, then this error will be reflected in the structure of the protein, and it will not work. This is a genetic disease," Severinov explains.
According to him, the first major breakthrough in molecular biology and in the field of its application to medicine occurred in the 70s of the last century, when biologists discovered a process in bacteria that is now called molecular cloning. "The discovery of molecular cloning has given rise to a whole class of fundamentally new drugs, as well as those fears that are inherent in those people who are afraid of genetically modified organisms. In fact, they are afraid of repeating this in the human body, but this is impossible from the point of view of molecular biology. What's really going on?".
As Severinov explains, there is a special, as he calls it, "selfish type" of DNA in bacteria, which scientists call plasmids or pseudochromosomes. They are small circular strands of DNA, "thinking that they are also chromosomes," capable of dividing and being inherited. It is these molecules that are responsible for the acquisition of antibiotic resistance.
"Werner Arber, Hamilton Smith and Daniel Nathans discovered in the seventies of the twentieth century a special system in bacteria – the so-called molecular scissors, a special protein that can cut plasmid DNA. This system is able to recognize a special sequence of "letters" inside the plasmid and crack the thread strictly in this place. Foreign DNA obtained from other bacteria or from the external environment can penetrate into this incision and attach to the cut ends. Thanks to this, microbes can exchange "recipes" for protection against antibiotics."
Scientists realized almost immediately that plasmids inside bacteria can be used for the benefit of humanity – with their help, you can "train" a microbe or yeast to produce molecules of antibiotics or other drugs, the assembly instructions of which are contained in the genomes of other microbes.
"Is it good or bad? Two years after this discovery, Arber called a conference of biologists and invited them to discuss the possibility of banning this technology. There were reasons for this – in some countries, including the Soviet Union, it began to be used to create bacteriological weapons. No one prevents you from inserting a plasmid into a harmless E. coli that encodes something completely bad, turning it into a killer microbe. But at the same time, no one prevents you from doing something the opposite," Severinov explains.
According to the professor, the discovery of plasmids gave humanity the first example of how molecular biology and medicine can improve our lives and save millions of people. We are talking about the transplantation of genes necessary for the production of insulin into bacterial plasmids, which opened the way for the mass production of this hormone, which millions of people need regular injections of today.
"Insulin is produced in the pancreas of humans. How to get it? One of the options is to take corpses and secrete the hormone, but, firstly, you will not get enough corpses, and secondly, there is very little insulin in them. Therefore, doctors have been using another source of insulin for quite a long time – the pancreas of pigs or cows slaughtered in a slaughterhouse. It is very similar in structure to the human hormone, but still differs from it by one amino acid, which is why, with the long-term use of animal insulin, a lot of extremely unpleasant side effects occurred in the body of diabetics. Of course, we don't turn into pigs, but it gets very bad. How do we do this? The answer is molecular cloning," the biologist continues.
But bacterial insulin, as it turned out, is also not very good – it needs to be cleaned and it also has side effects. Therefore, over time, with the development of molecular biology, all laboratories in the world switched to the production of insulin in special cultures from human cells, in which something similar to a bacterial plasmid is inserted. The market volume for this industry, as the professor notes, is tens of billions of dollars.
"All people who are afraid of GMOs should now understand that almost all insulin, on which the life of all diabetics on earth depends, is born in genetically modified bacteria or human cells. Similarly, interferon, an antiviral drug, and erythropoietin, a drug to fight leukemia, are produced. This is a huge market, and the number of recombinant proteins will increase more and more"
The "domestication" of bacteria and the discovery of the mechanism of molecular cloning gave doctors another fundamentally new way to fight infections, which has its roots in vaccines and how the body fights pathogens. In the 80s of the last century, molecular biologists realized that they could use the immune system for the controlled production of antibodies. "If you remember, in order to create a vaccine or vaccinate, we need to find someone, catch up with him and inject him with something. Now we don't need it thanks to the new, extremely powerful and promising technology of monoclonal antibodies",
According to Severinov, it works as follows: "an antigen is injected into an animal or a test subject – a certain solution of a substance, parts of a pathogen that are interesting to you for some reason. The immune system will begin to react to them and produce various antibodies in the cells that are concentrated in the spleen. And at this moment, once in a lifetime, we can thank God, nature or anyone else for the fact that cancer exists. It turns out that it is possible to merge those cells that produce antibodies and cancer cells. A new cell, a hybridome, will arise, which will acquire eternal life from a cancer cell, and from an immune cell – the ability to produce antibodies. There is a whole molecular factory in a test tube, producing the same molecule."
Such antibodies can be produced not only to fight bacteria and viruses, but also with other threats – for example, with the same cancer. In principle, as Severinov explains, antibodies can be "trained" to recognize special protein outgrowths on the surface of cancer cells that are not present on ordinary cells, and make them noticeable to the human immune system.
To date, there are several dozen such drugs that noticeably prolong the life of people with a cancerous tumor or help them get rid of cancer. There are monoclonal drugs to fight rectal cancer, lymphoma and many other diseases. However, this technology also has problems – antibodies obtained in this way are often not completely compatible with the human immune system due to differences in the structure of our genes and the genes of mice that control its work.
Molecular biology has also found an answer to this challenge – at the end of the 80s, biologists learned to replace mouse genes responsible for the immune system with their analogues from human DNA. Thanks to the creation of such "humanized" mice in 4-5 years, Severinov estimates that dozens of new anti-cancer drugs will appear on the market, 100% compatible with the human immune system.
But what to do, the lecturer asks the audience, if the problem is not in bacteria, viruses, parasites or even cancer cells, but in small errors in the DNA itself or in disorders in the body itself that lead to the development of such serious diseases as leukemia or Parkinson's disease? Recent advances in the field of molecular biology allow us to hope that doctors will find a solution for them.
First of all, we are talking about reprogrammed stem cells – ordinary skin cells or other connective tissues, which scientists have forced to "forget" their former functions and turn into an analogue of embryonic cells capable of turning into any tissues of an adult organism. This discovery was made quite recently – in 2005 or 2006, the Japanese molecular biologist Shinya Yamanaka published an article in which he described a method for converting cells contained in blood into stem cells.
"Garages and fences often write about "stem cell treatment". I must warn you right away that everything you have heard or will hear from such people is a complete scam. There are no clinically approved stem cell treatment technologies, except – formally – procedures for transplantation of hematopoietic parts of the bone marrow in leukemia," Severinov warns.
What, then, can stem cells be used for today? According to the biologist, first of all we are talking about personalized selection of medicines and modeling of complex and incurable diseases, such as Parkinson's or Alzheimer's disease. "What does this mean? The vast majority of medicines today are tested on animals. In general, it's a pity for people, it was during the Second World War that they could experiment with antibiotics, and today all clinical trials are conducted initially on mice with fundamentally different physiology. Stem cells allow us to create human tissues and test new drugs on them. It's not exactly what people imagine, but it's exactly what will be done in the near future."
Organs and tissues of the human body suitable for transplantation can be grown only in the distant future, when doctors and biologists will learn to control the main feature of stem cells – their ability to unlimited division and change of "specialization". The fact is that today no one can guarantee that a cancerous tumor will not arise inside an organ grown from stem cells or inside their culture.
"Unfortunately, stem cells are almost cancer cells, or vice versa. Yes, indeed, it is possible to obtain a population of stem cells and then try to treat some disease in this individual with multiplied "semi-adult" cells. But with a high probability, you will introduce the embryos of future tumors together with normal cells. The only exception here is the hematopoietic tissue – its cells turn into erythrocytes, inside which there is no DNA and which, accordingly, cannot become cancerous," explains Severinov.
Even if this problem is solved, the massive spread of cell therapy in clinics around the world will be hampered by the fact that stem cells are extremely difficult to create and multiply in large quantities.
"For this reason, all these Russian stem cell banks and other similar projects are a complete fraud. They promise that if something happens to you, then bang - a stem cell – and you're fine. For example, something happened to the spinal cord. Yes, it can really be repaired if the progenitor cells of neurons are introduced in a few days. However, the specialists of these centers do not know when misfortune will happen to you, and until they unfreeze the stem cells and grow the necessary organs from them, several months will pass, and it turns out that this cannot be done. We need not just a bank of stem cells, but a whole warehouse of "spare parts" suitable for this person," says the biologist, warning gullible citizens.
There are two ways to solve this problem. The first of them is to create a giant national stem cell bank, which will store cells and ready–made tissues compatible from the point of view of immunology with relatively wide groups of people. Such projects already exist – in Japan, under the leadership of Yamanaki, such a bank will be created by 2022. Japan, as the lecturer emphasizes, is a mono–national and homogeneous country, and therefore such a project will work there for 9 out of 10 Japanese. In Russia and in other parts of the world with a rich history of migrations of peoples and ethnically diverse populations, this will not work.
To the aid of Russia and other multinational countries comes a technology that was discovered quite recently – in 2013, but which was invented by nature hundreds of millions of years ago. As Severinov notes, two years ago, molecular biologists discovered in one of the bacteria a unique genetic "antivirus" – a special CRISPR protein that constantly reads the DNA of the microbe, searches for fragments inserted by the virus in it, focusing on the built-in genomic database of "viral signatures", and removes them.
Another group of scientists led by California biologist Zheng Feng realized last year that this bacterial "antivirus" can be used for virtually unlimited editing of the genome of humans and other animals, inserting and deleting genes or replacing specific "letters" in their structure.
"I must admit to you that I am also involved in the development of these technologies. This protein is a universal molecular scalpel that allows you, if you know where the typo is, to change it. It works perfectly like a clock. Now absolutely monstrous money is going there, a revolution is coming, similar to what happened in the 70s with molecular cloning. And now we are moving on to molecular surgery," Severinov explains.
According to him, the opening of this system allows you to combine all the innovations that he mentioned above. In the case of stem cells, it is possible to solve the problem of finding suitable donors by creating universal cell cultures, creating human antibodies faster, and directly protecting against viruses and bacteria. According to Severinov, the public will see the first medical fruits from the discovery of CRISPR in about 4-5 years.
Portal "Eternal youth" http://vechnayamolodost.ru27.11.2014