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George Church – turning the clock back / Madrobots / SurprizingFacts Blog

Foreword by Steve Hill

Many of you probably already know Professor George Church, because he is an important member of the research community involved in the treatment of aging, his goal is to prevent or reverse age-related diseases, not to mention all kinds of other applications of genetic engineering. For those who are not familiar with it, a short biography follows.

George Church is Professor of Harvard and Massachusetts Institute of Technology, co-author of more than 425 works, 95 patent publications and books "Regenesis". He developed methods for the first sequencing of the genome back in 1994, and played a significant role in reducing the price of it, using a new generation of sequencing, nanopores and barcodes, DNA assembly on a chip, editing, recording and re-encoding the genome
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He initiated genomic projects in 1984 and 2005 to create and interpret the world's only open, personalized medical data. He also participated in the launch of the BRAIN Initiative in 2011.

We were able to communicate with him, and he was kind enough to answer our questions about his work, and his vision of what breakthroughs we can expect in the field Aging research in the near future.

Interview with George Church

Hill : Hello Professor, you were recently introduced to Toronto Sun, where you "predicted that we were going to put an end to the aging process. In the next five years – certainly! "Although progress in biotechnology of rejuvenation is indeed very fast, could you clarify, is it five years to reach it in human cells, clinical trials or how exactly?

Church : Within five years, the FDA-approved clinical trials in dogs – gene therapy aimed at aging in general, but most likely designated for the treatment of specific diseases (and soon thereafter in humans) are more than real.

Hill : How do you propose to take the various processes of the one hundred

Church : Combinations of gene therapies aimed at most of the known mechanisms of aging, although there are serious problems in effective delivery.

Hill ]: Do you agree that the epigenetic changes described in Hallmarks of Aging are the main causes of the aging process and can we safely use OSKM reprogramming factors (OCT4, SOX2, KLF4 and MYC) and, possibly, additional factors for Treatment of cell aging in humans, as Belmonte and his group Na recently conducted in mice?

Church : Yes. Epigenetics is very important, but it's only part of Hallmarks of Aging – and OSKM, in turn, will be only a part of it. Other examples are the factors of heterochronous parabiosis. Efficacy can depend on different tissues.

Note. The cells can be converted into induced pluripotent stem cells (iPS) by ectopic expression of OCT4, SOX2, KLF4 and MYC (OSKM). This restores them to an earlier state, they become less differentiated and easier to transform into other types of cells. Last year, Belmonte and his team showed that temporarily inducing these four factors in the cell, you can reset her age without changing the type of cell. This allowed specific tissues and organs to retain their structure and function, rejuvenated cells and increased life span in mice.

Hill : Mice should be designed to respond to doxycycline in order to express these factors. Is there an elegant solution that does not include small molecules and all the side effects associated with them?

Church : Since both small molecules and their relationship to age genes can be changed, we can choose The safest small molecules. For example, we are developing alternatives to doxycycline, based on sucralose and dozens of others recognized as safe (GRAS) molecules.

Note. This means that scientists can create their own molecules to induce OSKM without side effects. This opens the door for reprogramming cells in mammals and relieving the cell age without the need to genetically design the body. Ultimately, it can lead to the restoration of the young function of cells and tissues in humans as soon as technology passes through clinical trials in the future.

Hill : It is assumed that DNA damage is the main reason we are aging. Can it be restored by affecting TFAM (transcription factor A, mitochondrial precursor) to increase the amount of NAD (coenzyme in all living cells that promotes energy production), which is known to facilitate DNA repair?

Church : We worked on TFAM and successfully improved the level of NAD. NAD-dependent recovery is not the only way – we can prevent DNA damage (through free radical monitoring), prevent the impact of such damage (for example, duplication of tumor suppressor genes), support certain types of repair (gene conversion and non-homologous end- Which restores breaks of two strands in DNA) or induce apoptosis in cells acquiring potentially oncogenic mutations.

Note. Transcription factor A, the mitochondrial precursor (TFAM) is a molecule that regulates the mitochondrial function and facilitates the creation of cellular energy through nicotinamide adenine dinucleotide (NAD), a coenzyme found in all living cells and playing a role in DNA repair.

Hill : Cancer is caused by an unstable genome caused by DNA damage, and it can be considered a consequence of age-related diseases, can we use CRISPR to defeat it?

Church : Genome editing (TALEN, CRISPR, etc.) and transgenic methods (CART) are applied "successfully", but there is as yet no evidence of community and long-term remission. Effective alternatives are prophylactic – vaccines against some of 11 infectious, cancer-causing agents (eg, HPV), genome sequencing, genetic counseling, preventive surgery and prevention of environmental risk factors.

Some strategies that work in cancer prevention in Mice may be useful in germline engineering or more efficient delivery of gene therapy (since single cells are more important in cancer than in other diseases).

Hill [1 9459010]: A recent article showed that CRISPR-cas9 causes many undesirable mutations; in your opinion, can we solve such problems using CRISPR-cpf1 or other variants that are better suited for mammalian cells?

Church : Three groups, including ours, noted serious problems with their findings here, here and here. Many groups have been studying unwanted mutations since the first article on using CRISPR to avoid mis-targeting. Undesired mutations may be lower than the rate of spontaneous mutations, and probably less than 0.01% of them will be fatal.

Hill : As the aging grows, the thymus decreases and loses the ability to produce T- Cells, which makes us vulnerable to infection and disease.

Church : We are developing improved methods for obtaining transplanted cells and organs (for example, in Juno and Egenesis). Initially, they will be directed to the rejection of organs and cancer, but within this and in parallel include the development of the immune system for the treatment of immunological tolerance, inflammation, aging and pathogens.

Note: Immunological tolerance is the inability to establish an immune response to an antigen. It can be in two forms:

  • Natural. This is the inability to attack the body's own proteins and other antigens. If the immune system reacts to your body, an autoimmune disease may occur.
  • Induced. It is tolerance to external antigens. Examples of this are: manipulation of the immune system to reduce the excessive immune response from allergies, reducing the immune response to transplanted organs and beneficial bacteria in the intestine.
  • Hill: : Do you think at the present time what is the best aging biomarker in humans?

    Church : It is important to use the full spectrum of biomarkers – from molecular (DNA 5mC , SA-beta-gal, telomeres) to systemic functions (immune, muscle strength, damage repair time and cognitive tests).

    Note. In principle, a large panel of biomarkers is best, because each of them has potential drawbacks, and the use of better markers helps to build a more consistent and reliable picture of what is happening.

    Hill : Do you think we can learn useful knowledge, applicable to people, from the sequences of entire genomes of long-lived species, such

    Church : The most promising information is likely to come from the genomes of organisms closest to ordinary humans, for example, a naked digger, rhinoceros and human superhumans .

    Even more important is the inexpensive high-precision testing of hypotheses based on these sequences, plus hundreds of hypotheses from model organisms and cell biology (see GenAge database).

    Hill : In your opinion, is it possible to manage diseases such as the senile form of Alzheimer's disease with the help of gene therapy? If not, what other methods are most promising for neurodegenerative diseases?

    Church : Yes. Genetic counseling as a preventive measure is probably more economical, ethical and humane than the existing alternatives. In addition, several gene therapies are being developed and tested (for example, NGF, NEU1, NGFR, miR-29b, BACE1-siRNAs, anti-amyloid antibodies, APP-sα). And new ones can be detected and tested using in vitro neural AD models, as in Yankner Lab.

    We would like to thank Professor Church for finding time to talk with us and wish him every success in all his endeavors. His work inspires us here at the LEAF, and when he says that the aging processes will be under medical control after a while, we can not help admiring our future.