"The main thing for life is death": an interview with epigeneticist Sergei Kiselyov

Sergey Kiselev - Doctor of Biological Sciences, Professor and Head of the Laboratory of Epigenetics at the Institute of General Genetics named after N. AND. Vavilov Russian Academy of Sciences. In his public lectures, he talks about genes, stem cells, mechanisms of epigenetic inheritance and biomedicine of the future.

Lifehacker talked to Sergey and found out how the environment affects us and our genome. And we also learned what biological age is assigned to us by nature, what this means for humanity and whether we can make predictions about our future with the help of epigenetics.

About epigenetics and its impact on us

- What is genetics?

Originally genetics was the cultivation of peas by Gregor Mendel in the 19th century. He studied seeds and tried to understand how heredity affects, for example, their color or wrinkling.

Further, scientists began not only to look at these peas from the outside, but also climbed inside. And it turned out that the inheritance and manifestation of this or that trait is associated with the cell nucleus, in particular, with the chromosomes. Then we looked even deeper, inside the chromosome, and saw that it contains a long molecule of deoxyribonucleic acid - DNA.

Then we assumed (and later proved) that it is the DNA molecule that carries the genetic information. And then they realized that genes are encoded in this DNA molecule in the form of a certain text, which are informational hereditary units. We learned what they are made of and how they can code for different proteins.

Then this science was born. That is, genetics is the inheritance of certain traits in a series of generations.

— What is epigenetics? And how did we come to the conclusion that genetics alone is not enough for us to understand the structure of nature?

We climbed inside the cell and realized that genes are associated with a DNA molecule, which, as part of chromosomes, enters dividing cells and is inherited. But after all, a person also appears from just one cell, in which there are 46 chromosomes.

The zygote begins to divide, and after nine months, a whole person suddenly appears, in which the same chromosomes are present. Moreover, they are in every cell, of which there are about 10 in the body of an adult.¹⁴. And these chromosomes have the same genes that were in the original cell.

That is, the original cell - the zygote - had a certain appearance, managed to divide into two cells, then did it a couple more times, and then its appearance changed. An adult is a multicellular organism made up of a large number of cells. The latter are organized into communities that we call fabrics. And they, in turn, form organs, each of which has a set of individual functions.

The cells in these communities are also different and perform different tasks. For example, blood cells are fundamentally different from hair, skin, or liver cells. And they are constantly dividing - for example, due to the influence of an aggressive environment or because the body simply has a need for tissue renewal. For example, in our entire life we ​​lose 300 kg of epidermis - our skin simply sloughs off.

And during the repair, the gut cells continue to be the gut cells. And skin cells are skin cells.

The cells that form the hair follicle and give rise to hair growth do not suddenly become a bleeding head wound. The cell cannot go crazy and say, "I am now blood."

But the genetic information in them is still the same as in the original cell - the zygote. That is, they are all genetically identical, but they look different and perform different functions. And this diversity of them is also inherited in an adult organism.

It is this kind of inheritance, supragenetic, which is above genetics or outside of it, that came to be called epigenetics. The prefix "epi" means "out, above, more."

- What do the epigenetic mechanisms look like?

There are different types of epigenetic mechanisms - I will talk about two main ones. But there are others, no less important.

The first is the standard of inheritance of chromosome packing during cell division.

It provides readability of certain fragments of a genetic text consisting of nucleotide sequences encoded with four letters. And in every cell there is a two-meter strand of DNA consisting of these letters. But the problem is that it is difficult to handle.

Take an ordinary two-meter thin thread, crumpled into a kind of structure. We are unlikely to figure out where which fragment is located. You can solve it like this: wind the thread on spools, and lay them on top of each other in cavities. Thus, this long thread will become compact, and we will quite clearly know which fragment of it is on which spool.

This is the principle of packaging genetic text in chromosomes.

And if we need to get access to the desired genetic text, we can just unwind the coil a little. The thread itself does not change. But it is wound and laid in such a way as to give a specialized cell access to certain genetic information, which is, conventionally, on the surface of the coil.

If the cell performs the function of blood, then the laying of the thread and the coils will be the same. And, for example, for liver cells, which perform a completely different function, the styling will change. And all this will be inherited in a number of cell divisions.

Another well-studied epigenetic mechanism that is most talked about is DNA methylation. As I said, DNA is a long polymer sequence, about two meters long, in which four nucleotides are repeated in various combinations. And their different sequence determines a gene that can encode some kind of protein.

It is a meaningful fragment of a genetic text. And from the work of a number of genes, the function of the cell is formed. For example, you can take a woolen thread - a lot of hairs peep out of it. And it is in these places that the methyl groups are located. The protruding methyl group does not allow synthesis enzymes to attach, and this also makes this DNA region less readable.

Let's take the phrase “you can't have mercy to execute”. We have three words - and depending on the arrangement of commas between them, the meaning will change. The same is with the genetic text, only instead of words - genes. And one of the ways to understand their meaning is to wind them in a certain way on a coil or place methyl groups in the right places. For example, if “execute” is inside the loops, and “pardon” is outside, then the cell will only be able to use the meaning of “have mercy”.

And if the thread is wound differently and the word "execute" is at the top, then there will be an execution. The cell will read this information and destroy itself.

The cell does have such programs of self-destruction, and they are extremely important for life.

There are also a number of epigenetic mechanisms, but their general meaning is the placement of punctuation marks for the correct reading of the genetic text. That is, the DNA sequence, the genetic text itself, remains the same. But additional chemical modifications will appear in DNA, which create a syntax sign without changing the nucleotides. The latter will simply have a slightly different methyl group, which, as a result of the resulting geometry, will stick out to the side of the thread.

As a result, a punctuation mark arises: "You cannot be executed, (we stammer, because there is a methyl group here) to have mercy." So another meaning of the same genetic text appeared.

The bottom line is this. Epigenetic inheritance is a type of inheritance that is not related to the sequence of the genetic text.

- Speaking roughly, is epigenetics a superstructure over genetics?

This is not really a superstructure. Genetics is a solid foundation, because the DNA of an organism is unchanged. But a cell cannot exist like a stone. Life must adapt to its environment. Therefore, epigenetics is an interface between a rigid and unambiguous genetic code (genome) and the external environment.

It enables the unchanged inherited genome to adapt to the external environment. Moreover, the latter is not only what surrounds our body, but also each neighboring cell for another cell within us.

- Is there an example of epigenetic influence in nature? How does it look in practice?

There is a line of mice - agouti. They are characterized by a pale reddish-pink coat color. And also these animals are very unhappy: from birth they start to get sick with diabetes, have an increased risk of obesity, they develop cancer early, and they do not live long. This is due to the fact that a certain genetic element was incorporated in the region of the "agouti" gene and created such a phenotype.

And at the beginning of the 2000s, American scientist Randy Girtl set up an interesting experiment on this line of mice. He began to feed them plant foods rich in methyl groups, that is, folic acid and B vitamins.

As a result, the offspring of mice raised on a diet high in certain vitamins, the coat turned white. And their weight returned to normal, they stopped suffering from diabetes and died early from cancer.

And what was their recovery? The fact that there was a hypermethylation of the agouti gene, which led to the emergence of a negative phenotype in their parents. It turned out that this could be fixed by changing the external environment.

And if future offspring are supported on the same diet, they will remain the same white, happy and healthy.

As Randy Girtle said, this is an example that our genes are not destiny and we can somehow control them. But how much is still a big question. Especially when it comes to a person.

- Are there examples of such an epigenetic influence of the environment on humans?

One of the most famous examples is the famine in the Netherlands in 1944-1945. These were the last days of the fascist occupation. Then Germany cut off all food delivery routes for a month, and tens of thousands of Dutchmen died of hunger. But life went on - some people were still conceived during that period.

And they all suffered from obesity, had a tendency to obesity, diabetes and reduced life expectancy. They had very similar epigenetic modifications. That is, the work of their genes was influenced by external conditions, namely, that short-term starvation in parents.

- What other external factors can affect our epigenome in such a way?

Yes, everything affects: a piece of bread eaten or a slice of orange, a smoked cigarette and wine. How it works is another matter.

It's simple with mice. Especially when their mutations are known. People are much more difficult to study, and research data is less reliable. But there are still some correlation studies.

For example, there was a study that examined DNA methylation in 40 grandchildren of Holocaust victims. And scientists in their genetic code identified different areas that correlated with genes responsible for stressful conditions.

But again, this is a correlation on a very small sample, not a controlled experiment, where we did something and got certain results. However, it shows again: everything that happens to us affects us.

And if you take care of yourself, especially when you are young, you can minimize the negative effects of the external environment.

When the body begins to fade, it turns out worse. Although there is one publication where it says that it is possible, and in this case, we can do something about it.

- Will the change in a person's lifestyle affect him and his descendants?

Yes, and there is plenty of evidence for this. This is all of us. The fact that there are seven billion of us is proof. For example, human life expectancy and its numbers have increased by 50% over the past 40 years due to the fact that, in general, food has become more affordable. These are epigenetic factors.

- Earlier you mentioned the negative consequences of the Holocaust and famine in the Netherlands. And what has a positive effect on the epigenome? The standard advice is to balance your diet, quit alcohol, and so on? Or is there something else?

I do not know. What does nutritional imbalance mean? Who came up with a balanced diet? What is now playing a negative role in epigenetics is excess nutrition. We overeat and fat. In this case, we throw 50% of the food into the trash. This is a big problem. And nutritional balance is a purely trade feature. This is a commercial duck.

Life extension, therapy and the future of humanity

- Can we use epigenetics to predict the future of a person?

We cannot talk about the future, because we do not know the present either. And predicting is the same as guessing on the water. Not even on the coffee grounds.

Everyone has their own epigenetics. But if we talk, for example, about life expectancy, then there are general patterns. I emphasize - for today. Because at first we thought that hereditary traits were buried in peas, then - in chromosomes, and at the end - in DNA. It turned out that after all, not really in DNA, but rather in chromosomes. And now we even begin to say that at the level of a multicellular organism, taking into account epigenetics, the signs are already buried in a pea.

Knowledge is constantly being updated.

Today there is such a thing as an epigenetic clock. That is, we have calculated the average biological age of a person. But they did it for us today, following the model of modern people.

If we take the person of yesterday - the one who lived 100-200 years ago - for him this epigenetic clock may turn out to be completely different. But we do not know which ones, because these people are no longer there. So this is not a universal thing, and with the help of this watch we cannot calculate what the person of the future will be like.

Such predictive things are interesting, entertaining and, of course, necessary, since today they give a tool in hand - a lever, like Archimedes. But there is no fulcrum yet. And now we are chopping left and right with a lever, trying to understand what can be learned from all this.

- What is the life expectancy of a person according to DNA methylation? And what does this mean for us?

For us, this only means that the maximum biological age that nature has given us today is about 40 years. And the real age, which is productive for nature, is even less. Why is that? Because the most important thing for life is death. If the organism does not free up space, territory and food area for a new genetic variant, then sooner or later this will lead to the degeneration of the species.

And we, society, are invading these natural mechanisms.

And, having received such data now, in a couple of generations we will be able to conduct a new study. And we will surely see that our biological age will grow from 40 to 50 or even 60. Because we ourselves create new epigenetic conditions - as Randy Girtl did with mice. Our fur is whitening.

But you still need to understand that there are purely physiological limitations. Our cells are filled with garbage. And during life, not only epigenetic, but also genetic changes accumulate in the genome, which lead to the onset of diseases with age.

Therefore, it is high time to introduce such an important parameter as the average length of a healthy life. Because unhealthy can be long. For some, it starts quite early, but on drugs these people can live up to 80 years.

- Some smokers live 100 years, and people who lead a healthy lifestyle can die at 30 or become seriously ill. Is this just a lottery or is it all about genetics or epigenetics?

You've probably heard the joke that drunkards are always lucky. They can fall even from the twentieth floor and not break. Of course, this can be. But we learn about this case only from those drunks who survived. Most do crash. So it is with smoking.

Indeed, there are people who are more prone to, for example, diabetes due to sugar consumption. My friend is a teacher for 90 years, and she eats sugar with spoons, and her blood tests are normal. But I decided to give up sweets, because my blood sugar began to rise.

Each individual is different. This is what genetics is needed for - a solid foundation that lasts all life in the form of DNA. And epigenetics, which enables this very straightforward genetic basis to adapt to its environment.

For some, this genetic basis is such that they are initially programmed to be more sensitive to something. Others are more stable. It is possible that epigenetics has something to do with this.

- Can epigenetics help us create drugs? For example, from depression or alcoholism?

I don't really understand how. There was an event that affected hundreds of thousands of people. They took several tens of thousands of people, analyzed and found that after that, with some mathematical probability, they have something, something they don't.

It's just statistics. Today's research is not black and white.

Yes, we find interesting things. For example, we have elevated methyl groups scattered throughout the genome. So what? After all, we are not talking about a mouse, the only problematic gene of which we know in advance.

Therefore, today we cannot talk about creating a tool for targeted impact on epigenetics. Because it is even more diverse than genetics. However, to influence pathological processes, for example, tumor processes, a number of therapeutic drugs that affect epigenetics are currently being investigated.

- Are there any epigenetic achievements that are already being used in practice?

We can take your body cell, like skin or blood, and make a zygote cell out of it. And from it get you yourself. And then there is the cloning of animals - after all, this is a change in epigenetics with unchanged genetics.

- What advice can you give the readers of Lifehacker as an epigeneticist?

Live for your pleasure. You only like to eat vegetables - eat only them. If you want meat, eat it. The main thing is that it soothes and gives you hope that you are doing everything right. You need to live in harmony with yourself. And this means that you need to have your own individual epigenetic world and control it well.