17 August 2015

Show your genes

Adam Piore, "Nautilus", USA: Bring Us Your Genes. Translation: InoSMI

Viking scientist challenges terrible diseases. The second part (see the beginning here). 

Scientists have discovered that the bulk of the genetic material transmitted to the child from each of the parents is a superbly structured system consisting of a fixed set of genes stretched into chains. For the most part, their number is unchanged and combined into a group called a haplotype. It is believed that haplotypes originated at a very early stage of human evolution. This means that only a small number of common features have been transmitted to each person.

In 2002, the International Consortium for Genetics set a task: to detect and catalog individual mutations that are believed to be characteristic of each of the known haplotypes, and compile their directory. By the fall of 2005, scientists had catalogued almost one and a half million point substitutions of nucleotides in DNA (the so–called "single nucleotide polymorphism", or SNP - snip for short) associated with individual haplotypes that can be quickly isolated from blood samples using ingenious SNP chips. SNPs play the role of a kind of "signature" characteristic of a given haplotype (or haplotype regions). If you identify SNP substitutions in DNA that are characteristic of people with a well-defined disease, then you can detect this area of the haplotype and identify mutations that cause this disease.

When the first SNP chips were delivered to Decode headquarters in 2006, Stefansson gathered his assistants for a meeting to develop a further strategy. One day, as Stefansson describes, his brilliant computer scientist and statistics expert Daniel Gudbjardsson, a certified electrical engineer from the University of Massachusetts, ran into his office. He was literally glowing with enthusiasm. On the same day, Decode received news from the committee of the Icelandic Government Commission on Information Protection and Ethics: the company receives permission to conduct research on atrial fibrillation (the most common form of arrhythmia). So, Gudbjardsson ran in to report that his research team had discovered the location of two genetic variants that increase, respectively, by almost 70 and 40% the probability of this very atrial fibrillation.

These two genetic variants (together with two copies of a more powerful variant – one from each of the parents) increase the likelihood of developing this disease. Atrial fibrillation causes an increased heartbeat, chronic heart failure, and also increases the risk of stroke four to six times. The scientists had only to pick up the appropriate DNA from the existing ONES in their genetic library and launch an SNP chip looking for genetic mutations that cause atrial fibrillation.

It took three hours to find the genetic causes of this disease using new methods. In the following months, Decode was able to identify common variants of genes that cause glaucoma, sleep disorders, breast cancer, heart attack, osteoporosis, obesity. "With the help of SNP chips, we have made a lot of discoveries and pulled ahead," says Stefansson.

At the same time, skepticism about the possibilities of new technologies has been increasing for several years. David Goldstein, head of the Institute of Genomic Medicine at Columbia University, collaborated with Decode on the last two stages of research. But after 2007 (the company was then conducting research with the support of a research institute at Oxford University) he became a critic. For two years, a study was conducted in which fifty scientific groups took part, studying the genes of 17 thousand people. This study was called the largest in history. As a result, scientists were able to identify twenty-four genes characteristic of the seven most common diseases, including cardiovascular, type I and type II diabetes mellitus, manic-depressive psychosis (MDP) and Crohn's disease.

But Goldstein was surprised that only one TIR gene was identified during the study (it is believed that this disease develops under the influence of hereditary factors), and the number of cases of TIR caused by this gene is "not significant". In fact, open genes, apparently, cannot explain all the cases of diseases considered in the study. Perhaps, Goldstein and other scientists believed, the cause of most diseases is not general gene changes, but rather a wide range of mutations – very rare so that they can be detected in haplotypes.

But Stefansson did not give up: even if common mutations only partially explain the disease, it is still enough to find treatments; knowledge of the chemical mechanisms of the disease allows you to create drugs.

But then January 2009 came and Decode had problems – only $ 3.7 million remained in the accounts. At the same time, difficulties arose with obtaining a loan, besides, the Icelandic government could not help, because the country was teetering on the verge of default. And in November, Decode announced its bankruptcy.

However, Stefansson did not admit defeat. He knew at least two financiers who seemed to be able to support his company. When Decode first went public, two venture funds offered their help – Arch Venture Partners from Seattle and Polaris Venture Partners from Massachusetts. Full of enthusiasm, Stefansson tried to get them to cooperate so that they would get involved in the case. They transferred $40 billion to Decode's accounts in exchange for shares. "I think the company is promising," said Terry McGuire, a partner at Polaris.

And indeed, in January 2010, Decode avoided bankruptcy. And soon a new innovation (the technology of faster and cheaper than before, sequencing of the human genome), created by the company, began to gradually conquer the market; compared to SNP chips, it turned out to be more advanced. Now you can compare the links of the genetic code in any fragment of DNA, and then use powerful computers to select those rare mutations that cause the disease. In 2000, it was announced that within the framework of the Human Genome Project, the estimated cost of the first fully sequenced genetic code would be about 500 thousand dollars. And already in 2010, for the same money, Decode acquired a new equipment created by the biotech company Illumina. With this equipment, three DNA samples could be sequenced at once every ten days at the same time. And Stefansson signed a contract for the purchase of four such sequencers.

The invention and mass production of devices capable of sequencing the entire genome was a real breakthrough. Previously, scientists believed that the key to understanding the disease lies in the search for common mutations transmitted from generation to generation and detected using SNP chips. But, according to many experts, this approach was limited. The common haplotypes were "old". If a mutation causes a disease, doesn't it lower the probability of survival? In this case, will it not reduce the probability of DNA transmission from an individual to his descendants? Can't natural selection exclude mutations?

Now, full genome sequencing has made it possible to find extremely rare, relatively new mutations – mutations so strong that they are likely to be quickly eliminated in a given population by natural selection. These mutations are so deadly that the probability of their transmission to offspring decreased. Therefore, such mutations cannot be found in ancient common haplotypes.

After Decode avoided bankruptcy in 2010, new trends began to spread around the office. Several times a week, Stefansson and his deputies gathered in a small conference room behind glass panes. Stefansson sat at the head of a large table and, together with his experts, discussed the effectiveness of using new equipment for sequencing the complete genome. The company's scientists began to do this in two stages: first they looked for Icelanders with as far a degree of kinship as possible (this was necessary in order to identify disparate genomes existing in each of these groups), and then in each of these groups selected individuals suffering from rare diseases of particular interest to scientists.

Decode announced that it had succeeded in sequencing DNA from 2,635 Icelanders, on the basis of which it was possible to evaluate the genomes of more than one hundred thousand Icelanders.

In his youth, working as a neurologist, Stefansson studied the brain tissue of patients suffering from Alzheimer's disease, and reflected on the plaques and tangles characteristic of this disease. In the winter of 1997, Stefansson traveled by car with his wife and one of the investors along the picturesque west coast of Iceland, collecting blood samples for sequencing in nursing homes.

One day in 2011, Torlakur Jonsson, who headed the project on the study of Alzheimer's disease, was looking through one of the reports on a gene that is part of the so-called transmembrane precursor protein beta-amyloid (APP). As you know, APP is the main component of amyloid plaques (improperly packaged proteins that are abundantly present in the brain tissues of patients suffering from Alzheimer's disease); many believed that it was these plaques that cause this terrible disease. It has previously been shown that mutations in the genes that characterize APP increase the likelihood of developing Alzheimer's disease.

But when Jonsson took a closer look at the report, he saw something unexpected – computer algorithms marked the APP mutation not because it was characteristic of patients suffering from Alzheimer's disease, but, on the contrary, because those who had it were less prone to it. How can this be?

All this allowed Stefansson to approach the question that had been occupying him for a long time. He was always struck by the fact that many features that seem to be characteristic only of Alzheimer's disease (especially amyloid plaques and neurofibrillary tangles) were also found in elderly patients who did not suffer from this terrible disease.

Stefansson knew that cognitive decline is associated with the aging process. In young people, cognitive decline, as well as plaques and neurofibrillary tangles were not detected. So, Stefansson thought, plaques and tangles characteristic of Alzheimer's disease, in all likelihood, can cause a decrease in cognitive abilities. Stefansson wondered: if this mutation protects against Alzheimer's disease, can it also prevent the process of cognitive decline? If it can, Stefansson reasoned, then we will get "an extremely strong argument in support of the point of view that Alzheimer's disease is just an accelerated form of brain aging."

To test this hypothesis, Decode employees sequenced the genes of a control group (elderly patients of the same age, whose lifestyle does not differ from each other). Comparing the results obtained in a group of elderly patients with and without reduced cognitive abilities, they proved the following idea: elderly patients who had a DNA mutation showed no signs of cognitive decline. And in those who did not have mutations (even in patients who did not suffer from Alzheimer's disease), cognitive decline was often not observed at all.

Decode's publication of its findings about the new gene has become a global event. If drug manufacturers had found a way to replicate this gene, they would have been able to create a drug capable of curing Alzheimer's disease and other forms of senile dementia.

And the Decode company was once again on the crest of a wave. In 2012, its vice president Augustine Kong, who is responsible for statistical modeling, began to study data related to fully sequenced samples taken from patients suffering from schizophrenia and autism, paying special attention to the so-called "de novo" mutations (that is, spontaneous mutations that appear only in children and are not detected in parents). Kong decided to identify "de novo" mutations in patients with schizophrenia, autism and other diseases. To do this, he compared the DNA of these individuals and the DNA of their parents, and then began to identify those common traits in the parents that were thought to be related to these mutations.

And here the following feature was found: in more than 90% of cases, the increased number of mutations, apparently, is somehow related to the age of the father. Stefansson was intrigued by this fact. Together with Kong, he checked the Decode genealogical database for several centuries and analyzed the dynamics of changes in the age of young fathers. To the surprise of scientists, the following turned out: in the nineteenth century, the average age of fathers at conception was much higher than the corresponding age of fathers in the twentieth century. Then, in the 1980s, this indicator increased again, and this somehow correlates with an increase in cases of autism.

In an article published in 2012 in the journal Nature, Stefansson, Kong and others presented their arguments by analyzing information on 219 samples taken from 78 groups of three people (that is, both parents and a child suffering from autism or schizophrenia). In addition, they sequenced the genomes of families with a high risk of autism and schizophrenia to find out if any inherited genes could be found that increase the likelihood of this disease. Interestingly, at the same time, the following pattern was established: the older the father, the higher the probability of schizophrenia and autism. The article by scientists from the Decode company aroused great interest in the scientific world. In fact, according to Stefansson, the study not only reveals the alleged cause of schizophrenia and autism, but also explains almost all the reasons for the differences in the frequency of new mutations appearing in different populations around the world. The older the age of the father at the time of conception of the fetus, the greater the change in the population will be observed.

Itsik Pe'er, an associate professor of computational genomics at Columbia University, argues that there is now a widespread view of the relationship between the age of the father and the rate of mutations, as well as the idea that such mutations increase the likelihood of autism and schizophrenia. However, according to him, mutations occur in nature all the time, so dangerous mutations can occur in offspring from young fathers (that is, the occurrence of dangerous mutations in the fetus is not due to the age of the father).

In 2012, when Stefansson and his company published the results of their new research, rumors began to reach that Amgen, the world's largest biotechnology company, had shown its attention to Decode. Two of the most promising drugs produced by this company appeared as a result of the recent discovery of exactly those mutations that Decode is working on. A month later, Amgen acquired Decode for $415 million. But the residents of Iceland turned out to be dissatisfied with this deal, because it turns out that Decode will profit from the use of DNA and medical data on the health status of Icelanders, who will not receive anything in return. Some blogger even joked that, they say, Decode signed the agreement, and "gave the Icelanders just a T-shirt" as compensation.

In 2015, Stefansson told me that Amgen almost broke up his company with the Icelanders. But he is a patriot of his country. "Citizens have provided us with the most sincere assistance in conducting scientific research. What is our duty and duty towards them?" asks Stefansson. In his opinion, it is necessary to develop rules for interaction with health authorities and ethics in order to inform those Icelanders who are carriers of "dangerous mutations" (for example, carriers of the gene that causes breast cancer). "If this is not done, then we will commit a crime. But this does not fit with the principles of our society. We must help those who are at serious risk. And now, we see how our Minister of Health has already actively taken up the case."

In March 2015, Decode published four articles in the journal Nature. They said that the company managed to sequence the DNA of 2,635 Icelanders. This made it possible to cover, based on genealogical data and the frequency of mutations, the genomes of more than one hundred thousand Icelanders whose genomes were not sequenced (eleven thousand genomes were processed in total). Using the same statistical methods, Decode can make assumptions about the presence or absence of certain mutations in almost the entire population of Iceland, because scientists now know the frequency of mutations, risk groups, and DNA that are common to the entire population of the country.

Decode specialists were able to detect rare mutations, the presence of which dramatically increases the risk of Alzheimer's disease, gallstones, atrial fibrillation, liver and thyroid diseases – these mutations arose as a result of "knocking out" genes or due to the absence of certain fragments in DNA. But perhaps the most interesting thing is the application of the results obtained to such an area as criminology. Decode identified a total of 1,171 "knocked out" genes present in 8% of 104 thousand surveyed residents. In order to try to determine the impact that these, so to speak, "errors of nature" have on the human body, it is necessary to compare these "knocked out" areas with medical records and phenotypic data.

Daniel MacArthur, a geneticist at the Massachusetts General Hospital, along with one of the associate professors at Harvard Medical School, called the results surprising. "Over the past decade, Decode has managed to collect a remarkable set of genetic data – without a doubt, here we see the most detailed genetic study of the population living in a single country." However, according to him, in such an isolated people as the Icelanders, "you can find a relatively small percentage of ["knocked out"] genes." However, Decode specialists have learned to identify mutations that cause disease in residents of Iceland alone. It is clear that some teams of scientists will want to continue their repair and switch to studying the genome of residents of other countries.

..On that winter day, sitting in his office, Viking Stefansson added the following at the end of the interview: "When I ask myself what I've been doing all this time in science, then here's the answer," and he respectfully pointed to the photo of his brother, who instilled in him a love of literature. – And if there are no such reasons, then science is not worth doing. I am sixty-three years old, and I never forget about the most important thing in my life. I wish I was perfect. It is a pity that he was not a good husband and citizen. But I have done something in my life, and probably the most interesting thing is the discoveries I made in the laboratory. After all, I also helped people find out what a person is made of."

"If we ask what condition is the most important for the existence of life on our planet, we will get this answer – the information contained in DNA. If we ask how the poet Walt Whitman differs, for example, from "a leaf of grass" (U. Whitman is the author of the poetry collection "Leaves of Grass" – approx. trans.), then the answer will be: just the arrangement of nitrogenous bases – adenine, guanine, thymine and cytosine. DNA is truly the Holy Grail of life."

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