Author: NY Weekly Staff

According to P. Spork, a German neurophysiologist, a lifestyle change causes a chain of biochemical modifications that insensibly but persistently help both you and all next generations until the end of life on Earth. The scientist is sure that epigenetics is the breakthrough science and will forge progress in the 21^st century.

The aim of genetics is to study those processes that transform DNA and genes, and epigenetics research how gene changes as compared to the previous DNA structures. This science is looking for the answers to the following questions: What are the specifics of epigenetic mechanisms functioning? Are they able to overcome social inequality? What genomic interventions could save the world from incurable diseases? Is big data a burden or blessing for scientists?

Epigenetics — a younger sister of genetics

Epi- is a Greek prefix meaning “upon” or “over”. It means that we are dealing with something above genetics. The role of epigenetic mechanisms in embryonic development cannot be overestimated: embryonic cells sharing the same DNA are used to grow specialized cells of an adult body. According to scientists, genetic activity is responsive to external stimuli, e.g. physical activities, diurnal rhythms, and stress levels.

Diving into the history of the discipline development, initially it was treated with total disregard, although it was discussed for quite a long time. Back to the 1940s, C. Waddington, an English biologist, suggested the “epigenetic landscape” concept where he explained how a body was formed [1]. Metaphorically the notion can be described as following: if body development were a river, the fertilization would be its source, physical maturity would be its mouth, and the landscape around the river would represent external conditions that have an impact on the body development.

At the turn of the 21^st century, it became apparent that epigenetic mechanisms of genomic impact both control a single body’s system and are also transferred to the next generations. In 2003, R. Jirtle and R. Waterland, American scientists introduced the diet supplemented with B12, folic acid, methionine, and choline to pregnant agouti mice. It resulted in healthy offspring born from obese yellow mice [2]. The supplements happened to inactivate the gene triggering the disorders. The vitamins displayed a long-lasting effect: all further generations of agouti mice were healthy, as well.

In 2005, M. Skinner, a scientist from Washington University, published an article in Science journal where he described the experiment carried out in relation to pregnant rats fed with a pesticide. This diet de facto caused infertility of the male progeny, because the number of their viable sperm cells decreased dramatically. What is important, this effect passed on four subsequent generations [3].

Both the rodents and infants

The hypothesis was gradually becoming more and more evident. In late 2000, US and Dutch scientists researched Dutch individuals born after WWII. Those were conceived in 1944-45 known as the period of great stress and dearth. As a consequence, the babies were born underweight, and when growing older, they had diabetes, obesity, and cardiovascular diseases more often than those people who were born several years earlier or later [4].

Ultumately, P. Gluckman and M. Hanson, New Zealand academics, introduced the “mismatch concept” explaining this phenomenon [5]. They suggested that the fetus could forecast the future environment and adapted to it (if the mother is eating badly, it means that there is not much food, and thus it is necessary to become metabolically provident). In case the predictive adaptive response is correct, when born the child has an improved immune system. If this response is incorrect, the adaptation turns into maladaptation, a disease, e.g., obesity.

In the 1970s, B.F. Vanyushin, a Russian professor, stated that DNA methylation directly related to food, emotional background, and other aspects was one of the epigenetic mechanisms [6]. It is considered to be capable of “switching on and off’ certain genes. This process can be effective only if B12, folic acid, and methionine act as methyl group donors. Besides, methylation inactivates the embryo’s X chromosome, takes part in cellular differentiation and genomic imprinting, and protects the child from disorders during gestation, such as Down syndrome. And if the future mother starts taking iodine pills, this has a direct impact on the future child’s intellectual abilities.

Therefore, it became vivid that when planning the pregnancy and during gestation it was possible to influence future life of the baby, i.e., mental activity, emotional stability, and physical capacity. In its turn this enables obtaining higher social status in an extremely highly competitive labor market.

There is good news about this: unlike relatively stable genetic data, it is possible to reverse the epigenetic information. That is why modern science is making an attempt to stop the most common diseases and mutations that are caused by epigenetic malfunctions. This is not a coincidence that a lot of experts call the 21^st century as the age of epigenetics.

The CRISPR/Cas panacea

If epigenetics has already done its dirty deed, there are still opportunities to use so-called “molecular scissors” of the CRISPR/Cas gene editing system that for the first time was described by Y. Ishino, a Japanese scientist.

If taken in nature, CRISPR/Cas is the adaptive immune system that is used by bacteria for countering various pathogens. It works according to the following principle: once a bacterium is attacked by a virus, its specialized Cas proteins rapidly cut out parts of the virus and insert them into the CRISPR cassette in a certain order. This process aims at “learning the enemy’s face” and developing a specialized response of the immune system.

Afterwards, scientists began to hope that they could use the CRISPR-Cas9 system of Streptococcus bacteria for editing genomes of other organisms and fighting genetic disorders. CRISPR-Cas9 is already applied to treat various diseases. In spring 2020, scientists informed about the first intraretinal injection of a changed virus to a patient who suffered from Leber congenital amaurosis (a disease-causing blindness). The new method engages point base editing of RPE65 gene mutations.

Two years ago, the results of the first successful editing of P-Thalassemia sickle cell anemia mutations were published in The New England Journal of Medicine [9].

Discovering the CRISPR/Cas9 “genetic scissors” and their potential for point editing was the object of the Nobel Prize in Chemistry in 2020 awarded to E. Charpentier (France) and J. Doudna (USA).

However, CRISPR/Cas9 abilities go far beyond the above: gene editing can be also helpful against cancer. In 2019, scientists conducted an experiment on mice: a new therapeutic was applied to destroy Lipocalin 2, a breast cancer-promoting gene [10].

Moreover, a lot of scientists focus their efforts on fighting viral diseases, e.g., hepatitis and HIV. It is supposed that the pathogen lives in the body as viral DNA built in the cell genome and can be merely cut away. The US biologists did it by “removing” HIV-1 from human T-cell cultures [11]. In September 2021, Excision BioTherapeutics company announced that the Food and Drug Administration had cleared its clinical trials of a CRISPR/Cas-based therapy for chronic HIV infection by involving volunteers with HIV-1. We are sure to soon find out whether the scientists managed to outwit this trickiest virus.

Big Data in science: advantages and disadvantages

Genetic or epigenetic research seem to be unimaginable without information technologies. Bioinformatics methods are widely used in computational epigenetics, as well as experimental studies. Due to the explosive growth of epigenomic data sets, computational methods are getting more and more important.

For example, experimental ChIP-seq, ChIP-on-chip, and bisulfite sequencing methods are used for genome-wide mapping of epigenetic data. They all produce large amounts of data and require efficient ways of processing and quality control. In one respect, big data immensely helps scientists. Some time ago, the whole genome sequencing took years and demanded millions of dollars. However, the next-generation sequencing method provides the same results for $1,200 within a day.

In other respect, there are experts who have a skeptical attitude to big data, because it is impossible for scientists to keep up with great volumes of information. Moreover, the use of supercomputers monitors the scientists’ work. In 2015, F. Mazzocchi, an Italian biologist stated that classical methods used in the science are already outdated in the age of data and supercomputing, where theories, hypotheses, and discussions become obsolete [12]. Scientists do not search for models any more, while correlations offered by big data are replacing causality. M. Fricke also warns his colleagues not to trust machines too much. He insists that “data-driven science will or would find many spurious connections. Data-driven science could easily lead to apophenia and a wild outbreak of hornswoggling” [13].

This is only the time that will tell the actuality of these concerns. However, there is something that is entirely clear: there will be no way back to the old ones, because treatment of the most complicated diseases is on the verge of a breakthrough.

               About the Author

               Rustam Gilfanov is an IT entrepreneur and a venture partner of the LongeVC fund.