25 April 2022

The Era of DNA technology

Chimera Humans and Edited Twins — What we know about the human genome

Maria Bozhovich, Pravmir

With the help of DNA analysis, today they are looking for criminals, make medical diagnoses and determine the presence of coronavirus. How else can new technologies change our lives? On DNA Day, we talked about this with molecular biologist Elena Kleshchenko, author of the book "DNA and its Man".

Chimera people

— In your book, you tell about an American couple who, after their divorce, donated blood for a routine DNA test so that the mother could receive financial assistance from her ex-husband for their common children. And it turned out that he is their genetic father, but she is not the mother. How can this be? 

— Yes, the sensational case of Lydia Fairchild. She was lucky to find an intelligent lawyer who remembered that such incidents had already happened. Lydia turned out to be a chimera — there are no more than a hundred of these people in the world. Biologists call chimeras organisms that consist of cells of two different individuals. In humans, chimerism can occur during multiple pregnancies, when the mother carries twins and the two fetuses exchange cells. The children's grandmother, Lydia's mother, was genotyped, and it turned out that she was their grandmother. That is, the mysterious mother of the children could be Lydia's sister. 

"Did she have a sister?"

— It's still more interesting. When Lydia took a swab from the cervical canal, from the cervix, and looked at his DNA, this sample matched the samples of all three children. Her blood cells had one genotype, and oocytes— cells of the reproductive system— another. 

Apparently, when Lydia's mother was pregnant, she was carrying not one girl, but two non-identical twins who developed from different eggs. The second embryo died, but some of its cells got into the "neighboring" embryo. Then a completely ordinary singleton pregnancy developed, which ended with Lydia. 

But when Lydia had her own children, it genetically looked like she was their surrogate mother, and the biological mother is her sister, who was not born. 

Omicron predicted by bioinformatics

— What technologies related to the discovery of DNA have changed our lives?

— Everyone now knows what PCR is — this is probably the only benefit of covid. In Russia, a PCR test can be done almost everywhere. What was planned to be implemented for ten years was done in a year or two. 

Polymerase chain reaction uses the main property of nucleic acids — to be copied on its own matrix. This property, thanks to which children receive the parental genome and parental traits, is used purely mechanically for DNA research. 

Many copies of a certain unique site are created, and seeing how the number of copies increases, we conclude that this fragment of the genome of interest to us — characteristic of the coronavirus or the influenza virus — is present in the sample. So the virus test is positive. 

PCR is bad because the sample must be heated to fairly high temperatures, then cooled, this requires a thermostat, which is inconvenient to carry with you. Now the so-called isothermal amplification has appeared. There, too, fragments of nucleic acids multiply, but at a constant temperature. It's easier and cheaper. 

— How is PCR different from DNA sequencing?

— When we do PCR, we see only a fragment of the nucleotide sequence, and when sequencing, we trace it entirely. 

PCR is how to see how many times Napoleon is mentioned in the novel "War and Peace". And sequencing is to read the whole novel in a row, or at least part of it.

Now the so-called massive sequencing has become very widespread. DNA is cut into many small pieces, all of them are read simultaneously and very quickly, and then they are put together on a computer, like a puzzle, into a single sequence.

— Sequencing allows you to quickly track the appearance of new strains?

— Yes, that's what happened with omicron in November. Even before it got its name and entered the first lines of the news, I looked into the group where bioinformatics communicate, and saw that a new strain had apparently appeared. There was an active discussion about him, and the participants used rather strong expressions — in the sense that he was somehow surprisingly disgusting. The nucleotide sequence showed many mutations in the spike protein, which means that the new variant will be very contagious and will be able to get away from antibodies perfectly. Subsequently, what was already clear from the sequel was confirmed both experimentally and epidemiologically.

Edited Twins

— Let's forget about the coronavirus. What else do we need sequencing for?

— For everything in the world. This is information about all creatures, large and small — the genomes of animals, plants, and people are needed for medical purposes or for population genetics to find out where a particular people came from. We have in our hands a huge amount of information for fundamental and applied science — everything that we dreamed of when Watson and Crick discovered the DNA double helix.

However, as one snide person said, "we bought an encyclopedia, but we don't know how to read." But we are learning, and quite quickly. 

— The Nobel Prize in 2020 was given for the CRISPR-Cas method — the so-called genomic scissors. Why is this so important? 

— The method allows you to make an incision in a certain fragment of the genome. They were able to do this before, but they needed specific proteins that recognized the desired area. It was expensive. CRISPR-Cas recognizes the site due to the guide RNA, which is easier to obtain than a protein, and with the help of the nuclease enzyme Cas cuts the nucleic acid in a certain place. Then the cell itself glues the incision. In this way, mutant organisms are obtained for experiments, thanks to which many discoveries have already been made. 

— That is, we haven't really learned how to read yet, and have already taken a swing at editing?

— If you're talking about editing the human genome, it's not allowed anywhere in the world yet. Chinese doctor He Jiankui has just served time in prison for this. He edited with CRISPR the genomes of two twin girls from an HIV-infected father, changing the receptors on the cells of the immune system through which this virus can enter the body. Many people on earth have such a mutation, and they are protected from HIV to some extent. In China, it is not widespread, but in Russia, for example, it is much more common. 

That is, Dr. He didn't make any superhumans, he just reproduced a mutation that already exists.

— What was he imprisoned for then?

— Sometimes CRISPR-Cas gets to the wrong place where it was targeted and introduces unwanted mutations.

To date, the consensus among scientists is that the accuracy of the method does not allow us to proceed to experiments on humans.

But Dr. He's patients were apparently lucky. They will soon be four years old, and nothing terrible seems to have happened to them.

There is complete privacy, neither the faces nor the names of these twins are known to the general public — this is how it should be according to the rules of medical ethics. But if something bad had happened to them, He Jiankui would hardly have been released from prison

— If the method is completely safe, will it be able to save, for example, from cystic fibrosis?

— Theoretically, yes. Let's say both parents have cystic fibrosis, but they really want to have children. With the help of IVF, they receive a fertilized egg and change it so that there is no gene for this disease in it.

It may be that the parents are not sick, but each of them has one copy of the gene of this disease, which can meet with a similar copy in a partner and lead to the birth of a sick child with a probability of 1:4. In this case, during IVF, the one with no mutation is selected from several eggs.

For many people, such selection is ethically unacceptable, and editing could just get rid of it. If you can fix the cell, then why destroy it? 

But for this, the CRISPR-Cas method must work without misfires, which is still out of the realm of fiction.

"The Golden State Killer"

— There are genomic databases where the police are looking for criminals. How does it work? 

— Police genomic databases appeared in developed countries quite a long time ago, in the 1990s and the noughties. We also have them. They contain DNA fingerprints, or barcodes of the human genome.

There are repeating fragments in certain parts of our genome. The number of repetitions in each section is different for each person. And if you examine 20 such sites using PCR, you can get an individual barcode of a person. In two different people, it can match only if they are twins.

This method was invented in the 80s of the last century by the British scientist Alec Jeffries, and in 1987 a criminal case was solved with his help for the first time - a maniac who killed girls was found in an English town. 

The police have a database where samples of convicts and suspects are placed. In the USA and in other countries, there are heated discussions: if a person was a suspect, and a swab was taken from him, and then it turned out that he was innocent, should his data be removed from the police database? The public believes that it is necessary. The police, of course, don't really want to. If everyone was genotyped, it would be much more convenient for her to work. 

— It is amazing that not only the police create genomic databases for their own purposes, but also people themselves voluntarily post their genetic information. What for?

— A genetic barcode helps not only to identify a person, but also indicates family ties, since we get half of our DNA from mom and half from dad. This is the same analysis that Lydia Fairchild did.

Some enthusiasts upload their DNA fingerprints to international genealogical databases to find relatives. By the way, with the help of such a database, California police in 2018 identified a serial maniac, who has had at least 13 murders and 50 rapes since 2001. He was called the "Golden State killer."

A criminal's DNA sample was found at the scene of another crime, but how do you know who it belongs to? It is only clear that he most likely lives somewhere in the United States. They decided to upload the sample to the genealogical database — supposedly an ordinary person came to look for relatives (which, of course, was a violation of police ethics). They found distant genetic relatives, traced family ties and figured out who the killer was. It turned out, by the way, that he was a former policeman — that's why he managed to deceive the police for so long. 

The fact that DNA testing will appear, samples will be stored for decades, and then they will go into business, of course, he could not have foreseen. At the time of his arrest, the "Golden State killer" was already quite elderly. 

There are no "healthy" and "sick" peoples

— In recent years, genetic tests have become fashionable, which allow you to find out which peoples your ancestors belonged to. Is this a real thing or a marketing ploy?

— Population genetics is based on quite working, scientific methods. It is possible to compare the genome of an individual with databases that contain the genomes of representatives of different peoples. Moreover, not only modern, but also ancient, obtained from paleomaterials. 

To do this, it is not necessary to read the genomic sequence completely, it is enough to look at certain points — the so-called single-nucleotide polymorphisms, SNPs, or snips. And if such points are distributed throughout the genome, then you can get a fairly complete idea of which part of the genome of a particular person is characteristic of the people as a whole, and therefore, where the ancestors of this person could have come from.

But there is always the question of how well commercial tests work. As always, there is a balance between cheapness and quality. It happened that identical twins sent their samples to two different companies, received different results.

— Population genetics leads scientists to the fact that certain national diseases are characteristic of certain peoples, although in modern society a nation is not a biological concept at all. How to overcome ethical ambiguity?

— First of all, this does not mean that one nation is worse than another. And also that the people, among whose representatives predisposition to a particular disease is more common, are less "healthy". As a rule, some one minus is compensated by an evolutionary plus.

For example, genetic variants associated with sickle cell anemia, a hereditary blood disease, are common in Africa. And these same options prevent the disease of malaria. 

Such things are very important for medical geneticists to know — for example, because the same drugs interact differently with different variants of cellular receptors. It happens that the drug has passed clinical trials with a bang, for example, in Japan. He was taken to America, and there the results are much worse. 

One way or another, it is necessary to take into account population gene differences in medical genetics, just as it is necessary to align groups by gender in clinical trials. After all, sometimes the same drug acts differently on men and women. It does not follow that doctors have less respect for women or men.

— Will humanity have entirely individual medicines, or is it a utopia?

— This is very important right now when it comes to the treatment of certain types of cancer. All cancer cells want the same thing: to divide uncontrollably, to evade drugs and the immune system, but in each organism this evolution goes differently. Every person has their own cancer. 

It is necessary to invest money in personalized medicine, at least in order to choose the right one from existing medicines right away, and not by trial and error. 

And ideally, one day we should start creating individual medicines for each person.

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