Biography: Rafal Smigrodzki is a practicing neurologist and the Chief Clinical Officer at Gencia Corporation, which focuses on the development of therapeutics related to mitochondria. His research has focused on mitochondrial mutation, or microheteroplasmy, as a contributing factor to aging and age-related diseases such as Parkinson’s disease. He has also conducted research into treatments to improve oxidative metabolism and memory-related behavior in aging mice. He is also knowledgable about cryopreservation and has made useful contributions to online discussions about brain preservation and related issues.

Andy McKenzie: Your research as well as other research in your field has shown that mitochondrial DNA levels and function decreases with aging. Since mitochondria can affect cell stress responses, and cell stress is difficult to avoid during brain preservation, how do you think that the relative functioning of mitochondria might affect a given preservation quality, if at all?

Rafal Smigrodzki: Since cryopreservation usually occurs after some period of ischemia, the research on mechanisms protecting tissues after ischemia, such as ischemic preconditioning, does have value for cryonics. It is clear that there is a mitochondrial component to the process of ischemic preconditioning. Insulin resistance, which is an aspect of mitochondrial dysfunction, reduces ischemic preconditioning capabilities of brain tissue. It is therefore plausible that pre-existing mitochondrial dysfunction, such as is present in diabetes or Alzheimer’s disease, could impair brain’s ability to maintain integrity in the context of cryosuspension, just as it reduces ischemic preconditioning.

This said, there is woefully little research published on mitochondrial aspects of cryopreservation, and to the best of my limited knowledge of the field, there are no decisive experiments showing that boosting mitochondrial activity could improve outcomes of organ cryopreservation.

Andy McKenzie: Would you please elaborate slightly more on what you mean by ischemic preconditioning in this context? Specifically, is there anything actionable that people interested in a high-quality preservation could do to achieve this, or is this more of an angle that could be useful for researchers in interested in improving cryopreservation protocols?

Rafal Smigrodzki: Ischemic preconditioning is an increase in the resistance to ischemic injury that occurs when tissue is exposed to a significant but sub-lethal degree of ischemia. After such exposure, followed by a period of re-perfusion, the tissue is capable of surviving much longer periods of ischemia than tissue that has not recently been exposed to ischemia. This probably does not have any implications for emergency cryopreservation, although it may offer some insights to researchers working on improving protocols.

Andy McKenzie: What do you consider one of the most important steps to achieve so that brain preservation (cryonics, currently) could be done as an emergency procedure in a more formal medical setting?

Rafal Smigrodzki: Have a very prominent set of identifiers (bracelets, dog tags, wallet cards) that would assure that medical providers are aware of your post-mortem wishes. Prepare extensive and detailed documents (medical Power of Attorney, will) and make sure these documents are accessible to medical providers (have multiple copies with PoAs, online, with cryonics provider). Make arrangements for multiple medical power of attorney persons, preferably highly intelligent, motivated, resourceful and fully committed to help with your preservation, to act on your behalf if incapacitated. Contact the administration of hospitals to which you would be likely to be delivered after cardiac arrest or other emergency and obtain their cooperation for possible future standby and preservation.

Andy McKenzie: Legal considerations aside, what do you consider one of the most important steps to achieve so that brain preservation could be done as an elective procedure for a patient diagnosed with a terminal illness in a more formal medical setting?

Rafal Smigrodzki: If there were no legal impediments, elective cryopreservation would offer potentially vastly better chances of survival, compared to the present practice of waiting until cardiorespiratory arrest before starting suspension. In that situation, probably the main considerations would be to choose the best time for cryosuspension and use the best technology available at the time.

Choosing the right moment would require accurately modeling likely future health trajectories, in order to avoid both unnecessarily early suspension (which entails losing life-time in the present), and dangerously late suspension (which may result in brain damage and poor recovery in the future). Generally, suffering from a neurodegenerative condition with progressive damage to the brain (i.e. dementia), or a progressive untreatable life-threatening medical condition (cancer, severe cardiac, hepatic or pulmonary dysfunction due to e.g. cardiomyopathy, liver cirrhosis, or chronic obstructive pulmonary disease), especially with low quality of life, would be an argument in favor of earlier elective suspension, before significant damage to brain or sudden death occur.

The best cryosuspension technology is likely to keep evolving and it’s difficult to predict what advances may happen. My greatest hope is for high-pressure cold gas tissue persufflation, which may solve the issue of cryogenic fracturing and would offer orders of magnitude improved cooling and warming times, which would reduce the concentrations and therefore also the toxicity of cryoprotectants.

If the law changed in favor of elective cryonics at least in one jurisdiction, and if gas persufflation lives up to its promise, we could have potentially fully reversible suspension in the not ridiculously far future.

Andy McKenzie: Thank you, Dr. Smigrodzki!