What will genomic technologies lead to?
About the genetics of the future and monomolecular sequencing
Today, having the opportunity to read the genome, we have a lot of information – what to do with it? How to use this information in life? Literally four or five years ago, it became possible to read a lot of nucleotides, whole genomes.
For basic research, this is an undeniable advantage: scientists analyze a lot of data from the point of view of evolutionary problems, genomics and epigenomics. However, this has also given rise to a number of informational problems – how to store and transmit this information. How to apply this new knowledge to everyday life is a big question.
At a conference in Heidelberg on the cancer genome, the fact was given that only the German part of the Heidelberg project generates five and a half terabytes of information per day! For example, Twitter generates about 12 terabytes, Facebook - seven. This is a kind of challenge to modern, not only scientific, society – what to do with this information?
Today, the technology of determining the sequence of genetic letters is in demand in many areas of human life – this is criminology, medicine, history, and industry. To solve these problems, we read a little bit at a time, read very small sections of DNA. And reading a lot, whole genomes, and working with this information is becoming more accessible today, but the demand for such "reading" in ordinary life is small. This is primarily due to the fact that we do not fully understand genetic texts.
However, as our knowledge of genetic texts accumulates, the utility of sequencing will only increase. Already today there is one application that people really need and it is unthinkable without a large amount of sequencing. The so-called "non-invasive determination of fetal aneuploidy". We are talking about the early diagnosis of pregnancies in which the fetus carries chromosomal aneuploidy. First of all, trisomies on chromosomes 13, 18 and 21 (trisomy on chromosome 21 – Down syndrome, 18 – Edwards syndrome, 13 – Patau syndrome – <url>). For such an analysis, only 5 ml of the mother's blood is required. Blood sampling can be done at the clinic without resorting to hospitalization.
In maternal blood, in addition to cells – lymphocytes, leukocytes, erythrocytes and others – there is a small amount of free DNA that was formed as a result of lysis or apoptosis of both blood cells and placental cells, which, as is known, carries the genotype of the fetus (lysis – dissolution, destruction of cells and their systems – <url>). Isolation of freely circulating fetal DNA from the mother's bloodstream makes it possible to analyze the quantitative composition of the chromosomes of the unborn child. Of course, the mother's DNA is also present in the analysis, in general, the separation of the genome of the mother and fetus is a mathematical problem. It turns out that about 95% of the freely circulating DNA is the DNA of the mother, and only 5% is the DNA of the fetus. Imagine that the fetus has a trisomy of 21 chromosomes, if all the other chromosomes are normal, then how many "extra" 21 chromosomes in the general analysis? – just a little bit. You can feel it a little bit statistically, for this you need to collect a lot of data. Counting everything in a row, without resorting to selective reading of the genome, it is possible to detect trisomy not only on chromosome 21, but also on the 13th, on the 18th, in which chromosomal abnormalities in the fetus are most common.
There are American, Chinese, and Singaporean companies that are actively introducing this technology to the market, because it is in demand, because it is safe and inexpensive, and most importantly, the specificity and sensitivity of the method reach almost 99%.
And what else can we learn from the genome? Relatively speaking, it will be possible to make some association between diseases, between life expectancy and fate, between the main phenotypic and genetic characteristics.
All these are the most difficult mathematical tasks for the transmission, storage and analysis of information. Three billion parameters are analyzed (and in fact more, given the diploid nature of the genome, and we are not talking about epigenetic information), on the one hand, and about a hundred, and maybe more phenotypic/medical parameters, on the other hand. And it is necessary to find some association between them.
Modern man lives in the information space, he wants to know everything and about everything. He makes the same demands on his genome: a person wants to find out from his genome what will happen to him, whether he will get sick, what will happen to his head, whom he will marry. Of course, we do not have answers to most of these questions today. Only in rare cases, looking at the genome, you can say for sure that you will get sick, more often you can talk about a predisposition to a certain disease.
I recently heard that the British government has set the task of sequencing 100,000 people, mostly sick. This is the accumulation of large amounts of data. We are at the beginning of the era of accumulation of this knowledge. So far, the main purpose of analyzing these data is to increase the effectiveness of disease treatment.
I have a feeling that in the future the genomes of every person born will be sequenced. I don't think we are in danger of any Gattaca in the near future (Gattaca is a 1997 dystopian thriller by New Zealand director Andrew Niccola - <url>). But whether the time will come when genetic testing will be carried out during employment and insurance depends on the speed of technological progress in the field of sequencing, the availability of this technology to meet any needs of society. In my opinion, now you cannot insure your life for more than $2 million without passing a genetic test for Huntington's disease, which can be 100% predicted. But this is rather a rare exception to such a monofactor disease, which manifests itself not from birth, but in adulthood.
There is already an ethical moment in the analysis of the genome, and it will arise more and more often, due to the possibility of access to individual genetic information. The European Community tracks everything here very accurately. You can deposit a genome, but no one will know about your name in connection with your genome. Probably, both Europeans and Americans would like to have as many genomes as possible – impersonal, but with a medical history. How to make sure that the personal secret of a person, his family and their sores is not revealed?
Can you identify some trends in theoretical and technological terms? From the point of view of the nearest scientific and scientific-practical prospects, there are two directions.
First– personal therapy will be introduced, in particular, in the treatment of cancer, when a biopsy is taken, the genotype of this tumor is established. Now huge efforts are being spent on classifying tumors. Depending on which pathway of molecular signaling is disrupted in the tumor, a targeted effect will be carried out on it. And this will be a purely individual approach, developed based on the genotype of a particular person's tumor.
Given the fact that the heterogeneity of cancer is very large, clusters of pathways will be created that are disrupted in the work of the tumor cell. According to this criterion, after clustering of the tumor, optimal therapy can be created for each tumor. That's what the prospect is with cancer.
Regarding the technological perspective. From the point of view of DNA, it is a transition to monomolecular sequencing. The simplest story is when you have a nanopore. It can be organic or inorganic, like a hole in some polymer. We drag a DNA molecule through this nanopore under the influence of an electric field. We make a "survey" of how the distances between the atoms of the pore are deformed depending on which letter of the genetic alphabet "crawls" through it. This will be monomolecular sequencing. Having a large number of such pores and being able to detect their deformations, you can read genetic texts without resorting to preliminary sample preparation, primarily PCR. Avoiding the PCR stage can potentially reduce the number of errors in texts, those errors that are associated with polymerase amplification (amplification is the process of forming additional copies of sections of chromosomal DNA - <url>). This is a certain technological perspective around DNA.
The next possible step is protein sequencing. Now we are talking about genetic information, in fact, without being implemented, the information is worth little. Of course, we get sick, or we are the way we are, because we are made up of proteins. Proteins do not work efficiently enough, because some enzymatic center has been destroyed. Therefore, protein sequencing, or even better – with all the variety of their modifications, i.e. reading amino acid texts is the next step.
However, technologically it looks problematic. The fact is that polymerase chain reaction (PCR) is at the heart of any manipulation with DNA. You can multiply any molecule to micrograms, to a reasonable amount that can be manipulated in the laboratory. There is nothing like that with proteins. The emergence of single-molecule sequencing technology with a single molecule without its amplification gives rise to the hope that proteins can also be sequenced. However, proteins carry a lot of modifications, which will affect the variations in the "breathing" of the nanopore when dragging the amino acid. And there are also a lot of protein modifications. But if you learn how to do it, then the prospects are simply great.
The cell consists of a lipid membrane, inside of which there are many proteins. DNA is a small part, it only stores information. It stores information about proteins, like a charter. The charter is a text, it's DNA, and what you do is proteins.
Okay, then I'll ask for your brief futuristic forecast. My prediction is the transition to single–molecular DNA sequencing, this will simplify the problem of working with a very low concentration of DNA, in many ways, even when working with PCR, you can make an error.
If this technology starts working, it will be able to adapt it for protein sequences as well.
As for medicine, what interests people, the most urgent question is to understand the genetics of multifactorial diseases, where there are many factors, and not only genetic. If it becomes clear that genetics plays at least some serious role in the causes of, say, a heart attack, if it is proven, then it can affect the entire lifestyle of a person. Medicine will become personal. This will become a healthy lifestyle medicine. It will be possible to predict diseases, rather than treat the patient after the fact.
Egor, we talked a lot about technology, tell me, what interests you in the field of ideas, what is most important for you here? There cannot be many such gigantic developments as the discovery of the genetic code, the discovery of DNA.
The changes are not as large-scale as Watson and Crick's discovery of the DNA helix when the world changed. But, say, about seven years ago, a whole direction was discovered – RNA interference.
My main interest is in the field of epigenetics, what I grew up on, and what has always interested me. Molecular problems of memory, molecular problems of consciousness are an interesting area. This is to some extent related to epigenetics, some scientists say that this is due to the histone code in a particular neuron, and, in fact, with the technologies that appear based on the analysis of the genetic material of one cell, you can try to do it all.
What is connected with stem cells and cell reprogramming, when you can take a somatic cell, when you can then differentiate it and make "spare parts" – there are a lot of problems, but also prospects. All somatic reprogramming is directly related to the modification and rewriting of epigenetic information.
The next most interesting direction: people have learned how to edit the genome. Let's say there is a mutation that leads to some kind of disease. You can take a somatic cell, first reprogram it, turning it into an induced pluripotent one, and then eliminate a single mutation in its genetic material. It turns out that this is your genome, except for one harmful mutation. Subsequently, the edited stem cells can be differentiated into the type of tissue affected by the disease and try to carry out cell therapy with their help.
But even now, very interesting things are happening. Ideas about how modern man came about are changing. We understand who the Neanderthals are, what contribution they have made to the formation of modern man. We can assume the ancestral homeland of the first Indo-Europeans.
A lot of interesting things are happening in a particular field of knowledge in molecular biology. Unfortunately, our country is not very much involved in the formation of this knowledge. But to paraphrase the words of my colleague – as long as we can read and understand what is written in leading scientific publications, as long as we can consider ourselves involved in this civilization.
The lifetime of articles in the Nature-level journal is catastrophically shortened. If you look at who refers to articles from 2003-2005, then they refer to single articles. For most articles there is a peak of citation, the width of this peak at half-height is very small and is constantly decreasing. I have a feeling that publications in top Western magazines are often dictated by considerations of fashion and scientific politicking. People are trying to publish their results at any cost, people need to renew their grants. What will happen next if we further increase the resolution of scientific knowledge? Will there be something fundamentally new in the basic blocks: DNA is the carrier of genetic information, then RNA reading, then protein? Will a new science arise on the basis of classical molecular biology, as quantum physics arose on the basis of Newtonian and Maxwellian laws of classical physics?
You definitely need to stop at some point and catch your breath in this race for publications, for a specific extension of your grant. I want to look not only at my specific hole that you have hollowed out in this granite of science, but to see what it looks like in general, to look at this general knowledge. Is society ready to digest the amount of information that we are ready to give it? What will society do with genomes? Perhaps society is not keeping up with the progress that is in genomics. Society means politicians, sociologists, philosophers. They do not have time to comprehend this picture. What does this mean for a person, for his reproduction, for the formation of a family? It is obvious that behavioral patterns have changed dramatically over the past hundred years, the destruction of traditional society has occurred.
Genomic information – isn't this a real Gattaka?What will happen if I am not hired based on genomic information?
Is it true? Or are scientists like priests, maybe they invented everything and none of this exists? Maybe it's a fiction, but in fact I'm just being discriminated against? But we will face both social fears and behavioral phobias caused by the genomic information revolution.
Theoretical knowledge is tested experimentally, but still technology is advancing so fast that the majority of the population will always take everything on faith.
What about this?Society must digest the information of this genomic revolution.
We haven't talked at all about minimal genomes, about creating a new life. While we are talking about mycobacteria, small organisms that we can form, first come to a minimal genome, and then saturate the genome with useful properties. This is the same story as with the TV, with nuclear energy, as any achievement of reason and civilization, you can either use it for good or turn it to harm a person.
There is also a lot of politics around genomics. The Chinese company Beijing Genomics Institute (BGI) is the Beijing Genomic Institute, although they are sitting next to Hong Kong – now it is a private company, it is a giant sequencing factory.
There are more than a hundred of the most powerful sequencers, and they are all produced by almost one company – Illumina, practically a monopolist in the sequencer market. What the Beijing Genomic Institute consumes accounts for a third of Illumina's revenue. And suddenly BGI had an interest in the American company Complete Genomics, which is to some extent a competitor of Illumina. The Chinese offered $117 million for Complete Genomics, and Illumina offered $120 million. But Complete Genomics decided to go to the Chinese, then Illumina appealed to the US State Department, saying that the Chinese would create bioweapons and would destroy American people. The deal was frozen for political reasons. BGI found itself in such a situation that Illumina stopped supplying reagents, their life somehow stopped. But this is also bad for Illumina, because they lose a third of their turnover. (This whole situation as of December 2012 – January 2013, now I don't really follow how it ended... – EP).
The situation requires reflection. And, of course, the decision was made not by scientists who understand that before the creation of bioweapons as before the Moon, but by politicians who live and think in completely different categories. How much society is ready for such collisions is a question.
People should understand that they are entering a reality where there is (will be) cloning of human organisms and a huge flow of genomic information. Reproduction has ceased to be a topic only for science fiction writers. We need to think about this, because technologically we are developing at a rapid pace, but we do not have time to comprehend.
Portal "Eternal youth" http://vechnayamolodost.ru23.04.2013