02 December 2013

FDA vs. 23andMe: Details

Spitting into the future
Enthusiasts of "genomics at home" were deprived of testsSofia Dolotovskaya, Tape.


Biomedical company 23andMe has received an order to stop selling home-based genetic tests. The reason for the ban was the claims of the US Food and Drug Administration (FDA), which fears that users may perceive the company's services as a full-fledged diagnostic product and take an unjustified medical risk. Does this mean that the era of personal medicine has ended without having begun, <url> found out.

The company 23andMe owes its origin to asparagus. In February 2005, Ann Vozhitsky, a friend of Google founder Sergey Brin, who later became his wife, was sitting at the annual "billionaires' dinner" in California, asking guests if they felt an unpleasant smell in their urine after eating asparagus. Many of those present were only puzzled by her question, but Vozhitski, who had already worked for 10 years in a fund investing in biotech companies, knew what she was talking about: the ability to smell methylmercaptan (methanethiol) formed during asparagus metabolism is genetically determined.

The conversation at the billionaires' table soon turned to the need to create an open database in which people could "Google" information about their genome. And a few months later, Linda Avey read about this dinner in the book The Google Story David Vise and Mark Malseed. Evie, who has worked in pharmaceutical companies for 20 years, has long been hatching the idea of creating a genetic test that analyzes a whole complex of innate human characteristics. To implement this idea, she lacked only money and computing resources – that is, exactly what Google had in abundance. Therefore, having invited Vozhitski to a meeting, Evie quickly found a common language with her, and the following year they founded the company 23andMe ("23 and I"), whose name comes from the number of pairs of chromosomes in a normal human somatic cell. The first investor of the company was Sergey Brin, who invested $ 4 million in the launch.

Neanderthals and earwaxThe main service of 23andMe is to provide everyone with information about their genetic characteristics.

After placing an order on the company's website and paying $ 99 (at first the price of the service was $ 999, but in 2008 it dropped to $ 399), the buyer receives a "spitting kit" by mail.

Image: 23andmeIt is enough to "chew" the inside of the cheek a little, spit out saliva into a test tube and send it by mail – the company takes care of the rest.

It extracts DNA from saliva (more precisely, from the cells that got into it), conducts genotyping, and soon the client receives his "genetic passport".

The passport contains information about the predisposition to 122 different diseases – for example, Alzheimer's disease, asthma, bipolar disorder, various types of cancer and diabetes.

The passport holder also receives data on 60 "harmless" features of the body, such as the likelihood of baldness, the consistency of earwax, the time of menopause or the tendency to sneeze when exposed to bright light from the dark. And, of course, about the ability to distinguish the smell of methylmercaptan in urine.

Together with the passport, the user receives individual recommendations for maintaining health. They basically boil down to advice to visit a doctor and take special tests or contain fairly obvious tips regarding lifestyle and diet. For example, with a high risk of obesity, it is not recommended to eat a lot and move a little, and with a high probability of melanoma, it is recommended to sunbathe for a long time.

In addition, based on the data obtained, you can learn something about your origin. For example, a client can get information about how many percent of his DNA is inherited from Neanderthals, evaluate his African, Scandinavian or East Asian roots and try to trace his own ancestry 10 thousand years ago on the maternal side (using mitochondrial DNA analysis) or on the paternal side (using the Y chromosome).

All this variety of data can be shared with other 23andMe users. The company's website is actually a social network where participants can exchange genetic data with each other, mark relatives and trace the origin of specific traits in their family. However, the company's creators urge customers to think carefully before disclosing their data, since it is unknown what value they may acquire in the future. It is no coincidence, for example, that in the USA in 2008, the Act on Genetic Non–Discrimination was adopted, prohibiting insurance companies from increasing the cost of insurance based on data on a client's genetic predisposition to certain diseases, and employers from making hiring or dismissal decisions based on such data.

23andMe operates in 56 countries. Russia is not included in this number – the legislation does not allow sending biological material abroad; this was done out of fear that "ethnically directed genetic weapons" could be created against residents of the Russian Federation (no, this is not a joke). How this ban affects the work of Russian biologists is a topic for a separate conversation, but it had a completely predictable effect on business: 23andMe clones appeared in Russia, for example, Genotek and "My Gene". However, they, of course, are still far from the amount of data that the American company has collected.

Chip and snipTo make it clear why the FDA took up arms against 23andMe, you need to briefly explain what the tests are.

The technique by which the company operates is called genotyping using microchips. Microchips in this case are understood not as silicon processors, but as small pieces of glass on which DNA fragments of a known sequence are deposited. If you add human DNA labeled with fluorescent dye to such chips, it will bind at certain points of the chip. By the distribution of the luminous spots of the dye, it will be possible to determine which nucleotides are in certain positions in the genome.

Photo: niagara.eduGenotyping does not replace classical genome-wide sequencing.

This is its simplified, but much cheaper option (at least for now). The 23andMe test analyzes single nucleotide polymorphisms (SNP, single nucleotide polymorphism, in Russian literature they are often called "snips"). These are variations of the DNA sequence in one nucleotide, which occur both in genes and in non-coding DNA regions. Although the number of variations of one SNP is limited by the number of nucleotides – A, T, G or C (and for most SNPs the number of alleles does not exceed two at all), due to the huge number of such polymorphisms, each person has an almost unique combination of SNPs. In total, 23andMe analyzes 400-900 thousand variations, for which there are corresponding markers on the microchip.

Image: 23andmeThe presence of certain SNPs in the genome correlates with certain diseases, which potentially allows them to be used either for diagnosis or to assess the likelihood of pathology.

But it is important to understand that it is one thing to determine the presence of a particular SNP in the genome and quite another to draw the right conclusions from it. If the first is a purely technical task (which, by the way, is performed not by 23andMe itself, but by an accredited laboratory), then the second is a scientific, medical, and even ethical issue.

Unfortunately, very few cases of a simple correlation of a mutation with a disease are known. These include the so-called monogenic diseases, that is, those that are determined by a "breakdown" in one gene. This is, for example, phenylketonuria, a violation of the metabolism of the amino acid phenylalanine, or hemophilia, known to everyone from a school textbook of biology. To diagnose such diseases, it is enough to check for the presence of a mutation in a particular gene.

However, such simple inheritance is the exception, not the rule. Most often, the properties of an organism are determined by the work of many genes, therefore, most hereditary diseases are associated with many mutations. Not to mention the fact that not all diseases that we call hereditary are fully such, that is, they develop in 100 percent of cases if there are appropriate features.

In such cases, all that scientists can afford is to assess the likelihood of the disease. To do this, the so-called odds ratio is used, which shows how many times more often a particular polymorphism occurs in sick people than in the general population. For example, it is known that carriers of some variants of two SNPs in the APOE gene (rs7412 and rs429358) are ten times more likely to develop Alzheimer's disease. There are SNPs that increase the risk of postpartum depression by five times and even correlate with school performance. The list can be continued indefinitely: there are a huge number of polymorphisms for which one or another connection with diseases has been established. In one of the many polymorphism databases, SNPedia, there are almost 50 thousand of them.

But are these data statistically reliable for all human populations? How are disease-correlating SNPs related to the mechanism of disease occurrence? Is there any way to prevent or prepare for an unpleasant diagnosis that promises SNP analysis, and if so, do the risks of prevention (for example, breast removal) outweigh the very likelihood of the disease? Should I know anything at all about the likelihood of developing a disease if it is incurable? What to do with such knowledge?

These are all difficult questions. Some of them require large–scale clinical studies, others require individual medical advice, and others require personal volitional choice. 23andMe leaves it up to the users themselves to decide what to do with the collected data. Formally, the company itself only provides them with information and links to scientific papers, and also provides a platform for discussion in the form of a social network. It is not surprising that such liberalism almost immediately led the company to clash with the main bureaucratic authority in the field of American medicine – the FDA.

23andMe and the FDA: A history of the relationshipIn 2008, the New York City Department of Health sent letters to companies conducting genetic tests (including 23andMe), reminding them that such tests cannot be carried out without a doctor's referral.

Soon similar letters were sent out by the Department of the State of California, requiring companies to obtain a license for clinical laboratories. Then 23andMe excused themselves by saying that the company does not conduct medical tests, but simply provides customers with personal information about their DNA, to which they have every right and with which they can then go to the doctor. We also managed to figure out the requirement to obtain a license from a clinical laboratory: all genetic tests for 23andMe are conducted by a third-party laboratory with the necessary certification. As a result, 23andMe received permission to continue business.

In 2010, the regulator stated that genetic tests are equivalent to medical devices and must be approved for sale. 23andMe, however, has not taken any active action on this issue for almost two years. It wasn't until 2012 that the company finally applied to the FDA for permission to sell the tests as medical devices.

On November 22, 2013, the FDA, having not waited for constructive solutions from the company, sent Ann Vozicki an official (but no less irritated) letter. The document states that 23andMe, despite holding "14 face-to-face meetings and teleconferences, hundreds of emails and dozens of written appeals," has not yet complied with the regulations put forward by the FDA in response to the 2012 applications. Then, as follows from the letter, the company was offered a choice: either to prove that the tests correspond to the degree of reliability approved by the FDA, or to change the labeling of the tests, which would allow the regulator to create a separate classification group for them. However, since 23andMe has not done either (and has not responded to the FDA's letters since May 2013), the regulator decided to withdraw the 2012 applications and ban the sale of tests until it receives the appropriate permission. However, while 23andMe continues to ignore the FDA: a week after the ban, on November 29, it is still possible to order a "spit kit" for the test on the company's website.

Concerns of the FDA are caused, firstly, by the possible unreliability of the test results, and secondly, by the unconsciousness of customers who, having incorrectly assessed the data obtained or simply being afraid of the high risk of a particular disease, may take rash actions. As a hypothetical example, the FDA cites false positive and false negative results when assessing the risk of breast or ovarian cancer. Having received false positive results, the user, the FDA believes, can go for preventive organ removal or chemoprophylaxis (how he will do this without consulting a doctor is not specified). False negative results, on the contrary, can lead to the fact that a person, underestimating the risk of developing the disease, will not turn to a doctor in time. In addition, the FDA points out the danger of assessing drug susceptibility, which the test gives: customers, based on these data, can self-medicate, arbitrarily canceling or changing the dosage of the drugs prescribed to them. However, the regulator does not confirm its words with statistics or real cases.

One of the real claims to 23andMe is the story of German programmer Lukas Hartmann, whose genetic test showed the presence of two SNPs (rs28933693 and rs28937900) associated with Leiden dystrophy. This disease is characterized by dystrophy of the pelvic and shoulder girdle muscles, leading to almost complete immobility, progresses over the course of life and remains incurable for the time being. Horrified by the results, but not finding any symptoms of the disease, Hartmann took up reading scientific literature and studying the raw results of the 23andMe test. He found out that the polymorphisms rs28933693 and rs28937900 are localized in two different genes. Each of these polymorphisms leads to the disease only in the homozygous state (that is, in the presence of two identical alleles). In Hartmann's case, both of these SNPs were in a heterozygous state — one copy for each gene. However, 23andMe specialists, analyzing the test results, mistakenly "recorded" both polymorphisms into one gene — and the mutation was thus interpreted as homozygous. After Hartmann wrote about it in 23andMe, the company admitted its mistake and apologized to him.

Trust the experts23andMe, however, has something to object to the FDA's claims.

The company positions itself as a service for providing data – and only without claiming medical status. All disease risk and drug susceptibility assessments are based on scientific publications carefully listed on the website for each disease. Information about all the analyzed signs is accompanied by a warning that the data "are intended only for research and educational purposes and should not be used as diagnostic." Finally, even the genetic tests themselves for 23andMe are conducted by a third–party laboratory - the company, thus, only supports the interface by uploading information about new scientific research to the site, conducting surveys and arranging "spit parties" (spit parties), at which it collects the saliva of celebrities, for example, Warren Buffett.

Competitors of 23andMe, in order not to attract the attention of regulators, resort to various tricks. For example, Navigenics used the services of doctors from the very beginning – they were the ones who officially ordered tests for patients. Other companies received licenses from clinical laboratories after the 2008 letters, including Iceland's deCODE genetics, which in April 2013 refused direct interaction with customers. Some companies are only engaged in determining kinship and origin (FamilyTreeDNA, Ancestry.com ) or genome sequencing for clinical and research laboratories (for example, Complete Genomics). All of them are not related to medicine, and therefore they have no problems with their legal status.

The competitor most similar to 23andMe, Gentle, offers tests to identify more than 1,700 diseases and conditions based on a large-scale analysis of the entire exome (the coding part of the genome). The status of a genetic consulting company saves Gentle from conflicts with regulators: the test results are analyzed by molecular genetics specialists, and doctors cooperating with the company interact with the client – they give the user all the recommendations and explain the results obtained. Pathway Genomics, which has a clinical laboratory license, works in a similar way: here the client can receive test results only from a doctor registered in the system.

23andMe's dispute with the FDA, in fact, boils down to the question of whether it is worth giving people free access to their genetic data or whether they are so dangerous that it is better to leave this right only to specialists. It is difficult to say how this not so much a legal, as a worldview dispute will end. Meanwhile, a petition has already appeared online calling on the FDA to lift the ban on the sale of genetic tests. Supporters themselves decide what to do with information about their own genome, at the time of writing, there were three and a half thousand people.

Portal "Eternal youth" http://vechnayamolodost.ru02.12.2013

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