“Coming Back from the Dead” Is No Longer Science Fiction
Last year, there were widespread reports of a 53-year-old Frenchman who had suffered a cardiac arrest and "died," but was then resuscitated back to life 18 hours after his heart had stopped.
The once black-and-white line between life and death is now blurrier than ever.
This was thought to have been possible in part because his body had progressively cooled down naturally after his heart had stopped, through exposure to the outside cold. The medical team who revived him were reported as being "stupefied" that they had been able to bring him back to life, in particular since he had not even suffered brain damage.
Interestingly, this man represents one of a growing number of extraordinary cases in which people who would otherwise be declared dead have now been revived. It is a testament to the incredible impact of resuscitation science -- a science that is providing opportunities to literally reverse death, and in doing so, shedding light on the age-old question of what happens when we die.
Death: Past and Present
Throughout history, the boundary between life and death was marked by the moment a person's heart stopped, breathing ceased, and brain function shut down. A person became motionless, lifeless, and was deemed irreversibly dead. This is because once the heart stops beating, blood flow stops and oxygen is cut off from all the body's organs, including the brain. Consequently, within seconds, breathing stops and brain activity comes to a halt. Since the cessation of the heart literally occurs in a "moment," the philosophical notion of a specific point in time of "irreversible" death still pervades society today. The law, for example, relies on "time of death," which corresponds to when the heart stops beating.
The advent of cardiopulmonary resuscitation (CPR) in the 1960s was revolutionary, demonstrating that the heart could potentially be restarted after it had stopped, and what had been a clear black-and-white line was shown to be potentially reversible in some people. What was once called death—the ultimate end point— was now widely called cardiac arrest, and became a starting point.
From then on, it was only if somebody had requested not to be resuscitated or when CPR was deemed to have failed that people would be declared dead by "cardiopulmonary criteria." Biologically, cardiac arrest and death by cardiopulmonary criteria are the same process, albeit marked at different points in time depending on when a declaration of death is made.
The apparent irreversibility of death as we know it may not necessarily reflect true irretrievable cellular damage inside the body.
Clearly, contrary to many people's perceptions, cardiac arrest is not a heart attack; it is the final step in death irrespective of cause, whether it be a stroke, a heart attack, a car accident, an overwhelming infection or cancer. This is how roughly 95 percent of the population are declared dead.
The only exception is the small proportion of people who may have suffered catastrophic brain injuries, but whose hearts can be artificially kept beating for a period of time on life-support machines. These people can be legally declared dead based on brain death criteria before their hearts have stopped. This is because the brain can die either from oxygen starvation after cardiac arrest or from massive trauma and internal bleeding. Either way, the brain dies hours or possibly longer after these injuries have taken place and not just minutes.
A Profound Realization
What has become increasingly clear is that the apparent irreversibility of death as we know it may not necessarily reflect true irretrievable cellular damage inside the body. This is consistent with a mounting understanding: it is only after a person actually dies that the cells in the body start to undergo their own process of death. Intriguingly, this process is something that can now be manipulated through medical intervention. Being cold is one of the factors that slows down the rate of cellular decay. The 53-year-old Frenchman's case and the other recent cases of resuscitation after prolonged periods of time illustrate this new understanding.
Last week's earth-shattering announcement by neuroscientist Dr. Nenad Sestan and his team out of Yale, published in the prestigious scientific journal Nature, provides further evidence that a time gap exists between actual death and cellular death in cadavers. In this seminal study, these researchers were able to restore partial function in pig brains four hours after their heads were severed from their bodies. These results follow from the pioneering work in 2001 of geneticist Fred Gage and colleagues from the Salk Institute, also published in Nature, which demonstrated the possibility of growing human brain cells in the laboratory by taking brain biopsies from cadavers in the mortuary up to 21 hours post-mortem.
The once black-and-white line between life and death is now blurrier than ever. Some people may argue this means these humans and pigs weren't truly "dead." However, that is like saying the people who were guillotined during the French Revolution were also not dead. Clearly, that is not the case. They were all dead. The problem is not death; it's our reliance on an outdated philosophical, rather than biological, notion of death.
Death can no longer be considered an absolute moment but rather a process that can be reversed even many hours after it has taken place.
But the distinction between irreversibility from a medical perspective and biological irreversibility may not matter much from a pragmatic perspective today. If medical interventions do not exist at any given time or place, then of course death cannot be reversed.
However, it is crucial to distinguish between biologically and medically: When "irreversible" loss of function arises due to inadequate treatment, then a person could be potentially brought back in the future when an alternative therapy becomes available, or even today if he or she dies in a location where novel treatments can slow down the rate of cell death. However, when true irreversible loss of function arises from a biological perspective, then no treatment will ever be able to reverse the process, whether today, tomorrow, or in a hundred years.
Probing the "Grey Zone"
Today, thanks to modern resuscitation science, death can no longer be considered an absolute moment but rather a process that can be reversed even many hours after it has taken place. How many hours? We don't really know.
One of the wider implications of our medical advances is that we can now study what happens to the human mind and consciousness after people enter the "grey zone," which marks the time after the heart stops, but before irreversible and irretrievable cell damage occurs, and people are then brought back to life. Millions have been successfully revived and many have reported experiencing a unique, universal, and transformative mental state.
Were they "dead"? Yes, according to all the criteria we have ever used. But they were able to be brought back before their "dead" bodies had reached the point of permanent, irreversible cellular damage. This reflects the period of death for all of us. So rather than a "near-death experience," I prefer a new terminology to describe these cases -- "an actual-death experience." These survivors' unique experiences are providing eyewitness testimonies of what we will all be likely to experience when we die.
Such an experience reportedly includes seeing a warm light, the presence of a compassionate perfect individual, deceased relatives, a review of their lives, a judgment of their actions and intentions as they pertain to their humanity, and in some cases a sensation of seeing doctors and nurses working to resuscitate them.
Are these experiences compatible with hallucinations or illusions? No -- in part, because these people have described real, verifiable events, which, by definition are not hallucinations, and in part, because their experiences are not compatible with confused and delirious memories that characterize oxygen deprivation.
The challenge for us scientifically is understanding how this is possible at a time when all our science tells us the brain shuts down.
For instance, it is hard to classify a structured meaningful review of one's life and one's humanity as hallucinatory or illusory. Instead, these experiences represent a new understanding of the overall human experience of death. As an intensive care unit physician for more than 10 years, I have seen numerous cases where these reports have been corroborated by my colleagues. In short, these survivors have been known to come back with reports of full consciousness, with lucid, well-structured thought processes and memory formation.
The challenge for us scientifically is understanding how this is possible at a time when all our science tells us the brain shuts down. The fact that these experiences occur is a paradox and suggests the undiscovered entity we call the "self," "consciousness," or "psyche" – the thing that makes us who we are - may not become annihilated at the point of so-called death.
At New York University, the State University of New York, and across 20 hospitals in the U.S. and Europe, we have brought together a new multi-disciplinary team of experts across many specialties, including neurology, cardiology, and intensive care. Together, we hope to improve cardiac arrest prevention and treatment, as well as to address the impact of new scientific discoveries on our understanding of what happens at death.
One of our first studies, Awareness during Resuscitation (AWARE), published in the medical journal Resuscitation in 2014, confirmed that some cardiac arrest patients report a perception of awareness without recall; others report detailed memories and experiences; and a few report full auditory and visual awareness and consciousness of their experience, from a time when brain function would be expected to have ceased.
While you probably have some opinion or belief about this based upon your own philosophical, religious, or cultural background, you may not realize that exploring what happens when we die is now a subject that science is beginning to investigate.
There is no question more intriguing to humankind. And for the first time in our history, we may finally uncover some real answers.
In October 2006, Craig Mello received a strange phone call from Sweden at 4:30 a.m. The voice at the other end of the line told him to get dressed and that his life was about to change.
"We think this could be effective in [the early] phase, helping the body clear the virus and preventing progression to that severe hyperimmune response which occurs in some patients."
Shortly afterwards, he was informed that along with his colleague Andrew Fire, he had won the Nobel Prize in Physiology or Medicine.
Eight years earlier, biologists Fire and Mello had made a landmark discovery in the history of genetics. In a series of experiments conducted in worms, they had revealed an ancient evolutionary mechanism present in all animals that allows RNA – the structures within our cells that take genetic information from DNA and use it to make proteins – to selectively switch off genes.
At the time, scientists heralded the dawn of a new field of medical research utilizing this mechanism, known as RNA interference or RNAi, to tackle rare genetic diseases and deactivate viruses. Now, 14 years later, the pharmaceutical company Alnylam — which has pioneered the development of RNAi-based treatments over the past decade — is looking to use it to develop a groundbreaking drug for the virus that causes COVID-19.
"We can design small interfering RNAs to target regions of the viral genome and bind to them," said Akin Akinc, who manages several of Alnylam's drug development programs. "What we're learning about COVID-19 is that there's an early phase where there's lots of viral replication and a high viral load. We think this could be effective in that phase, helping the body clear the virus and preventing progression to that severe hyperimmune response which occurs in some patients."
Called ALN-COV, Alnylam's treatment hypothetically works by switching off a key gene in the virus, inhibiting its ability to replicate itself. In order to deliver it to the epithelial cells deep in the lung tissue, where the virus resides, patients will inhale a fine mist containing the RNAi molecules mixed in a saline solution, using a nebulizer.
But before human trials of the drug can begin, the company needs to convince regulators that it is both safe and effective in a series of preclinical trials. While early results appear promising - when mixed with the virus in a test tube, the drug displayed a 95 percent inhibition rate – experts are reserving judgment until it performs in clinical trials.
"If successful this could be a very important milestone in the development of RNAi therapies, but virus infections are very complicated and it can be hard to predict whether a given level of inhibition in cell culture will be sufficient to have a significant impact on the course of the infection," said Si-Ping Han, who researches RNAi therapeutics at California Institute of Technology and is not involved in the development of this drug.
So far, Alnylam has had success in using RNAi to treat rare genetic diseases. It currently has treatments licensed for Hereditary ATTR Amyloidosis and Acute Hepatic Porphyria. Another treatment, for Primary Hyperoxaluria Type 1, is currently under regulatory review. But its only previous attempt to use RNAi to tackle a respiratory infection was a failed effort to develop a drug for respiratory syncytial virus (RSV) almost a decade ago.
However, the technology has advanced considerably since then. "Back then, RNAi drugs had no chemical modifications whatsoever, so they were readily degraded by the body, and they could also result in unintended immune stimulation," said Akinc. "Since then, we've learned how to chemically modify our RNAi's to make them immunosilent and give them improved potency, stability, and duration of action."
"It would be a very important milestone in the development of RNAi therapies."
But one key challenge the company will face is the sheer speed at which viruses evolve, meaning they can become drug-resistant very quickly. Scientists predict that Alnylam will ultimately have to develop a series of RNAi drugs for the coronavirus that work together.
"There's been considerable interest in using RNAi to treat viral infections, as RNA therapies can be developed more rapidly than protein therapies like monoclonal antibodies, since one only needs to know the viral genome sequence to begin to design them," said David Schaffer, professor of bioengineering at University of California, Berkeley. "But viruses can evolve their sequences rapidly around single drugs so it is likely that a combinatorial RNAi therapy may be needed."
In the meantime, Alnylam is conducting further preclinical trials over the summer and fall, with the aim of launching testing in human volunteers by the end of this year -- an ambitious aim that would represent a breakneck pace for a drug development program.
If the approach does ultimately succeed, it would represent a major breakthrough for the field as a whole, potentially opening the door to a whole new wave of RNAi treatments for different lung infections and diseases.
"It would be a very important milestone in the development of RNAi therapies," said Han, the Caltech researcher. "It would be both the first time that an RNAi drug has been successfully used to treat a respiratory infection and as far as I know, the first time that one has been successful in treating any disease in the lungs. RNAi is a platform that can be reconfigured to hit different targets, and so once the first drug has been developed, we can expect a rapid flow of variants targeting other respiratory infections or other lung diseases."
The Biggest Challenge for a COVID-19 Vaccine
Although no one has conducted a survey on the topic, it's safe to say that a single hope unites much of humanity at the present moment: the prospect of a vaccine for COVID-19, which has infected more than 9 million people worldwide, killed nearly 500,000, and sent the global economy into a tailspin since it first appeared in China last December.
"We've never delivered something to every corner of the world before."
Scientists are racing to make that vision a reality. As of this writing, 11 vaccine candidates are in clinical trials and over 100 others are in preclinical development, in a dozen countries. Pointing to new technology and compressed testing protocols, experts predict a winner could emerge in 12 to 18 months—a fraction of the four years it took to develop the previous record-holder, the mumps vaccine, in the 1960s. Teams at Oxford University and Boston-based Moderna Therapeutics say they could have a product ready even sooner, if the formulas they're testing prove safe and effective. A just-announced White House initiative, Operation Warp Speed, aims to fast-track multiple candidates, with the goal of delivering 100 million doses in November and another 200 million by January 2021.
These timetables could prove wildly over-optimistic. But even if the best-case scenario comes true, and a viable COVID-19 vaccine emerges this fall, a gargantuan challenge remains: getting the shot to everyone who needs it. Epidemiologists figure that at least 70 percent of Earth's population—or 5.6 billion people—would have to be inoculated to achieve "herd immunity," in which each person who catches the disease passes it to less than one other individual. "In order to stop the pandemic, we need to make the vaccine available to almost every person on the planet," Microsoft co-founder Bill Gates blogged in April, as his foundation pledged $300 million to the effort. "We've never delivered something to every corner of the world before."
The difficulties are partly logistical, partly political, and largely a combination of the two. Overcoming those obstacles will require unprecedented cooperation among national governments, international organizations, and profit-minded corporations—in an era when nationalist rivalries are rampant and global leadership is up for grabs.
That may be tougher than developing the vaccine itself.
Logistical Conundrums
Manufacturing and distributing billions of vaccine doses would be a daunting task even in the most harmonious of times. Take the packaging problem. The vaccines under development range from old-school (based on inactivated or weakened viruses) to cutting-edge (using snippets of RNA or DNA to train the immune system to attack the invader). Some may work better than others for different patient groups—the young versus the elderly, for example. All, however, must be stored in vials and administered with syringes.
Among the handful of U.S. companies that manufacture such products, many must import the special glass tubing for vials, as well as the polypropylene for syringe barrels and the rubber or silicone for stoppers and plungers. These materials are commonly sourced from China and India, where lockdowns and export bans restrict supply. Rick Bright, the ousted director of the federal Biomedical Advanced Research and Development Authority (BARDA), claims he was ignored when he warned the Trump Administration that a medical-glass shortage was looming before the coronavirus crisis hit; securing enough to vaccinate 300 million Americans, he told Congress in May, could take up to two years.
Getting the vaccine to poorer countries presents further hurdles. To begin with, there's refrigeration. Inactivated or live vaccines must be kept between 2 and 8 degrees Centigrade (or 35 to 46 degrees Fahrenheit); RNA vaccines typically require much colder temperatures—as low as -80 degrees. This makes storage and transport challenging in parts of the world that lack reliable electricity. DNA vaccines don't need cold storage, but (like RNA vaccines) they remain experimental. They've never been approved to treat any human disease.
Tracking vaccine distribution is another conundrum for low- to-middle-income countries. "Supply chain management is really about information," explains Rebecca Weintraub, assistant professor of global health and social medicine at Harvard Medical School and director of the Better Evidence project at Harvard's Ariadne Labs. "It's about leveraging data to determine demand, predict behavior, and understand the flow of the product itself." Systems for collecting and analyzing such data can be hard to find in poorer regions, she notes. What's more, many people in those areas lack any type of ID card, making it difficult to know who has or hasn't received a vaccine.
Weintraub and two coauthors published an article in April in the Harvard Business Review, suggesting solutions to these and other developing-world problems: solar direct-drive refrigerators, app-based data-capture systems, biometric digital IDs. But such measures—not to mention purchasing adequate supplies of vaccine—would require massive funding.
And that's where the logistical begins to overlap with the political.
Global Access Versus "Vaccine Nationalism"
An array of institutions have already begun laying the groundwork for achieving worldwide, equitable access to COVID-19 vaccines. In February, the World Bank and the Norway-based Coalition for Epidemic Preparedness Innovations (CEPI) cohosted a global consultation on funding vaccine development and manufacturing. In late April, the World Health Organization (WHO), in collaboration with dozens of governments, nonprofits, and industry leaders, launched a program called the Access to COVID-19 Tools Accelerator to expedite such efforts.
Soon afterward, the European Union, along with six countries and the Bill and Melinda Gates Foundation, held a Coronavirus Global Response telethon that raised $8 billion to support Gavi, the Vaccine Alliance—a public-private partnership that subsidizes immunization in low-income countries. The United States and Russia, however, chose not to participate.
This snub by the world's remaining superpower and one of its principal challengers worried many observers. "I am concerned about what I call vaccine nationalism," CEPI executive director Richard Hatchett told the Los Angeles Times. "That's the tension between obligations elected leaders will feel to protect the lives of their citizens" versus the imperative for global sharing.
Some signs point to a possible rerun of the hoarding that accompanied the 2009 H1N1 influenza pandemic, when wealthy nations bought up virtually all vaccine supplies—denying them to poorer countries, and sometimes to one another. Operation Warp Speed has declared an "America First" policy for any vaccine arising from its efforts. Pharma giant Sanofi recently suggested that it would take a similar approach, since the U.S. was first to fund the company's COVID-19 research. (Sanofi's CEO backtracked after officials in France, where the firm is headquartered, protested.) The Oxford group, which is partnering with British-based drug maker AstraZeneca, intends to prioritize Great Britain.
Yet momentum is building for more generous strategies as well. In May, over 100 current and former world leaders, along with prominent economists and public health experts, issued an open letter calling for a "people's vaccine" for COVID-19, which would be patent-free, distributed globally, and available to all countries free of charge. At the WHO's annual World Health Assembly, all 194 member states accepted a resolution urging that vaccines for the disease be made available as a "global public good"—though the U.S. dissociated itself from a clause proposing a patent pool to keep costs down, which it argued might disincentivize "innovators who will be essential to the solutions the whole world needs."
Gavi, for its part, plans to launch a mechanism designed to encourage those innovators while promoting accessibility: an advance market commitment, in which countries pledge to purchase a vaccine, with no money down. Future contributions will be based on the value of the product to their health systems and their ability to pay.
"It's essential to realize that a threat anywhere is a threat everywhere."
A few private-sector players are stepping up, too. U.S.-based Johnson & Johnson, which has received nearly half a billion dollars from the federal government for COVID-19 vaccine research, has promised to provide up to 900 million doses on a not-for-profit basis, if its trials pan out. Other companies have agreed to produce vaccines on a "cost-plus" basis, with a smaller-than-usual profit margin.
How Sharing Can Pay Off
No one knows how all this will work out if and when a vaccine becomes available. (Another wild card: Trump has announced that he is cutting U.S. ties to the WHO over its alleged favoritism toward China, which could hobble the agency's ability to coordinate distribution -- though uncertainty remains about the process of withdrawal and reversing course may still be possible.) To public health experts, however, it's clear that ensuring accessibility is not just a matter of altruism.
"A historic example is smallpox," Rebecca Weintraub observes. "When it kept getting reintroduced into high-income countries from low-income countries, the rich countries realized it was worth investing in the vaccine for countries that couldn't afford it." After a two-decade campaign led by the WHO, the last case of this ancient scourge was diagnosed in 1977.
Conversely, vaccine nationalism doesn't just hurt poor countries. During the H1N1 pandemic, which killed an estimated 284,000 people worldwide, production problems led to shortages in the United States. But Australia stopped a domestic manufacturer from exporting doses to the U.S until all Aussies had been immunized.
Such considerations, Weintraub believes, might help convince even the most reluctant rich-country leaders that an accessible vaccine—if deployed in an epidemiologically targeted way—would serve both the greater good and the national interest. "I suspect the pressures put on our politicians to act globally will be significant," she says.
Other analysts share her guarded optimism. Kelly Moore, who teaches health policy at Vanderbilt University Medical Center, oversaw Tennessee's immunization programs for more than a decade, and later became a member of the Sabin-Aspen Vaccine Science & Policy Group—a panel of international experts that in 2019 released a report titled "Accelerating the Development of a Universal Influenza Vaccine." The 117-page document provided a road map toward a long-sought goal: creating a flu shot that doesn't need to be reformulated each year to target changing viral strains.
"One lesson we learned was that it's crucial to deploy financial resources in a systematic way to support coordination among laboratories that would typically be competitors," Moore says. And that, she adds, is happening with COVID-19, despite nationalist frictions: scientists from Sanofi joining forces with those at rival GSK; researchers at other companies allying with teams at government laboratories; university labs worldwide sharing data across borders. "I have been greatly encouraged to see the amount of global collaboration involved in this enterprise. Partners are working together who would normally never be partners."
For Moore, whose 77-year-old mother survived a bout with the disease, the current pandemic has hit close to home. "It's essential to realize that a threat anywhere is a threat everywhere," she says. "Morally and ethically, we have a tremendous obligation to ensure that the most vulnerable have access to an affordable vaccine, irrespective of where they live."
[Editor's Note: This article was originally published on June 8th, 2020 as part of a standalone magazine called GOOD10: The Pandemic Issue. Produced as a partnership among LeapsMag, The Aspen Institute, and GOOD, the magazine is available for free online. For this reprinting of the article, we have updated the latest statistics on COVID-19 and related global news.]
CORRECTION: A sentence about DNA vaccines incorrectly stated that they require cold storage, like RNA vaccines. The error has been fixed.