Editing the genome, we must expect unforeseen consequences

Gene Editing Must Reckon With the Unforeseen
Jim Kozubek, Nautilus
Translated by Dmitry Ryder, XX2 century

Almost exactly a year ago, I took part in the International Summit on Human Genome Editing at the National Academy of Sciences of the USA. It was organized by Jennifer Doudna, possibly one of the inventors of CRISPR/Cas9. This is a new biotechnological tool – cheap, easy to use and reliable, which allows thousands of scientists around the world to change genes in plants, model organisms and living human cells.

One of the most important items on the agenda was the discussion of editing the germ line, the hereditary code contained in the sperm and egg, transmitted to future generations. The main interest is that CRISPR/Cas9 will open new ground for "market eugenics" – genome editing will be combined with in vitro fertilization methods. Of course, there is a motivation to explore this perspective: many mothers, when they are predicted that their child will have, for example, Down syndrome, choose abortion. If they are predicted that their child will have autism, or major depression, and if they have the opportunity to change genetic markers of intelligence or signs of risk of mental illness, they may be tempted to take advantage of it. Indeed, insurers may even provide the opportunity to pay for in vitro modification of autism-related genes, or, for example, genes that suggest a risk of developing breast cancer.

CRISPR/Cas9 is already used for "monogenic" disorders such as cystic fibrosis, sickle cell anemia, X-SCID (X-linked severe combined immunodeficiency) and rare, difficult-to-treat eye diseases. Many "enzyme deficiency diseases" such as lipoprotein lipase deficiency would be good candidates, and cancer researchers are using CRISPR/Cas9 to alter our own immune system, helping to fight cancer. But CRISPR/Cas9 is likely to be less useful in influencing such variable features as autism spectrum disorders, or markers that predict intelligence, anxiety and depression. The last two may not even be diseases in themselves, but simply ways of existence in the world. Nevertheless, there is a strong mass interest in studying these markers, their operation and marketing, and, perhaps, someday, changing them for the better.

In 1979, the philosopher Michel Foucault coined the expression "bio-power". He wrote: "Represented, in my opinion, by a rather important group of phenomena, namely, a set of mechanisms through which what determines the basic biological characteristics of the human species can penetrate into politics, into political strategy, into the general strategy of power. In other words, I would like to find out how society, in the face of new Western societies, since the XVIII century again began to take into account this fundamental biological fact: the human race is the human species of the animal kingdom. In fact, that's what I called and still call the word "bio-power"."

You might think that the advent of CRISPR/Cas9 has made and will continue to make his (Foucault's) concept more relevant. Scientists have already created a "Cas9 mouse", which further simplifies the process of gene modification: the cells of such a mouse contain the same protein as in CRISPR/Cas9 - which makes cuts in DNA – thus, only an easily delivered RNA molecule is required for gene modification. This determines the preliminary work to create a "Cas9-human" in whose cells the Cas9 protein is stably expressed, and which could be modified more easily, perhaps even with a simple injection. ("When we control genes, as the proponents of such control promise, we will be the masters of our fate," writes the historian of science Nathaniel Comfort in the article "Genes Are Overrated", published in The Atlantic in June.)

But biotechnological control over life does not come without resistance. Lawmakers, for their part, a few weeks after the summit added a provision preventing the U.S. Food and Drug Administration from considering any genetic modification of an embryo. Nature also creates resistance to biotechnological control. Treatments for multifactorial or complex diseases or signs may never be developed. In fact, it's tempting to think of mental disorders as "highly solvable issues" of genetics or data, and remove them from the context of social stressors such as financial situations. But this is an illusion. At the summit, Eric Lander, director of the Broad Institute (Eli and Edythe L. Broad Institute of MIT and Harvard, Broad Institute), a research center for genomics in Cambridge (Cambridge Resource Center for Comparative Genomics), where I once worked, hinted why.

He explained that researchers affiliated with the Broad Institute have identified a variant in the immune system gene called C4, which also binds to "neuronal synapses, dendrites, axons and cell bodies" and marks excess synaptic connections in the brain to remove them. Variants of this gene (which can increase the intensity of the removal of these connections too much) seem to increase the risk of developing schizophrenia, but not by much – from 1 percent in the general population to only 1.25 percent. Moreover, 10 percent of the risk of developing schizophrenia is associated with thousands of other genetic variants throughout the genome. The remaining 88.75 percent of the risk of developing schizophrenia is called the "mystery of missing heritability" – this may be due to epigenetic markers, the interaction of several genetic variants that we do not yet understand, or what happens in personal experience is related to development or environmental stress factors. So Lander, in his speech, correctly warns against any enthusiasm for using CRISPR/Cas9 to influence such complex signs as schizophrenia.

But within a few months, his mood had clearly changed. Returning to the Broad Institute, to which philanthropist Ted Stanley once gave $650 million to research the basis of neuropsychiatric disorders, Lander's team released a video "Opening the Black Box of Schizophrenia", which suggests that we are on the way to deciphering the mechanisms underlying mental illness. In fact, we are far from that. This fall, for example, it turned out that defects in DIXDC1 – a gene that directly interacts with the "candidate gene" of schizophrenia DISC1, and plays a role in regulating synaptic density - are associated with bipolar disorder, schizophrenia or autism spectrum disorders. There is another similar gene, SHANK3. But the associations in both cases are very weak, increasing the risk of these diseases by a fraction of a percent.

It would be nice if there was a gene for a mental disorder – then we could just change or cut it with a tool like CRISPR/Cas9. However, many of these variants responsible for various forms of psychosis can be pleiotropic, which means that they have different, often unrelated, effects in different cells and tissues. Also, their positive and negative effects may vary depending on their genetic background and other genetic variants with which they are inherited. Siddhartha Mukherjee, in his book The Gene, admits that perhaps we will never create a catalog of genetic variants of schizophrenia that would allow us to predict, based only on the human genome, the likelihood of developing the disease.

Many or most of these genetic variants may even provide an evolutionary advantage. We should not exclude the possibility that the underlying traits ("endophenotypes") that cause predisposition to diseases such as bipolar disorder, depression, schizophrenia or even autism may (with the right combination of dozens or hundreds of other genetic variants) represent evolutionary adaptive advantages that we cannot yet detect – autism and schizophrenia they remain in our species at a high level of registered cases. The contribution of people with autism is almost legendary. Some people with depression, like David Foster Wallace and Andrew Solomon, turn out to be fantastic writers. In 1995, Arnold Ludwig reported a 77 percent rate of mental disorders among famous writers. (Cognitive scientist Steven Pinker doubts that disorders among writers and poets are so frequent. "There is a romantic cultural stereotype that the authors themselves like to cling to –writing is a painful process that requires a secluded hut, you should hate a book tour," he told me. "I doubt this is true for most authors.")

As Comfort notes in The Atlantic, "Darwin's great guess is that although species change, they do not progress to a given goal: organisms adapt to local conditions using the means available at the time." The means available nowadays are radical: biotechnology wants to optimize the functions of genes to achieve the greatest benefits – in health, intelligence, athletic abilities, and so on, in order to create a better future.

But what often remains unrecognized is that there are no perfect genes. Rather, each version of the gene is accompanied by side effects. Therefore, genetic modification should be treated with caution: it can, depending on our ecological niche, cause a new disadvantage or loss of power that we cannot foresee.

Portal "Eternal youth" http://vechnayamolodost.ru  15.02.2017