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An Interview With Dr. Daniel Ives of Shift Bioscience

Daniel Ives InterviewDaniel Ives Interview

Shift Bioscience is a company aiming to solve the problem of mitochondrial dysfunction, one of the hallmarks of aging, by repairing the aging mitochondria in our cells so that they work as if they were younger.

Mitochondrial dysfunction is at the heart of aging

The mitochondria are often called the powerhouses of cells, and they convert the food we eat into usable energy in the form of a chemical called adenosine triphosphate (ATP). ATP supplies energy for many cellular processes, such as muscle contraction, nerve impulse propagation, and protein synthesis. ATP is found in all forms of life and is often referred to as the “molecular unit of currency” of intracellular energy transfer.

During the energy production process, the mitochondria produce free radicals as a waste byproduct, much like the smoke from a power station. These free radicals bounce around the interior of the cell, and, should they strike the fragile mitochondrial DNA (mtDNA), they can damage it, causing mutations and potentially cancer if that damage is not repaired properly.

Normally, the level of free radical production is fairly low, and the body can cope and repair the damage that it causes; however, as we age, our mitochondria become increasingly poor at creating ATP and functioning in general, and they create significantly more free radicals. This then leads to more damage to the mtDNA, an increasing rate of damaged, mutated mitochondria, and a rising risk of cancer and other age-related diseases.

Targeting the problem of dysfunctional mitochondria

Shift Bioscience is developing a unique approach to this problem by encouraging the cell to favor healthy mitochondria over damaged ones; this is how the company describes its therapy on its website:

It has been known for > 25 years that under certain conditions, the cell can reduce the proportion of damaged mitochondrial genomes (Tonsgard & Getz 1990, Dunbar & Holt 1995, Manfredi & Schon 1999). The mechanism was never uncovered and these experimental observations faded into obscurity.

During his PhD project at the MRC Laboratory of Molecular Biology at the University of Cambridge, Dr Daniel Ives harnessed bioinformatic databases and analytic tools to identify small molecule compounds that trigger this effect in cells from individuals with the orphan disease MELAS. He demonstrated that these could increase oxygen consumption in MELAS cells from ~5% to 100% the level of age matched healthy individuals.

Our subsequent research into the underlying mechanism of this effect suggests that these drugs act by increasing competition between mitochondria for scarce resources. Mitochondria import the majority of their proteins. When this protein supply is constrained, undamaged mitochondria are able to out-compete the damaged mitochondria and this gives them a replicative advantage.

SB002 is a molecule discovered by Shift Bioscience to be particularly effective in promoting this greater level of mitochondrial competition inside the cell. We have demonstrated that SB002 can be used to reduce the proportion of damaged mitochondria sourced from an individual with Parkinson’s disease, resulting in an increase in oxygen consumption.

Mice engineered to elevate the rate of damage accumulation in their mitochondrial genomes (POLG mice) exhibit accelerated aging. Recently we have demonstrated that SB002 can slow the progression of visible signs of aging in POLG mice. During treatment with the drug, internal aging markers (heart hypertrophy, elevated glucose) are reduced.

We will minimize costs and timescales for clinical development of this family of drug molecules by first targeting the orphan disease MELAS, which is caused by inherited mitochondrial dysfunction. A clinical trial for MELAS requires fewer participants due to the rarity of the disease and the larger degree of unmet clinical need. Drug efficacy is easier to demonstrate due to clearer biological/clinical endpoints.

Dr. Daniel Ives is the scientific founder of Shift Bioscience, and he first discovered the gene shifting targets that this novel approach is based on. We had the opportunity to speak to Daniel about his work and how the company is planning to tackle aging mitochondria and develop accurate clocks that can measure biological aging.

You are developing second generation epigenetic clocks to act as biomarkers of aging that are superior to those currently available. Can you tell us more about these new clocks and how they improve on the Horvath clock and similar existing clocks?Β 

When we talk to others about the power of epigenetic aging clocks, we’re often asked if it’s possible to use such clocks to perform a genetic screen (e.g. CRISPR) or drug screen for biological aging. Despite its tremendous accuracy, the epigenetic aging clock is a low-throughput technology, and, therefore, such screens are unfeasible.

One solution is to create a cell line that reports its age, fluorescing green while biologically young and fluorescing red as it ages. It’s possible to engineer such age-linked reporters by harnessing known gene expression or epigenetic changes linked to biological age. Such reporter-based clocks will be less accurate than the ‘gold standard’ Horvath clock but will solve the throughput bottleneck. You can imagine performing a CRISPR screen or drug screen, sorting out the green cells to discover genetic or pharmaceutical perturbations that keep the cells young. Any ‘hits’ can then be validated against the higher accuracy Horvath clock.

Using these new-generation clocks, you are proposing to search for small molecules that could potentially slow down the epigenetic clock. Can you tell us a little bit more about your drug screening process and how it differs from traditional high-throughput screening?

It is very difficult to implement high-throughput drug screening for biological aging, since contemporary assays of biological age are cell based and can take months to complete. This would require millions of cell lines to be maintained in parallel for months, and this is simply too cost prohibitive.

To overcome this challenge, we plan to utilize an approach called ‘protein interference’, where a library of protein fragments is delivered by virus to a population of cells containing a biological age-reporter. Each cell receives a unique protein fragment that may bind to any protein at any position, and through this binding, we could discover peptides that slow down, stop, or reverse biological aging. These protein fragments could be used as therapeutics or guide the design of small molecules.

Many of the hallmarks of aging influence the epigenetic aging clocks; what makes you consider the mitochondria the optimal target for therapeutic interventions?

The discovery of epigenetic aging clocks had particular significance to our company, as they provided the opportunity to audit our key hypothesis (e.g. mitochondrial dysfunction is an important part of aging). To do this, we measured Horvath’s clock in human cells without a functional citric acid cycle, which severely reduces energy production by mitochondria. This caused a 16-year acceleration of the clock compared to control cells, which, to our knowledge, is the largest acceleration reported.

So far you claim to have identified one family of small molecules that appear to slow the epigenetic clock by at least 50% by restoring mitochondrial function in aged cells. Does this mean that the mitochondria are being repaired or replaced?

In mice, we have preliminary data indicating a deceleration of biological aging by 40% in the brain and 60% in the heart due to the small molecules (as defined by the Wolf Reiks mouse epigenetic clock). Current evidence suggests that under such conditions, functional mitochondria are able to ‘outbreed’ dysfunctional mitochondria and become the dominant population. This is an example of overcoming damage by dilution, in contrast to conventional repair.

How are you measuring mitochondrial function and changes therein?

In human cells cultured in vitro, we estimate mitochondrial function by measuring oxygen consumption using an expensive machine called the ‘Seahorse’. In mouse tissues, we measure mitochondrial function using the COX/SDH assay – this is an enzymatic assay that monitors the mitochondrial metabolism of dyes.

Cells have the unfortunate habit of favoring mutated mitochondria over healthy ones, and these damaged mitochondria can take over a cell in a relatively short time. How might we prevent the cells from making this poor choice so that they retain their healthy mitochondria?

Though our small molecule approach is closest to clinical development, there are other exciting approaches to combating mutated mitochondria in development.

Aubrey de Grey has proposed transferring the mitochondrial DNA to the safety of the nucleus, an approach called ‘allotopic expression’. This is not as far-fetched as it might seem, since evolution has already encouraged the vast majority of mitochondrial DNA to transfer to the relative safety of the nucleus. Why not finish off the job that evolution started?

Indeed, and this approach was a project supported on, our crowdfunding platform for aging research during the MitoSENS campaign. You mentioned there were other approaches to the problem?

The second approach is to deliver endonucleases to mitochondria that specifically target and digest mutated mitochondrial DNA. Payam Gammage and others have recently validated this approach in mouse models of mitochondrial disease.

Are we seeing actual rejuvenation here, where the cell’s epigenetic age is reversed to that of a younger cell, or, rather, is its rate of epigenetic aging slowed down from that point onwards?

We have not yet achieved reversal of epigenetic age with our small molecules, only slowing of the epigenetic aging process. Others have already reversed and even reset epigenetic age to zero using reprogramming factors, but this approach is known to have a dramatic effect on epigenetic regulation. The worry is that reprogramming factors are only reversing the ‘hands’ of the clock, not the ‘cogs’ driving the hands (e.g. the underlying aging process). Characterizing the effect of reprogramming factors on alternative measures of biological age (e.g. transcriptome-based clocks) may clarify the significance of this exciting finding, since fundamental aging will drive changes across different biological age measures.

So where are you now in terms of development of a therapy and potential human trials?

We are currently creating an enhanced molecule that overcomes some of the limitations of this small molecule family (e.g. they are quickly cleared out of the bloodstream to the urine). Once validated in cellular and animal models, we plan to target rare inherited mitochondrial diseases with this enhanced molecule because they provide the fastest route to the clinic.

We would like to take the opportunity to thank Daniel for taking the time to do this interview with us and to give us insights into the unique approach that his company is taking to address mitochondrial function. We wish Shift Bioscience the very best of luck and hope they are successful in the near-future with development of this platform.

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About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
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