Genes for money
How does commercial genomics live
Alexey Aleksenko, Forbes, 03.11.2018
Worldwide, consumer genomics is an industry demonstrating record growth rates. What problems do Russian scientists and investors face?
The story of California police officer James DeAngelo shows how difficult – and vital – it is to anticipate the direction of technology development. Deangelo, a maniac rapist, killed 12 women in the 1970s and 1980s. His DNA remained at the crime scenes, but there was nothing to compare it with: this "respectable policeman" did not show up in the forensic databases.
The maniac remained at large for 40 years. But now the XXI century has come, and criminologists decided to look at old evidence in a new way: they tried to find matches in the GEDmatch database, where people voluntarily post data about themselves to compile genetic pedigrees. Several family lines, where similar genetic profiles were found, converged on the figure of a 72-year-old former policeman. In April 2018, he was arrested.
Who could have foreseen this back in the 1980s, when in California a maniac took out his psychological complexes on the victims, and in Stockholm Frederick Sanger received the Nobel Prize for the method of deciphering the structure of DNA? GEDmatch is only a small part of the rapidly growing field of business, commercial genomics. How does this business work and what does the future hold for humanity?
To know yourself
People like to study and classify themselves: horoscope, ancient Chinese calendar, character accentuation. And finally, the genotype. Apparently, Anna Wojcicki and Linda Avey relied on this kind of curiosity when they started the 23andMe company in the early 2000s.
Sergey Brin, a long-time friend of Wojcicki, who later became her husband, helped with the money (it was the Wojcicki family that owned the legendary garage from which the history of Google began). In total, Google then invested $3.9 million in 23andMe. The technology underlying the project was well developed by that time – it was the analysis of the genome using DNA microchips.
The first tests were quite expensive – more than $1,000, but by 2012 the price had dropped to $99, that is, below the cost of the chip itself. This commercial trick was based on a simple and elegant idea: the company sold not only genetic tests to self–aware citizens, but also databases of genetic data of these citizens to the inquisitive pharmaceutical industry. The interest of pharma was greatly promoted by a cleverly compiled questionnaire filled out by consumers. The more tests were performed, the more interest the data aroused in the industry, which made it possible to reduce the price and expand the audience even more aggressively.
The scheme seemed so simple and logical that many people immediately appeared willing to repeat it. And although no one else seems to have managed to jump on this escalator with the same elegance as 23andMe, but it was the example of the pioneers that pushed the first players in different countries, including Russia, to commercial genomics.
In 2008, when 23andMe topped the Time magazine's Inventions of the Year rating, the Genoanalytika laboratory in Russia launched the My Gene product, a paid genetic analysis in two varieties: the study of genetic medical predispositions ("My Gene is health") and ethnic roots ("My Gene is ethno"). In 2010, graduates of Moscow State University Valery Ilyinsky, Artem Elmuratov and Kirill Petrenko created the company Genotek.
These first startups of the noughties (Atlas company should also be added to the list of pioneers), largely inspired by the 23andMe model, and still remain key figures in the Russian commercial genomics market. However, over the past decade, the market has managed to change a lot, split into niches and specialize. Completely new players have appeared on it. What range of services can they offer to the consumer?
What are they looking for in genes
The human genome is 3.2 billion "letters", or "base pairs", as molecular biologists put it. Only 1% of these "letters" differ in humans and chimpanzees, and only about 0.1% are differences between people from each other. Nevertheless, it is precisely in these differences (there are several million of them in total) that the genetic uniqueness of a person is encoded. Such differences are called single nucleotide polymorphisms, or SNPs. Most of them, apparently, do not play any biological role at all, although they can occur with different frequency in different regions of the planet - they can be used to try to restore a person's ethnic origin or ancestry.
It is known about other polymorphisms that they statistically correlate with some properties of the organism. For example, people with the letter "A" in this position are slightly more likely to be obese (or, for example, to study music) than those with the letter "G". If we consider a million such positions and check them with a million people with different destinies, illnesses and achievements, then from these statistics we can get interesting recommendations for almost every person.
Finally, there is a third group: polymorphisms, or mutations, in those genes whose function is precisely known and breakdowns in which can lead to diseases. A classic example is the BRCA1 and BRCA2 genes, which became popular after genetic analysis revealed an unfavorable variant of these genes in Angelina Jolie. The probability of getting breast or ovarian cancer depends on which "letter"-base is found in one particular position of the gene, and this probability increases from an average of 12% for the female half of humanity to actual doom, as it was in the case of Mrs. Jolie.
The DNA chips used by 23andMe are able to detect polymorphisms of all three groups, but only at those points of the genome about which it is known in advance that there is diversity in them. Accordingly, the company issued all types of results to customers (except for the period 2013-2017, when the US Food and Drug Administration, the FDA, prohibited it from issuing medical information, including about the risks of diseases). The pioneers of the industry, inspired by the example of 23andMe, are trying to be equally universal. Soon, however, there was a division of commercial genomics into consumer, which can be called "entertainment", and medical.
A couple of years ago, Russian writer Boris Akunin published a test result on social networks, according to which it combines approximately equal parts of the genetic determinants of an Ashkenazi Jew and a native of the Caucasus, as well as a negligible proportion of markers that could indicate the presence of Yakuts in the pedigree. To satisfy the curiosity of Boris Akunin and millions of other people who order genetic analysis of origin, analysis using DNA chips is quite suitable. Such an analysis – it is called genotyping – is done in Russia by Genotek, Genoanalytika, Atlas and other companies.
But when it comes to the risk of serious and sometimes fatal diseases, this may not be enough. Then it is necessary not to be limited to known points, but to decipher the genes entirely. This is called sequencing and is noticeably more expensive, but gives a more complete result. This is relevant, for example, for oncosuppressor genes – any breakdown in them is fraught with a significant increase in the probability of malignant tumors, and if you limit yourself to a set of standard mutations, there is a risk of missing about half of the cases. Even more important is the wide search for mutations when working with rare hereditary anomalies, of which there are more than six thousand.
Wide specialization
In 2012, Genotek attracted the first $500,000 investment, and in 2016 another $2 million, including from the former head of the presidential administration Alexander Voloshin. A year later – another $1 million from Pharmstandard. At this point, investors for the first time seriously paid attention to the new industry. "Five years ago, our company consisted of three people. Now we employ 65 people, we occupy three floors and have our own laboratory base. We have not yet made public the absolute number of tests carried out, because by the end of the year we are waiting for a very round figure," says Valery Ilyinsky.
In recent years, Genotek's revenue has doubled from year to year – the effect of a low base is affecting, because five years ago the volume of this market was almost zero. According to Ilyinsky, now we are talking about thousands of tests a year, and he estimates the entire volume of the Russian market at 500 million rubles ("definitely not more than 1 billion rubles"). For comparison, 15 million genetic tests have already been done in the USA, of which 10 million have been done in the last 12 months. "As an ideal example, Iceland can be cited: there is a population of 300,000 people, and 150,000–200,000 of them have done genetic tests," says Ilyinsky. – More than half of the population with genetic tests is a blue dream for us. In such an optimistic scenario, the market capacity for Russia could be from 50 million to 70 million tests."
Genotek offers a wide range of services, from origin analysis to specialized DNA tests prescribed by a doctor. Ilyinsky is skeptical about the idea of a narrower specialization: "In the USA, everything is as specialized as possible – there are companies that deal only with origin or only with medical diagnostics. But there are no such huge niches in Russia today. Therefore, the only opportunity for us is to engage in several areas at once."
The state has already entered the promising market: a wide range of paid medical and genetic services, including those not related to diagnosis, is offered by the "Medical and Genetic Research Center" on the basis of the Institute of Medical Genetics of the Russian Academy of Medical Sciences. "Our position is as follows: the further you stay away from the state, the easier it is to work," Ilyinsky notes.
Sick and healthy
The company yRisk, created by Andrey Afanasyev and Anton Tikhonov, specializes in a narrow section of commercial genomics: analyzes (namely sequencing) the genes on which the risk of cancer depends, including the very BRCA.
"We work primarily with those who have a family history of cancer,– Afanasyev explains. – Their decision to do the test is completely understandable, because the risk figures, for example, for ovarian cancer vary 35 times depending on the "findings" in the genes. Among the "findings" – that is, the detected mutations – about 6% are pathogenic, and another 25% of variants of unknown significance."
According to general recommendations, it is not customary to inform patients about mutations of unknown significance in order not to unnerve people unnecessarily, but in practice personal circumstances are taken into account. "For example, one of our clients thought about allocating targeted funding for the study of a mutation found in him," Afanasyev says. – Cool idea: invest not in abstract science, but in what you definitely have. I myself am the lucky owner of two mutations of unknown significance at once."
Afanasyev is skeptical about "entertaining" genomics: "The problem can be noticed even in the advertising of broad-profile tests, which, for example, Ilyinsky and his Genotek are engaged in: "Do a test, and we will tell you everything at once: your origin, sensitivity to drugs, which sport to choose." It seems to me that this suggests that the companies themselves do not understand why their client buys the test. This is such a spreading of seeds wider, in the hope that something will sprout."
Biologist Fyodor Konovalov has implemented a number of projects at the Genomed clinic, from where his startup came out – the Laboratory of Clinical Bioinformatics, which deals exclusively with the interpretation of genomic tests. The laboratory works with the same "Genomed", Genetico and "Genoanalytics", the market leaders of medical tests. Konovalov calls the area of his scientific and practical interests "hardcore genetics": his genetic propensity to play table tennis, as well as his maternal roots, is of little interest to him.
Konovalov divides the market into "two genomics". The first is based on objective medical demand: these are sick people, mostly children, who are suspected of having a hereditary disease, or have been diagnosed with cerebral palsy or autism. "Here we often find a molecular cause. This at least helps families to stop traveling with their child to hospitals, switch from diagnosis to rehabilitation. People need a diagnosis, it can change their lives," says Konovalov.
However, investors are often skeptical about this area of genomics, because one in a hundred newborns suffers from monogenic diseases. The growth potential here is very limited, and if we also take into account geographical and financial accessibility, the availability of doctors who can send for analysis, it turns out that the entire market, according to Konovalov, is no more than tens of thousands of tests per year.
For investors, the remaining 99% of the population is much more attractive, but the problem is that healthy people do not need genetic research. Therefore, the markets of the sick and healthy do not differ a hundred times, they are approximately equal, Konovalov is sure. "I would like fewer investors to naively believe in the possibility of repeating the success of 23andMe, because this is a unique project that could only happen once," says the scientist and entrepreneur. – Money can be spent on something more fundamental - for example, by investing in one of the clinical genomics projects. After all, there is demand in medical genomics by definition, but in consumer genomics it must be created."
Creating demand
People treat genomics surprisingly kindly (if you compare, for example, with the topic of vaccinations). In many ways, this is the result of the right PR of commercial genomics, which focuses not on the sad topic of hereditary diseases, but on the entertainment part, like the percentage of Jewish blood. "Genes are fun," the man in the street says to himself and is distracted from unpleasant thoughts about universal mandatory genetic testing in a future dystopia.
A couple of years ago, sensational headlines flashed in popular periodicals, often with reference to Genotek: "Modern Russians are only 16% native Russians," "83% of Russians are relatives," "A third of Russians are genetically predisposed to suicide."
The desire to entertain the public with paranientific sensations is quite excusable if it increases interest in science and technology. However, this kind of public activity caused some irritation among the academic community. In the opinion of some scientists, the very idea of calculating a person's nationality by his genes is problematic. The historical past, which included gas chambers in some places, taught mankind to refrain from mentioning "genes" and "nation" in the same sentence at all.
"Commercial testing is a wonderful thing, but dangerous," says Oleg Balanovsky, head of the Laboratory of Genomic Geography at the Institute of General Genetics of the Russian Academy of Sciences. On the one hand, people have the opportunity to get to know genetics, and geneticists get to know people: testing generates databases much larger than those that scientists can create within the framework of academic funding. However, on the other hand, this mutual acquaintance is superficial, and the picture sometimes turns out to be distorted. "When people do something without a serious professional education, there is a great danger of leaving the field of science for pseudoscience, willingly or unwittingly," says Balanovsky.
Thoughtless use of terms like "native Russian" can really seriously undermine the credibility of test results. Does this discredit genetics itself? "In part, it's even good if there is healthy skepticism in society. Whether there will be disappointment or vice versa depends on those who bring the results to people," Balanovsky believes.
Why do doctors need genetics
Commercial genetic tests have a long way to go to turn from fun for social networks into the basis of personalized medicine of the future. What prevents the commercial genomics market in Russia from reaching the level of, if not the USA, then at least the average EU country?
"The main problem is that genetic tests are not integrated into Russian medicine as decision–making switches," Andrey Afanasyev believes. – First find an expert who is ready to interpret the test result for large-format genomics. Or a cardiologist who will change the dosage of the medicine based on the test. Doctors live in their own magical world, they do not see the problem of too frequent screenings or overdiagnosis." Valery Ilyinsky also speaks about this: "Unfortunately, 90% of doctors do not need genetics: they have lived without genetics and hope to somehow live on. With those doctors who were taught 20-30 years ago, nothing can be done. And new ones need to be taught genetics at the institute not for six months, as now, but as part of a system of continuous professional development."
Now there are only about 200 certified geneticists working in all of Russia. However, it's not so much a shortage of specialists, as the fundamental unavailability of the entire medical infrastructure. "The laboratory informs the patient of the test results: for example, he has a pathogenic allele of an oncosuppressor," says Fyodor Konovalov. – But I do not know what people do with this information. To report the result is great, but after that the person should be perfectly consulted. This is a very difficult task. It's good if he meets a professional geneticist."
Another problem is that commercial genomics cannot exist in isolation from academic science. Its very appearance in the world was the direct result of the Human Genome project – the complete decoding of the sequence of all 3 billion nucleotides on human chromosomes. In 2008, a logical continuation of this initiative was the Thousand Genomes project, designed to catalog the diversity of the human population in detail. In Russia, it was implemented under the name "Russian genomes" on the basis of St. Petersburg University, and it did not come to a thousand genomes: so far there was only enough money for three hundred. Meanwhile, in neighboring China, genomics has become almost a state task: the goal is to sequence not a thousand, but two million Chinese genomes, and the billions invested in this project will be a powerful impetus for the entire biomedicine in the country.
Five years ago, Stanford University professor Ron Davis wrote in Forbes magazine: "Genomics is now at a stage of evolution at which e-commerce was in the mid-1990s. Huge hopes were pinned on it, while the real volume of e-commerce was about half of the hair dryer market. Today, e-commerce is a $3 trillion industry. Think about it when someone speaks with skepticism about the prospects of genomics and personalized medicine."
We are not talking about skepticism: now, five years later, the hopes are still rosy, and the prospects are brilliant. And although the joyful expectation in Russia has been slightly delayed, scientists and entrepreneurs are confident of success. Catching up with the rest of the world is a familiar thing for them. Maybe everything will work out this time.
Portal "Eternal youth" http://vechnayamolodost.ru