28 July 2015

Give us your genes

Viking scientist challenges dangerous and incurable diseases

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

Once upon a time there was a Viking named Kveldulf in the ninth century-a Norwegian, so big and strong that no one could defeat him. For many years he sailed the seas on a wooden drakkar, long and narrow, plundered towns and villages in distant lands. Then he switched to a sedentary lifestyle, becoming known as a very rich man.

And Queldulf had two sons who grew up and also became mighty warriors. One of them entered the service of King Harald the Fair-Haired. And so, after some time, the king ordered the murder of this son, feeling fear of his growing power. And Queldulf swore revenge. Together with his second son and his allies, Queldulf caught up with the murderers, and killed up to fifty people with an axe. He sent the others to the king to tell them about his feat, and he sailed to Iceland, which had recently been discovered by that time. On the way, Queldulf died. But his second son Skallagrim landed on the west coast of Iceland. There he lived in prosperity.

Skallagrim had his own children, and those, too, had children. In a word, the blood and genes of Queldulf the Viking and his son Skallagrim have been passed on to the current generations of Icelanders. And so, in 1949, in the capital of Iceland, Reykjavik, one of his distant descendants named Kari Stefansson was born.

Stefansson has become as powerful as his ancestor Kveldulf – two meters tall, piercing eyes, beard. In his youth, Stefansson went to the universities of Chicago and Harvard in search of knowledge. But in the 1990s, at the dawn of modern genetics, he, having already become a neurologist, returned back to his homeland, wanting to study the very genes that he and three hundred thousand of his compatriots inherited from Queldulf and a small group of his associates, who, in fact, created Iceland.

Stefansson had a bold idea: he decided to create a DNA catalog of every inhabitant of Iceland. This catalog, together with genealogical data about the inhabitants of this island and medical data, will become a unique resource that will help scientists identify the causes of terrible diseases and suggest methods of their treatment.

In 1996, Stefansson founded a company called Decode and decided to explore Icelanders with the help of the latest achievements of the rapidly growing field of science engaged in the study of genes. "The genetic heritage of [Icelanders] is as much a natural resource as our fish and hot springs," says Stefansson after returning home to Iceland. 

Stefansson has started a grandiose project. Together with his team, he collected DNA from 150 thousand of his compatriots (that is, half of the country's population) and built a genealogical diagram that reflects the pedigree of almost every citizen of this small island nation. Then Stefansson's group managed to decipher three billion nucleotide sequences from more than eleven thousand Icelanders. And now scientists can work with individual genomes of the entire population of the country. Then Stefansson's group started searching for the missing DNA segments possessed by the rest of the country's inhabitants. Scientists have studied the effect of the so-called "knocked out" genes on the body of their carriers. And although this scientific work has just begun, very interesting results have already appeared.

In 2015, Stefansson's group identified a few mutations that increase the risk of Alzheimer's disease, the appearance of gallstones, atrial fibrillation and thyroid disease. If scientists uncover the causes of these mutations, they will be able to identify the causes of the most terrible diseases of mankind and even find methods of their treatment.

In the Middle Ages, in the Icelandic sagas, chroniclers depicted the legendary exploits of Queldulf the Viking and other legendary Icelandic travelers and noble families. So I, too, quite recently, in the dead of winter, decided to go to Iceland to write my saga about an Icelander conquering the genetic code.

Iceland in December is bitterly cold. The place is unattractive. The sun rises only at eleven o'clock in the morning to disappear at four o'clock in the afternoon. A sharp wind blows from glaciers that have settled on mountain peaks, walking through barren volcanic plains. And now, a dark morning has come, a piercing cold is in the air. I leave the hotel, located on the ocean, to meet with Stefansson. 

Decode's modern office is well-lit. It stands on the outskirts of Reykjavik, like a cozy medieval castle on the edge of a forest. Inside, the visitor, of course, will be pleased with the plants in tubs placed on the parquet. However, at first I shivered a little from fear, because I knew that Stefansson was famous for his lively temperament and that he could, say, calmly get up and leave if he didn't like the correspondent. Moreover, due to a misunderstanding, I was half an hour late.

A press secretary approached me near Stefansson's office, clearly angry. He warned that it was impossible to predict the boss's reaction. Does he still intend to give me time? "We'll see," the press secretary muttered.

Finally, Stefansson appeared. An elegant, tall man with a beard and a shock of gray hair, sneakers on his feet and a white striped jacket with a hood. He held out his hand, and I apologized for being late.

"Americans, as a rule, are arrogant, cunning and narrow–minded," Stefansson remarked with a chuckle and invited me into his office.

Stefansson likes to provoke. This is probably typical of Vikings. He was born into the family of a famous Icelandic radio journalist, and therefore assures that by nature he is the most humanitarian, because he grew up "in full confidence" that he would become some kind of writer or poet. Stefansson was very sure of this until fate intervened. One evening, in the last year of school, he had a good drink with a classmate. Young people wandered the streets as the bars were already closed.

"In the morning, half sober, we decided to turn into the university and apply to medical school. I wasn't interested. My friend wanted to go there. And then, all of a sudden, I found myself on the enrollment lists. Studying at medical school seemed terribly uninteresting to me. I don't know why I stayed there," says Stefansson.

But there was at least one reason to stay. By the time Stefansson began to live separately from his parents, he had his own view on the causes of dangerous and incurable diseases. Stefansson's beloved older brother, a gifted athlete who tried with great effort to introduce his younger brother to good literature and was a role model for him, had a mental disorder. Stefensson was greatly impressed by the delusional speech of his older brother (for example, he called him and apologized for attacking him with an axe, which did not happen at all) and the devastating effect that this little-studied mental illness had on their entire family.

"He's completely out of his mind. Schizophrenia is a disease of thoughts and emotions. But it is thoughts and emotions that make a person a person. As soon as a person has such a thing, he changes beyond recognition. For others, he becomes completely different," says Stefansson.

In search of an answer, he plunged into the literature on psychiatry, and for some time he thought of devoting his life to this science. But then I noticed that psychiatrists are "poorly educated", and "their approach to the treatment of this disease is uninteresting." Instead of psychiatry, Stefansson decided to study mental illness from the point of view of biology, neurology and pathology.

Since the time of Skallagrim, Icelanders have lived in geographical isolation, as a result of which they have become owners of a surprisingly similar set of genes; therefore, Icelanders are, as a rule, blue–eyed blondes who are close relatives to each other.

In 1977, Stefansson ended up at the University of Chicago with the intention of defending his degree, and eventually he was left on the faculty. It was there that Stefansson fell in love with science and found his true vocation. There he succeeded in studying the causes of multiple sclerosis, this terrible disease in which the human immune system hits the myelin sheath of nerve fibers ("white matter") the brain, which is important for the transmission of electrical impulses through the nervous system.

And so in the 1980s, a young professor Stefansson and a graduate student Jeffrey Gulcher (Jeffrey Gulcher) for many months searched in the brain tissues for individual proteins that most likely cause the body to strike the myelin sheath. If these proteins are identified, both scientists reasoned, then as a result it will be possible to create drugs that can neutralize them. But a difficulty arose: even if it were possible to find a protein that is believed to be responsible for the response of the immune system, it is still impossible to say for sure whether it is the cause of the disease or part of the body's response to this disease. 

Stefansson realized that it was best to use the help of genetics. About 20 thousand different genes can be isolated in a human cell. Each gene consists of paired bricks (there are from 27 thousand to 2.5 million) that form DNA – that is, four nitrogen compounds (nucleotides): cytosine, guanine, adenine and thymine; the sequence of these nitrogenous bases (denoted by the letters "A", "C", "G", "T") at the molecular level encodes instructions for each protein secreted by the body. These proteins, in turn, determine the characteristics of the human body, ranging from hair color to temperament. 

However, sometimes "typos" appear in the genome, so to speak, that is, errors in the sequence of the arrangement of nitrogenous bases, as a result of which everything goes awry in the body. Scientists believe that a combination of two factors (lifestyle changes and mutations in DNA) underlie most human diseases.

It seemed obvious to Stefansson that if you find differences in the genes encoding a protein that is characteristic of patients suffering from multiple sclerosis, then there is a high probability that this very protein plays an important role in the occurrence of this particular disease and, therefore, it becomes a target for drug treatment. 

In the 1980s, it seemed that identifying genetic differences was an extremely difficult task. At the very beginning, when Stefansson and Galcher began to study proteins and sequenced a DNA chain consisting of 7,500 elements that encoded a specific protein, they used the most advanced tools at that time. The whole job took three years.

By the early 1990s, Stefansson realized that the situation was beginning to change. The international Human Genome Project (Human Genome Project) worth three billion dollars was launched, whose task is to identify all the genes of human DNA and determine the sequence of almost three billion nitrogenous bases from which those genes are believed to consist. In 1993, Stefansson and Galcher began collaborating with Harvard Medical School, and the new technology proved to be a great help for the study of multiple sclerosis.

At Harvard, Stefansson proposed an interesting idea – to conduct a study of multiple sclerosis in Iceland. The fact is that the population in the USA is too heterogeneous, so it is difficult to separate the genes that cause this disease from other mutations, because there is a huge variety of individual mutations. Therefore, a US citizen can easily turn out to be a carrier of DNA that has experienced mutations characteristic of residents of Africa, Eastern Europe, Brazil, Russia, etc. That is why the search for a single mutation that is characteristic of multiple sclerosis among US citizens resembles an attempt to find a typo when comparing the text of a book in German with its French counterpart. 

Unlike Americans, Icelanders have lived in geographical isolation since the time of Skallagrim and his tribesmen, resulting in an unusually homogeneous gene pool – blue-eyed blondes who are close relatives to each other. If we study the genetic characteristics of islanders-Icelanders, it will be much easier to detect mutations characteristic of any disease, thereby gaining a clearer understanding of the causes of a wide range of human ailments. At Stefansson's request, Icelandic neurologists selected patients suffering from multiple sclerosis and asked them to come along with their healthy relatives to conduct a comparative study. But instead, many of them, wanting to help scientists, came in whole families.

Galcher and Stefansson returned to Boston with DNA samples from two hundred patients suffering from multiple sclerosis, as well as fifteen close and several hundred distant relatives. Most geneticists began to compare the DNA of close relatives. But Stephensson came to understand that when studying the genotype, distant relatives will be even more useful, since they have much fewer common genes than the closest relatives (for example, two children of the same parent have almost half the same DNA). On the other hand, it is not easy to find two distant relatives with the same "bad" mutation that causes the disease. And if such people can be found, then there will be fewer matching genes that need to be excluded. 

Stefansson didn't give up. He expanded his laboratory and became even more diligent in studying DNA sequences that could localize a single gene or several genes related to the occurrence of multiple sclerosis. When Stefansson and Galcher applied to the U.S. National Institutes of Health for funding for the project, they were disappointed. The reviewers were not at all impressed by the provided sample from the genome samples of Icelanders and their relatives. The reviewers asked why the sample of samples taken from close relatives is so small and a greater number of closely related pairs were not taken? They reminded Stefansson and Galcher that when conducting genetic research, close relatives are always studied, since they have a common DNA. However, critics have completely forgotten the fact that distant relatives also have similar DNA. 

Gulcher was furious, but Stefensson kept his cool. And even if they were given a grant, he did not believe that these funds would be enough to implement the ideas that he began to develop after returning from Iceland. In the mornings, talking with Galcher at the Starbucks cafe, heading to his Harvard laboratory, Stefansson talked about larger-scale plans. So Icelanders have always been obsessed with genealogy. In this country populated by altruists, patient medical histories have traditionally been well preserved. Beginning in 1915, Iceland began to store very detailed medical data and biological tissue samples taken after a pathoanatomic autopsy; in addition, after 1952, Icelanders began to store information about all cancer diagnoses. 

If Stefansson and Galcher had opened an institute or established a venture company, they would have been able to gain access to an extensive genetic database, as well as deepen their understanding not only of multiple sclerosis, but also of other diseases. If they could find funding, import modern biotechnologies and scientists to Iceland – all those who went abroad in search of prospects and received scientific degrees from Harvard and Stanford – then they would be given the widest support. Then they would have worked.

Stefensson and Galcher began to turn to venture capital companies. And in a couple of months, Stefansson managed to raise $ 12 million. Then he returned to Iceland and founded his own company. 

And what about his prestigious job at the most famous higher education institution in America? "Harvard is a lousy university. This is a loose confederation of independent institutions, and I wanted to leave there. I was bored there," says Stefansson. 

After Stefansson launched the Decode project in 1996, he gained access to Iceland's largest genealogical database, which some programmer wrote in his spare time for those who like to dig into their pedigree. It contained 400 thousand records, starting from the moment of settlement of the country. In particular, it included data from ancient manuscripts written on calfskin, church records, as well as data from the population census of 1703, which allows almost any Icelander to trace the origin of his family. But since the database was not complete, Stefansson instructed his staff to rummage through parish registers and data on other population censuses.

Since Icelandic politicians really wanted to build a powerful biotechnology sector in their country, in 1998 Stefansson began pushing the idea of creating a large database in which information about all residents of Iceland provided by the national health insurance system could be included; this database would have cross-references with genealogy data, as well as DNA samples. Most of the information provided by hospitals and other medical institutions from all over the country has already been entered into the database; however, the information has yet to be unified and standardized.

The Government of Iceland has submitted a bill providing for the granting of an exclusive right to Decode to create a database and exchange information with foreign scientists. The bill caused a storm of discontent, because it contains a provision that Icelanders thereby agree that Decode company should use personal information about each citizen of the country and store it anonymously if the citizen agrees to it. Critics compared such a bill to totalitarianism in the spirit of Orwell, and Harvard molecular biologist Richard Lewontin even likened Stefansson to his Viking ancestors ("at least they did not justify their predatory raids with public benefit") and called on the scientific world to boycott Iceland. The commissioner of the Dutch Data Protection Service has warned that Iceland may face charges from the European Court of Justice. But despite the sharp criticism, the Icelandic parliament still passed a bill on a national database. At the same time, a requirement was put forward to protect confidential information. In addition, Decode had to sponsor a specially created regulatory body. And these conditions forced Stefansson to abandon the attempt to cooperate with the government to create a database. "Because of this, we would have gone bankrupt in a moment," the scientist noted.

But then everything somehow settled down. Decode continued to collect medical data and conduct DNA analysis from volunteers – along with permission to reuse them for future scientific research approved by government bioethics and private information committees. Each volunteer was asked to fill out a questionnaire in which he had to report a variety of information about himself: hair color, cholesterol level, attitude to smoking, and so on – a total of 2500 questions. By 2001, Decode reported that it was able to detect and localize genes that are highly likely to cause preeclampsia (complication during pregnancy – approx. transl.), osteoporosis, schizophrenia, Alzheimer's disease, stroke, heart attack. The created database has become a repository of very valuable information.

In the same year, Decode made a public offering of its shares on the NASDAQ stock exchange for a total amount of one billion dollars. By the mid-2000s, Stefansson was at the head of a huge company that employed hundreds of geneticists, computer scientists, investor relations specialists and even anthropologists. The employees are housed in the brand-new headquarters of the company: there is a large and spacious dining room in the building, glass walls in the offices and laboratories on all floors, and all this is covered with a glass roof from above, so that sunlight through it during the white Icelandic nights flows all day on light wooden floors and upholstered walls.

In 2000, a draft version of the complete sequence of the human genome was published as part of the Human Genome Project. As it turned out, it contains more than three billion pairs of nitrogenous bases, the sequence of which is 99.9% identical in all people. This fact, according to many geneticists, means that the causes of common diseases are probably hidden in the remaining 0.1%. At the same time, all DNA sequences differ from each other, mainly by one nucleotide (this is called "single nucleotide polymorphism").

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