Short-Term Suspended Animation for Humans Is Coming Soon
A man gasps for air through deep ice, in a symbolic representation of human hibernation through induced hypothermia.
At 1 a.m., Tony B. is flown to a shock trauma center of a university hospital. Five minutes earlier, he was picked up unconscious with no blood pressure, having suffered multiple gunshot wounds with severe blood loss. Standard measures alone would not have saved his life, but on the helicopter he was injected with ice-cold fluids intravenously to begin cooling him from the inside, and given special drugs to protect his heart and brain.
Suspended animation is not routine yet, but it's going through clinical trials at the University of Maryland and the University of Pittsburgh.
A surgeon accesses Tony's aorta, allowing his body to be flushed with larger amounts of cold fluids, thereby inducing profound hypothermia -- a body temperature below 10° C (50° F). This is suspended animation, a form of human hibernation, but officially the procedure is called Emergency Preservation and Resuscitation for Cardiac Arrest from Trauma (EPR-CAT).
This chilly state, which constitutes the preservation component of Tony's care, continues for an hour as surgeons repair injuries and connect his circulation to cardiopulmonary bypass (CPB). This allows blood to move through the brain delivering oxygen at low doses appropriate for the sharply reduced metabolic rate that comes with the hypothermia, without depending on the heart and lungs. CPB also enables controlled, gradual re-warming of Tony's body as fluid and appropriate amounts of red blood cells are transfused into him.
After another hour or so, Tony's body temperature reaches the range of 32-34° C (~90-93° F), called mild hypothermia. Having begun the fluid resuscitation process already, the team stops warming Tony, switches his circulation from CPB to his own heart and lungs, and begins cardiac resuscitation with electrical jolts to his heart. With his blood pressure stable, his heart rate slow but appropriate for the mild hypothermia, Tony is maintained at this intermediate temperature for 24 hours; this last step is already standard practice in treatment of people who suffer cardiac arrest without blood loss trauma.
The purpose is to prevent brain damage that might come with the rapid influx of too much oxygen, just as a feast would mean death to a starvation victim. After he is warmed to a normal temperature of 37° C (~99° F), Tony is awakened and ultimately recovers with no brain damage.
Tony's case is fictional; EPR-CAT is not routine yet, but it's going through clinical trials at the University of Maryland and the University of Pittsburgh, under the direction of trauma surgeon Dr. Samuel Tisherman, who spent many years developing the procedure in dogs and pigs. In such cases, patients undergo suspended animation for a couple of hours at most, but other treatments are showing promise in laboratory animals, like the use of hydrogen sulfide gas without active cooling to induce suspended animation in mice. Such interventions could ultimately fuse with EPR-CAT, sending the new technology further into what's still the realm of science fiction – at least for now.
Consider the scenario of a 5-year-old girl diagnosed with a progressive, incurable, terminal disease.
Experts say that extended suspended animation – cooling patients in a stable state for months or years -- could be possible at some point, although no one can predict when the technology will be clinical reality, since hydrogen sulfide and other chemical tactics would have to move into clinical use in humans and prove safe and effective in combination with EPR-CAT, or with a similar cooling approach.
How Could Long-Term Suspended Animation Impact Humanity?
Consider the scenario of a 5-year-old girl diagnosed with a progressive, incurable, terminal disease. Since available treatments would only lengthen the projected survival by a year, she is placed into suspended animation. She is revived partially every few years, as new treatments become available that can have a major impact on her disease. After 35 years of this, she is revived completely as treatments are finally adequate to cure her condition, but biologically she has aged only a few months. Physically, she is normal now, though her parents are in their seventies, and her siblings are grown and married.
Such hypothetical scenarios raise many issues: Where will the resources come from to take care of patients for that long? Who will pay? And how will patients adapt when they emerge into a completely different world?
"Heavy resource utilization is a factor if you've got people hibernating for years or decades," says Bradford Winters, an associate professor of anesthesiology and critical care medicine, and assistant professor of neurological surgery at Johns Hopkins.
Conceivably, special high-tech facilities with robots and artificial intelligence watching over the hibernators might solve the resource issue, but even then, Winters notes that long-term hibernation would entail major disparities between the wealthy and poor. "And then there is the psychological effect of being disconnected from one's family and society for a generation or more," he says. "What happens to that 5-year-old waking to her retired parents and married siblings? Will her younger sister adopt her? What would that be like?"
Probably better than dying is one answer.
Back on Earth, human hibernation would raise daunting policy questions that may take many years to resolve.
Outside of medicine, one application of human hibernation that has intrigued generations of science fiction writers is in long-duration space travel. During a voyage lasting years or decades, space explorers or colonists not only could avoid long periods of potential boredom, but also the aging process. Considering that the alternative to "sleeper ships" would be multi-generation starships so large that they'd be like small worlds, human hibernation in spaceflight could become an enabling technology for interstellar flight.
Big Questions: It's Not Too Early to Ask
Back on Earth, the daunting policy questions may take many years to resolve. Society ought to be aware of them now, before human hibernation technology outpaces its dramatic implications.
"Our current framework of ethical and legal regulation is adequate for cases like the gunshot victim who is chilled deeply for a few hours. Short-term cryopreservation is currently part of the continuum of care," notes David N. Hoffman, a clinical ethicist and health care attorney who teaches at Columbia University, and at Yeshiva University's Benjamin N. Cardozo School of Law and Albert Einstein College of Medicine.
"But we'll need a new framework when there's a capability to cryopreserve people for many years and still bring them back. There's also a legal-ethical issue involving the parties that decide to put the person into hibernation versus the patient wishes in terms of what risk benefit ratio they would accept, and who is responsible for the expense and burdens associated with cases that don't turn out just right?"
To begin thinking about practical solutions, Hoffman characterizes long-term human hibernation as an extension of the ethics of cyro-preserved embryos that are held for potential parents, often for long periods of time. But the human hibernation issue is much more complex.
"The ability of the custodian and patient to enter into a meaningful and beneficial arrangement is fraught, because medical advances necessary to address the person's illness or injury are -- by definition -- unknown," says Hoffman. "It means that you need a third party, a surrogate, to act on opportunities that the patient could never have contemplated."
Such multigenerational considerations might become more manageable, of course, in an era when gene therapy, bionic parts, and genetically engineered replacement organs enable dramatic life extension. But if people will be living for centuries regardless of whether or not they hibernate, then developing the medical technology may be the least of the challenges.
Pioneering XPRIZEs, Longevity and Mindset with Dr. Peter Diamandis
XPRIZE founder and chairman Peter Diamandis launches XPRIZE Healthspan at an event on November 29.
A new competition by the XPRIZE Foundation is offering $101 million to researchers who discover therapies that give a boost to people aged 65-80 so their bodies perform more like when they were middle-aged.
For today’s podcast episode, I talked with Dr. Peter Diamandis, XPRIZE’s founder and executive chairman. Under Peter’s leadership, XPRIZE has launched 27 previous competitions with over $300 million in prize purses. The latest contest aims to enhance healthspan, or the period of life when older people can play with their grandkids without any restriction, disability or disease. Such breakthroughs could help prevent chronic diseases that are closely linked to aging. These illnesses are costly to manage and threaten to overwhelm the healthcare system, as the number of Americans over age 65 is rising fast.
In this competition, called XPRIZE Healthspan, multiple awards are available, depending on what’s achieved, with support from the nonprofit Hevolution Foundation and Chip Wilson, the founder of Lululemon and nonprofit SOLVE FSHD. The biggest prize, $81 million, is for improvements in cognition, muscle and immunity by 20 years. An improvement of 15 years will net $71 million, and 10 years will net $61 million.
In our conversation for this episode, Peter talks about his plans for XPRIZE Healthspan and why exponential technologies make the current era - even with all of its challenges - the most exciting time in human history. We discuss the best mental outlook that supports a person in becoming truly innovative, as well as the downsides of too much risk aversion. We talk about how to overcome the negativity bias in ourselves and in mainstream media, how Peter has shifted his own mindset to become more positive over the years, how to inspire a culture of innovation, Peter’s personal recommendations for lifestyle strategies to live longer and healthier, the innovations we can expect in various fields by 2030, the future of education and the importance of democratizing tech and innovation.
In addition to Peter’s pioneering leadership of XPRIZE, he is also the Executive Founder of Singularity University. In 2014, he was named by Fortune as one of the “World’s 50 Greatest Leaders.” As an entrepreneur, he’s started over 25 companies in the areas of health-tech, space, venture capital and education. He’s Co-founder and Vice-Chairman of two public companies, Celularity and Vaxxinity, plus being Co-founder & Chairman of Fountain Life, a fully-integrated platform delivering predictive, preventative, personalized and data-driven health. He also serves as Co-founder of BOLD Capital Partners, a venture fund with a half-billion dollars under management being invested in exponential technologies and longevity companies. Peter is a New York Times Bestselling author of four books, noted during our conversation and in the show notes of this episode. He has degrees in molecular genetics and aerospace engineering from MIT and holds an M.D. from Harvard Medical School.
Show links
- Peter Diamandis bio
- New XPRIZE Healthspan
- Peter Diamandis books
- 27 XPRIZE competitions and counting
- Life Force by Peter Diamandis and Tony Robbins
- Peter Diamandis Twitter
- Longevity Insider newsletter – AI identifies the news
- Peter Diamandis Longevity Handbook
- Hevolution funding for longevity
XPRIZE Founder Peter Diamandis speaks with Mehmoud Khan, CEO of Hevolution Foundation, at the launch of XPRIZE Healthspan.
Hevolution Foundation
Matt Fuchs is the editor-in-chief of Leaps.org and Making Sense of Science. He is also a contributing reporter to the Washington Post and has written for the New York Times, Time Magazine, WIRED and the Washington Post Magazine, among other outlets. Follow him @fuchswriter.
Important findings are starting to emerge from research on how genes shape the human response to the Covid virus.
From infections with no symptoms to why men are more likely to be hospitalized in the ICU and die of COVID-19, new research shows that your genes play a significant role
Early in the pandemic, genetic research focused on the virus because it was readily available. Plus, the virus contains only 30,000 bases in a dozen functional genes, so it's relatively easy and affordable to sequence. Additionally, the rapid mutation of the virus and its ability to escape antibody control fueled waves of different variants and provided a reason to follow viral genetics.
In comparison, there are many more genes of the human immune system and cellular functions that affect viral replication, with about 3.2 billion base pairs. Human studies require samples from large numbers of people, the analysis of each sample is vastly more complex, and sophisticated computer analysis often is required to make sense of the raw data. All of this takes time and large amounts of money, but important findings are beginning to emerge.
Asymptomatics
About half the people exposed to SARS-CoV-2, the virus that causes the COVID-19 disease, never develop symptoms of this disease, or their symptoms are so mild they often go unnoticed. One piece of understanding the phenomena came when researchers showed that exposure to OC43, a common coronavirus that results in symptoms of a cold, generates immune system T cells that also help protect against SARS-CoV-2.
Jill Hollenbach, an immunologist at the University of California at San Francisco, sought to identify the gene behind that immune protection. Most COVID-19 genetic studies are done with the most seriously ill patients because they are hospitalized and thus available. “But 99 percent of people who get it will never see the inside of a hospital for COVID-19,” she says. “They are home, they are not interacting with the health care system.”
Early in the pandemic, when most labs were shut down, she tapped into the National Bone Marrow Donor Program database. It contains detailed information on donor human leukocyte antigens (HLAs), key genes in the immune system that must match up between donor and recipient for successful transplants of marrow or organs. Each HLA can contain alleles, slight molecular differences in the DNA of the HLA, which can affect its function. Potential HLA combinations can number in the tens of thousands across the world, says Hollenbach, but each person has a smaller number of those possible variants.
She teamed up with the COVID-19 Citizen Science Study a smartphone-based study to track COVID-19 symptoms and outcomes, to ask persons in the bone marrow donor registry about COVID-19. The study enlisted more than 30,000 volunteers. Those volunteers already had their HLAs annotated by the registry, and 1,428 tested positive for the virus.
Analyzing five key HLAs, she found an allele in the gene HLA-B*15:01 that was significantly overrepresented in people who didn’t have any symptoms. The effect was even stronger if a person had inherited the allele from both parents; these persons were “more than eight times more likely to remain asymptomatic than persons who did not carry the genetic variant,” she says. Altogether this HLA was present in about 10 percent of the general European population but double that percentage in the asymptomatic group. Hollenbach and her colleagues were able confirm this in other different groups of patients.
What made the allele so potent against SARS-CoV-2? Part of the answer came from x-ray crystallography. A key element was the molecular shape of parts of the cold virus OC43 and SARS-CoV-2. They were virtually identical, and the allele could bind very tightly to them, present their molecular antigens to T cells, and generate an extremely potent T cell response to the viruses. And “for whatever reasons that generated a lot of memory T cells that are going to stick around for a long time,” says Hollenbach. “This T cell response is very early in infection and ramps up very quickly, even before the antibody response.”
Understanding the genetics of the immune response to SARS-CoV-2 is important because it provides clues into the conditions of T cells and antigens that support a response without any symptoms, she says. “It gives us an opportunity to think about whether this might be a vaccine design strategy.”
Dead men
A researcher at the Leibniz Institute of Virology in Hamburg Germany, Guelsah Gabriel, was drawn to a question at the other end of the COVID-19 spectrum: why men more likely to be hospitalized and die from the infection. It wasn't that men were any more likely to be exposed to the virus but more likely, how their immune system reacted to it
Several studies had noted that testosterone levels were significantly lower in men hospitalized with COVID-19. And, in general, the lower the testosterone, the worse the prognosis. A year after recovery, about 30 percent of men still had lower than normal levels of testosterone, a condition known as hypogonadism. Most of the men also had elevated levels of estradiol, a female hormone (https://pubmed.ncbi.nlm.nih.gov/34402750/).
Every cell has a sex, expressing receptors for male and female hormones on their surface. Hormones docking with these receptors affect the cells' internal function and the signals they send to other cells. The number and role of these receptors varies from tissue to tissue.
Gabriel began her search by examining whole exome sequences, the protein-coding part of the genome, for key enzymes involved in the metabolism of sex hormones. The research team quickly zeroed in on CYP19A1, an enzyme that converts testosterone to estradiol. The gene that produces this enzyme has a number of different alleles, the molecular variants that affect the enzyme's rate of metabolizing the sex hormones. One genetic variant, CYP19A1 (Thr201Met), is typically found in 6.2 percent of all people, both men and women, but remarkably, they found it in 68.7 percent of men who were hospitalized with COVID-19.
Lung surprise
Lungs are the tissue most affected in COVID-19 disease. Gabriel wondered if the virus might be affecting expression of their target gene in the lung so that it produces more of the enzyme that converts testosterone to estradiol. Studying cells in a petri dish, they saw no change in gene expression when they infected cells of lung tissue with influenza and the original SARS-CoV viruses that caused the SARS outbreak in 2002. But exposure to SARS-CoV-2, the virus responsible for COVID-19, increased gene expression up to 40-fold, Gabriel says.
Did the same thing happen in humans? Autopsy examination of patients in three different cites found that “CYP19A1 was abundantly expressed in the lungs of COVID-19 males but not those who died of other respiratory infections,” says Gabriel. This increased enzyme production led likely to higher levels of estradiol in the lungs of men, which “is highly inflammatory, damages the tissue, and can result in fibrosis or scarring that inhibits lung function and repair long after the virus itself has disappeared.” Somehow the virus had acquired the capacity to upregulate expression of CYP19A1.
Only two COVID-19 positive females showed increased expression of this gene. The menopause status of these women, or whether they were on hormone replacement therapy was not known. That could be important because female hormones have a protective effect for cardiovascular disease, which women often lose after going through menopause, especially if they don’t start hormone replacement therapy. That sex-specific protection might also extend to COVID-19 and merits further study.
The team was able to confirm their findings in golden hamsters, the animal model of choice for studying COVID-19. Testosterone levels in male animals dropped 5-fold three days after infection and began to recover as viral levels declined. CYP19A1 transcription increased up to 15-fold in the lungs of the male but not the females. The study authors wrote, “Virus replication in the male lungs was negatively associated with testosterone levels.”
The medical community studying COVID-19 has slowly come to recognize the importance of adipose tissue, or fat cells. They are known to express abundant levels of CYP19A1 and play a significant role as metabolic tissue in COVID-19. Gabriel adds, “One of the key findings of our study is that upon SARS-CoV-2 infection, the lung suddenly turns into a metabolic organ by highly expressing” CYP19A1.
She also found evidence that SARS-CoV-2 can infect the gonads of hamsters, thereby likely depressing circulating levels of sex hormones. The researchers did not have autopsy samples to confirm this in humans, but others have shown that the virus can replicate in those tissues.
A possible treatment
Back in the lab, substituting low and high doses of testosterone in SARS-COV-2 infected male hamsters had opposite effects depending on testosterone dosage used. Gabriel says that hormone levels can vary so much, depending on health status and age and even may change throughout the day, that “it probably is much better to inhibit the enzyme” produced by CYP19A1 than try to balance the hormones.
Results were better with letrozole, a drug approved to treat hypogonadism in males, which reduces estradiol levels. The drug also showed benefit in male hamsters in terms of less severe disease and faster recovery. She says more details need to be worked out in using letrozole to treat COVID-19, but they are talking with hospitals about clinical trials of the drug.
Gabriel has proposed a four hit explanation of how COVID-19 can be so deadly for men: the metabolic quartet. First is the genetic risk factor of CYP19A1 (Thr201Met), then comes SARS-CoV-2 infection that induces even greater expression of this gene and the deleterious increase of estradiol in the lung. Age-related hypogonadism and the heightened inflammation of obesity, known to affect CYP19A1 activity, are contributing factors in this deadly perfect storm of events.
Studying host genetics, says Gabriel, can reveal new mechanisms that yield promising avenues for further study. It’s also uniting different fields of science into a new, collaborative approach they’re calling “infection endocrinology,” she says.