Many of you will likely already know who Professor George Church is, and that he is an important and senior member of the research community engaged in treating the aging processes to prevent or reverse age-related diseases, not to mention all kinds of other applications for genetic engineering. For those who are not familiar with him, a short bio follows.
George Church is a professor at Harvard & MIT, the co-author of over 425 papers, 95 patent publications and the book Regenesis. He developed the methods used for the first genome sequence back in 1994 and he was instrumental in reducing the costs since then using next-generation sequencing and nanopores plus barcoding, DNA assembly from chips, genome editing, writing and re-coding.
He co-initiated the Genome projects in 1984 and 2005 to create and interpret the world’s only open-access personal precision medicine datasets. He was also involved in launching the BRAIN Initiative in 2011.
We had the opportunity to catch up with him and he was kind enough to answer some questions we had about his work and his vision of what breakthroughs we might expect in the field of aging research in the near future.
Hello Professor Church, you were recently featured in the Toronto Sun suggesting that you predict “we are about to end the aging process. In the next five years no less!” Whilst progress has indeed been rapid in the field of rejuvenation biotechnology, could you clarify, is this five years to achieving this in human cells, to clinical trials, or what exactly?
Within five years it seems plausible to have some gene therapies in FDA approved clinical trials in dogs – aimed at general aging reversal, but quite likely, labeled for specific diseases (and in humans soon thereafter).
How do you propose to bring the various aging processes under medical control?
Combinations of gene therapies aimed at most of the known major aging pathways, though there are major challenges in efficient delivery.
Do you agree that epigenetic alterations as described in Hallmarks of Aging are a primary driver of the aging process, and if so, do you think we can safely use cell reprogramming factors OSKM (OCT4, SOX2, KLF4 and MYC) and possibly additional factors to effectively reverse cell age in humans, like Belmonte and his team recently did in mice?
Yes. Epigenetics are important drivers, but it is only part of the Hallmarks of Aging — and OSKM would, in turn, be only part of that. Other examples are factors behind heterochronic parabiosis. Efficacy may depend on the various tissue types.
Note: Cells can be reprogrammed to induced pluripotent stem cells (iPS) by ectopic expression of OCT4, SOX2, KLF4 and MYC (OSKM). This restores them to an earlier developmental state, making them more flexible and easier to transform into other kinds of cells. The work last year by Belmonte and his team saw them transiently induce these four factors in cells briefly enough to reset their age but not so much that it changed the type of cells they were. It allowed specific tissues and organs to preserve their structure and function. This resulted in functionally younger cells and increased lifespan in mice.
With OSKM the mice have to be engineered to react to doxycycline, an antibiotic, in order to express these factors. Is there an elegant solution that does not involve small molecules and all the side effects that come with them?
Since both the small molecules and their coupling to the age-related genes can be modified, we can choose particularly innocuous small molecules. For example, we have been developing alternatives to doxycycline, based on sucralose and dozens of other Generally Recognized As Safe (GRAS) molecules.
Note: This means the scientists can design custom molecules to induce OSKM without the side effects. This opens the door to reprogramming the cells in mammals and resetting cell age without the need to genetically engineer the mammal first. Ultimately this could lead to the restoration of more youthful cell and tissue function in humans once the technique passes through clinical trials in the future.
DNA damage is proposed to be a primary reason we age. Can it be repaired by targeting TFAM (Transcription factor A, mitochondrial precursor) to increase NAD (a coenzyme in all living cells that facilitates the production of energy) levels that are known to facilitate DNA repair?
We have targeted TFAM and consequently raised NAD successfully. The NAD-facilitated repair is not the only route – we can prevent DNA damage (via the management of radical oxygen species), prevent the impact of such damage (e.g. duplicating tumor suppressor genes), favor specific types of repair (gene conversion vs Non-homologous end joining – a pathway that repairs double-strand breaks in DNA), or induce apoptosis in cells which appear to acquire potentially oncogenic mutations.
Note: Transcription factor A, mitochondrial precursor (TFAM) is a mitochondrial precursor that regulates mitochondrial function and facilitates the creation of cellular energy via Nicotinamide adenine dinucleotide (NAD), a coenzyme found in all living cells that plays a role in DNA repair.
Cancer is caused by an unstable genome resulting from DNA damage and could be considered the poster child of aging diseases. Can we use CRISPR to defeat it?
Genome editing (TALENs, CRISPR, etc.) and transgenic methods (CART) are being ‘successfully’ applied, but proof of generality and long remission is not here yet. Effective alternatives are preventative – vaccines against some of the 11 infectious, cancer-causing agents (e.g. HPV), inherited genome sequencing, genetic counseling, prophylactic surgery and avoiding environmental risk factors.
Some strategies which work to preventatively reduce cancer in mice might benefit from engineering germline or more efficient delivery of gene therapies (since single untreated cells matter more for cancer than other diseases).
A recent paper suggested CRISPR-cas 9 causes many unwanted mutations; do you believe we can solve such issues by using CRISPR-cpf1 or other variants that are better suited to mammalian cells?
Three groups, including ours, have pointed out serious issues with their conclusions here, here and here. Many groups have been studying unwanted mutations since the first paper on using algorithms to avoid off-target . Unwanted mutations can be lower than the spontaneous mutation rate and probably less than 0.01% of these would be deleterious.
As we age, the thymus shrinks and loses the ability to produce T cells, leaving us vulnerable to infection and disease. What would your solution to this be?
We have been developing improved methods for making transplantable cells and organs (e.g. at Juno and Egenesis). These will be initially aimed at organ failures and cancers, but as part of that and in parallel include engineering the immune system to handle Immunological tolerance, inflammation, senescence and pathogens.
Note: Immunological tolerance is the failure to mount an immune response to an antigen and can be in two forms:
Natural or “self” tolerance. This is the failure to attack the body’s own proteins and other antigens. If the immune system should respond to “self”, an autoimmune disease may result.
Induced tolerance. This is tolerance to external antigens. Examples of this include: Manipulating the immune system to reduce excessive immune responses from allergies, reducing the immune response to transplanted organs and preventing useful bacteria in the gut being attacked.
What do you think is currently the best biomarker of aging in humans?
It is important to use a full range of biomarkers – from molecular (DNA 5mC, SA-beta-gal, telomeres) to system functions (immune, muscle strength, damage recovery time and cognitive tests).
Note: Basically a broad panel of biomarkers is best as each of them has potential shortcomings, so using more quality markers helps to build a more consistent and reliable picture of what is going on. We talk about this topic in detail in an earlier article here.
Do you think we can learn useful knowledge that can be applied to humans from the whole-genome sequencing of long-lived species, such as the 400-year-old greenland shark?
The most promising sequencing insights will probably come from genomes closest to average humans, such as naked mole rat, bowhead whales and human supercentenarians.
Even more crucial is low-cost, high-accuracy testing of hypotheses flowing from those sequences, plus already hundreds of hypotheses from model organisms and cell biology (see the GenAge database).
In your opinion, can diseases like the senile form of Alzheimer’s be managed through gene therapy? If not, what other techniques look most promising for neurodegenerative diseases?
Yes. Genetic counseling as a preventative strategy is likely more cost-effective, ethical and humane than current alternatives. In addition, several gene therapies are being developed and tested (e.g. NGF, NEU1, NGFR, miR-29b, BACE1-siRNAs, anti-amyloid antibodies, APP-sα). And additional ones might be discovered and tested using in vitro neural AD models, like those from the Yankner lab.
We would like to thank Professor Church for taking the time to speak with us today and wish him every success in the many endeavors he is involved in. His work is an inspiration to us here at LEAF, and when he says the aging processes are something we can eventually bring under medical control we cannot help but be excited about what the future holds.
 Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., … & Araoka, T. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.
 Mali, P., Yang, L., Esvelt, K. M., Aach, J., Guell, M., DiCarlo, J. E., … & Church, G. M. (2013). RNA-guided human genome engineering via Cas9. Science, 339(6121), 823-826.
August 2, 2017
When was the photo shot?
gustav a ray
June 19, 2018
I would like to donate A1C tests for these dogs if that is helpful. I think it could provide interesting insight. Gus Ray, President of Baycom Diagnostics
June 20, 2018
I would urge you to contact Professor Church directly at their company working on dog longevity here: http://www.rejuvenatebio.com/
Write a comment: