George Church - turning back the clock

Preface 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 processes, 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, there should be a short biography.



George Church is a professor at Harvard and the Massachusetts Institute of Technology, co-author of more than 425 papers, 95 patent publications, and the book Regenesis . He developed methods for the first sequencing of the genome as early as 1994, and played a significant role in lowering the price for it using sequencing a new generation, nanopores and bar codes, assembling DNA on a chip, editing, recording and re-encoding the genome.



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 of research on aging in the near future.

Interview with George Church

Hill : Hello, professor, you were recently introduced to the 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 rejuvenation is really very fast, could you clarify, is it five years to achieve it in human cells, clinical trials, or how?



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



Hill : How do you suggest taking different aging processes under medical supervision?



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 cell reprogramming factors (OCT4, SOX2, KLF4 and MYC) and possibly additional factors for treatment of cellular aging in humans, how did belmonte and his group recently performed in mice?



Church : Yes. Epigenetics is very important, but this is only a part of Hallmarks of Aging - and OSKM, in turn, will be only a part of it. Other examples are heterochronic parabiosis factors. Efficacy may depend on various tissues.



Note. Cells can be transformed 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 are easier to transform into other cell types. Last year, Belmonte and his group showed that by temporarily inducing these four factors in a cell, you can reset its age without changing the cell type. This allowed specific tissues and organs to retain their structure and functions, rejuvenated the cells and increased the lifespan 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 association with age-related genes can be changed, we can choose the safest small molecules. For example, we are developing doxycycline alternatives based on sucralose and dozens of other recognized safe (GRAS) molecules.



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



Hill : DNA damage is assumed to be the main reason we age. Is it possible to restore it by influencing 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 increased the level of NAD. NAD-dependent repair is not the only way — we can prevent DNA damage (through control of free radicals), prevent exposure to such damage (for example, duplication of tumor suppressor genes), support certain types of repair (gene conversion and non-homologous terminal compound — a way which restores the breaks of two strands in DNA) or induce apoptosis in cells that acquire potentially oncogenic mutations.



Note. The transcription factor A, the mitochondrial precursor (TFAM) is a molecule that regulates 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 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 no evidence of generality and long-term remission. Effective alternatives are prophylactic - vaccines against some of the 11 infectious agents that cause cancer (for example, HPV), genome sequencing, genetic counseling, preventive surgery, and the prevention of environmental risk factors.



Some strategies that work in preventing cancer in mice may be helpful in germline engineering or in more efficient delivery of gene therapy (because single cells are more important in cancer than in any other disease).



Hill : A recent article showed that CRISPR-cas9 causes many unwanted mutations, do you think we can solve such problems using CRISPR-cpf1 or other options 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 studied unwanted mutations since the first article on the use of CRISPR to avoid mis-targeting. Unwanted mutations may be lower than the rate of spontaneous mutations, and probably less than 0.01% of them will be detrimental.



Hill : As we age, the thymus decreases and loses its ability to produce T-cells, which makes us vulnerable to infection and disease. What will be your decision?



Church : We are developing improved methods for obtaining cells and organs to be transplanted (for example, in Juno and Egenesis ). Initially, they will focus on organ failure 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 can occur.
• Induced. This is tolerance to external antigens. Examples of this are: manipulating 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 : What do you think is currently what is the best biomarker of aging in humans?



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



Note. In principle, a large panel of biomarkers is best, since each of them has potential drawbacks, and using better markers helps to build a more consistent and reliable picture of what is happening. We talked about them in detail in an earlier article .



Hill : Do you think we can get useful knowledge applicable to humans from the sequences of the entire genomes of long-lived species, such as the 400-year-old Greenland shark?



Church : The most promising information is likely to come from genomes of organisms that are closest to ordinary people, such as the bare digger, rhinoceros, and human super-long-dwellers.



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



Hill : In your opinion, is it possible to control diseases such as the senile form of Alzheimer's disease with the help of gene therapy? If not, what other methods seem to be the 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 developed and tested (eg, 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 the Yankner Lab .



We would like to thank Professor Church for taking the 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 process will eventually be under medical control, we cannot help but admire our future.

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