The State of Human Biostasis 2023

Introduction

Since the beginning of 2020, I've been working full time in the field of Human Biostasis and will do so for the coming decades. Hopefully, supported for many years by the great teams at Tomorrow Bio and EBF. My primary goal and motivation was and is to provide an alternative (backup) should the longevity field fail to achieve a relevant extension of maximum life span in our lifetime. Depending on how old you are, the estimations that maximum life extension will be available in our/your lifetime range from low to practically impossible. Some very optimistic people having shorter timelines  - but I'd much rather err on the side of caution (if it's this specific topic).
One, if not THE, crucial thing to make this "backup" a reality is to help the field grow  - enabling more funding for research, stability, security and so one.

While it's still a small field, much more is going on compared to the last few years. To keep people in the loop, I've decided to write an annual "State of" article, summarizing where we are and what might make sense to do next. It will be released annually at the end of January. Here goes for 2022/2023.

State of the Market

While - of course - still a niche sector, Human Biostasis has started to gain more attention. There is more media attention, general sentiment is positive or at least neutral, and more people in the longevity space start to consider it as an option. Both for themselves, and maybe a field to work in(?). Nevertheless, the fundamental divergence between interest ("I'm interested and might want to sign up some time") and actionable intent ("I will sign up tomorrow") still very much dominates the field. As a reminder, 20-30% of people reported to consider cryopreservation as an end of life option. But actual sign up rates don't reflect that sentiment.
Tomorrow Bio has been doing public outreach since mid 2021, by now, we've learned a good deal about how people think about the decision, what moves them from interest to intent, what the most common blockers are and so on. While we believe that we're getting closer to converting that data into more people making an informed decision to sign up, this does not show in the conversion rates or absolute sign ups as of yet.
We're growing much faster than other organizations (the delta is up to 10x), but still significantly too slow to make it to absolute membership numbers that would allow significant investments in R&D from cash flow. While this was always a long-term goal, the next step for 2023 (and 2024) will be laying a clear path to scalable growth to tens of thousand of members.

In 2023, growth will remain one of our three main objectives. In fact, it will likely be a top priority in the next years and the foreseeable future as well. For 2023, we'll concentrate on a) taking a more personal approach (e.g. more in-person events, webinars and direct contact with potential members), b) clearly focus on people who have a higher degree of prior knowledge instead of those who have just come across the topic, and c) significantly extend reach for that target groups (i.e. less performance marketing, more SEO, more specific PR, and content).

Global SST Capabilities

Speed is the biggest determinant of good preservation quality. Cooling and cardiopulmonary support need to start with the least possible delay after circulatory arrest. This simple sounding requirement is in fact a highly complex logistical challenge, best illustrated by the fact that on average preservation quality has not relevantly (or at all) improved over the last decades. Obviously, this is not acceptable.
Improving SST (Standby, Stabilization, and Transport) has been one of our main objectives since day one. There are only two solutions: a) building a distributed response infrastructure with SST capabilities close to wherever a member is, and b) concentrating members in regions with capabilities, either in the form of mobile SST teams or stationary locations/facilities. We've decided to go for a hybrid approach. So far we have our main facility in Switzerland, ambulances in Berlin and close to Amsterdam, partners and local teams in France, Spain, Italy, South of Germany, and so on. This isn't perfect by any means - but it's starting to cover Europe better than any other region in the world and provides a foundation to build upon.

In 2023, we'll double down on what we have done so far i.e. expand professional teams, form more partnerships, and establish and support additional local teams. Furthermore, more meaningful quality metrics will get more attention and we'll try to test if its feasible to build a stationary structure of self-sufficient locations that can be used for cases on an on-demand basis while providing adjacent services in the meantime. That would allow them to operate at a profit or at least break even independent of preservation cases. Candidates are: funeral homes, private clinics, and hospices.

Current Research Questions & State of the Art

We founded Tomorrow Bio to do two things. One, provide easy access to high quality preservation. Two, fund R&D from cash flow. Both require us and the field as a whole to grow significantly, to the tune of one or two orders of magnitude. For a long time, it will be more growth, more research, more growth, more research, ...
While there are endless topics that should be researched in more detail, a few are high-impact and solvable with the rather low funding amounts available right now. Here are the ones we'll mostly focus on in 2023:

Quality Metrics
For now it's relatively clear what's required for a high quality cryopreservation - at least based on the currently available outcome metrics. After preservation the brain should be CT-scanned to check for ice crystal formation and shrinkage. Counterintuitively, shrinkage is currently correlated with good preservation quality, as it shows that water has been removed. But with improvements in the procedure (most importantly the implementation of blood brain barrier openers), these two should be independent. High quality preservations would show no ice crystals and no shrinkage.
These quality metrics aren't perfect, they are only rough estimates of low level preservation quality. Standard medical CT scanners have relatively low spatial resolution, ice formation might be more or less problematic depending on the region of the brain, cellular ultrastructure might still be affected while macroscopic structures look fine, etc.
New (additional) metrics have been proposed such as S-MIX (Standardized Measure of Ischemic Exposure) and initial cooling rate normalized to patient weight. Both give an indication of how well the stabilization and transport part of the process has been performed.
Implementation of these new metrics should be the next steps, as well as showing that they are predictive of ultrastructural preservation (i.e. good looking on electron micrographs, a visual representation of good preservation at sub-cellular resolution).

Ischemia & Cooling Rates
The delay between circulatory arrest and the start of cooling as well as the rate of cooling determine preservation quality to a large degree. In simple terms, the slower or lower, the more ischemia (time without sufficient oxygen supply), leading to more edema (swelling of the tissue), which leads to perfusion impairment (the cryoprotective agent just doesn't get everywhere), which leads to incomplete vitrification, meaning that parts of the body/brain aren't protected from ice crystal formation.
To counteract that problem, there are three main concepts to reduce ischemia:
1) Be (logistically) fast: Have multiple teams, have local first aid teams, set up "Mini-Facilities", drill the organization to act fast, etc. Due to distance and the reliance on being informed about critical situations, not everything can be directly controlled. Nevertheless, any organization should consider it their responsible, even the parts that might - at first look - be considered "outside of their control" as they could have better educated their members and similar things. At least, this is how we see it for ourselves.
2) Cool fast: How fast can you reduce the core temperature once you get access to the patient? Multiple methods can be combined: external cooling with circulating ice water, nasopharyngeal lavage, peritoneal lavage, liquid ventilation, extracorporeal circulation with central or peripheral cannulation / or a combinations, etc. None of those alone is sufficient, so we've either established or are establishing all of them.
3) Handle ischemia better: Assuming that there will be some relevant amount of ischemia in almost any case, it's important to develop techniques and processes that allow for good perfusion and in turn good preservation quality in non-ideal situations. In a research project we compared different interventions after rather strong ischemia, but unfortunately none of them showed any significant improvement. Results are published and we will try again.

"Be fast, cool fast, and handle ischemia" is not about picking one. It's a requirement, where all of the factor need to be improved consistently.

Brain-Only Preservation
One of my biggest pet peeves with cryopreservation is the cost. It's unacceptable that cryopreservation is prohibitively expensive for a relevant percentage of the population. If someone decides that they would like to be cryopreserved at the end of their life, it should not depend on wealth. It should just be an informed choice. While it should be rather simple to make this a reality in the future, as almost all line items making up the currently high cost of cryopreservation go down remarkably with scale, the required scale will likely not be reached for years. While we actively work on it, it will take time.
To alleviate this problem at least somewhat, we've decided to offer brain-only preservation as an alternative to whole-body. The procedures are almost identical, just that only the brain is kept in long-term preservation. There are other upsides: 1) In situations where next of kin are diametrically opposed to cryopreservation, "brain donation to science" might be an acceptable "compromise". Ideally, the decision should not come down to this factor, but in reality it might in certain family constellations.
2) If long-distance transport by plane is required, brains can likely be shipped at cryogenics temperatures in dry shippers. Something that is not possible with whole-body patients but allows for higher quality preservation.
Important: For now, we do not actively recommend brain-only preservation. Whole-body cryopreservation is the better understood procedure and there might be some revival scenarios where whole-body is advantageous. In fact, we strongly suggest a call with everybody considering the brain-only option to make sure they understand the (potential) pros and cons.

Transport
In case of field cryoprotection, the patient is transported to a central facility for final cooldown after perfusion in the field or after washing out the blood in the case of field washout. (Note: Field washout is only done in the US, in Europe all cases are at least field cryoprotection). If transport over longer distances is required (e.g. cross continent or international), field washout is not advisable as the patient would still be exposed to cold ischemia. Field cryoprotection is advantageous as it allows cooling down below the freezing point, usually achieved with dry ice to ≈-78.5°C. But field cryoprotection has its own downsides: -78.5°C is well within the ideal temperature range for ice crystal growth and recrystallization of CPAs. Long story short, you don't want to keep the anything in that temperature range for any longer than absolutely necessary.
There are three approaches to this problem:
1) Reduce the distance that a patient needs to be transported after cryoprotection. So far, we've only accepted members in Europe where our facility in Switzerland can be reached a low amount of hours after the patient has reached dry ice temperature. Once we expand to the US, transport will be one of the biggest problems to solve. But even with non-ideal transport the trade off might still be positive, or dry shipping can be a solution (see 3).
2) Local field cryopreservation instead of field cryoprotection which would include cool down below the glass-transition temperature of ≈-125°C on site. This would require either a vehicle equipped with very complicated technology (possible, but highly complex) or local "Mini-Facilities" that allow controlled cooldown before transporting the patient by car (ship?, train?) while maintaining that temperature.
3) "Dry shipping" uses a specialized well insulated vessel with liquid nitrogen "bound" in a porous absorbent that can maintain cryogenic temperature for days. Since planes do not allow liquid nitrogen to be on board, this would enable patients to be transported by plane after field cryopreservation (e.g. across the Atlantic Ocean). For now the dry shipping approach seems feasible for small volumes (e.g. in the case of brain cryopreservation), albeit the exact procedures still need to be tested. Shipping a volume similar to a whole-body patient in a dry shipper has, to our knowledge, never been attempted.
Finding a realistic combination of these three approaches will be a major R&D topic for us in 2023.

Research Funding

Funding has been the most prominent issue for the biostasis field for many years. Likely, and unfortunately, this will remain the case for the foreseeable future. While Tomorrow Bio and the European Biostasis Foundation themselves are reasonably well funded for now, significantly more funds could be meaningfully deployed for research topics at our facility and other labs. With the current R&D infrastructure and in collaboration with other labs about an additional $25m / year could be deployed for 3-5 years while still focusing on low-hanging fruits and "quick wins".
Our internal setup currently looks as follows:
1) Tomorrow Bio - medical and engineering / development projects, implementation of research into day to day practice
2) European Biostasis Foundation - applied and translational research, some development projects (e.g. Intermediate Temperature Storage)
3) CryoDAO - New organization that focused on basic research and moonshots

In 2023, we won't focus on fundraising at Tomorrow Bio or EBF (except if opportunistic) but rather on growth and improving medical procedures and outcomes. Nevertheless, we will still dedicate resources to fundraising by a) working on evangelization in the longevity field, b) raising funds for CryoDAO and the first moonshot-like projects we have planned, and c) running a large invite-only fundraising event for HNWIs/UHNWIs (to be announced) who have shown interest but in most cases have not yet got themselves involved.

Community, Organizations & People

At Tomorrow Bio we only hire people with a high degree of intrinsic motivation, people who really care about making the topic work and who are willing to go the extra mile(s) for each cryopreservation case.
Around the core team we've started to form partnerships with local volunteer organizations in Germany and in other countries.

We'll do a few more things to support and expand the wider community in 2023:
- Building a network of doctors, lawyers, funeral directors, and local contacts for all countries. For us this infrastructure will help in cases without advance notice while providing at least some support to people who are signed up with other organizations.
- Establish closer contract to the medical field, firstly with a regular Doctors x Cryo dinner series that is currently in the planning stages.
- Help create a community around CryoDAO
- Support the Cryosphere Discord community
- We'll host a lot of events, both in person and virtual, to discuss in more depth and be available for questions
- We'll support anybody serious about starting a local team, local capabilities or even a full scale organization

Outreach & Communication

As mentioned a few times, Biostasis is still very much a nice topics. Market education and evangelization in, at least, a subset of population will be required to make any of the above plans work. Research results (bar crazy breakthroughs) usually, and unfortunately, do not sway public opinion. Outreach and better communication do, albeit slowly. Going forward, I plan to do way more public outreach and public communication about and for the topic. In 2022 I gave a good amount of interviews and spoke at a few conferences (e.g. longevity, tech, futurism, etc), in 2023 I plan to do way more of that and with a wider audience.

Roadmap

Last but not least, we'll initiate a large scale "R&D Roadmapping" project to assemble and visualize(!) a comprehensive plan of what should be done, and in which order to "make it work". From low-hanging fruits like improvements of surgical procedures and optimized equipment to translational topics such as validated medication compositions to moonshot topics like ultrafast rewarming technology.

TLDR / Summary

Not much has tangibly improved yet, but the fundamentals for change have been laid. More people are getting involved, the community is growing and better organized, more research is being done, new funding sources (albeit still way too few) are slowly showing themselves, and a more honest evaluation of what works and what doesn't has started. It feels like there is a plan, leading to some optimism. Nevertheless, 95+% of the work is still to be done :)

In 2023 we'll primarily work on membership growth, research, community building and more outreach.