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.
Jamie Rettinger was still in his thirties when he first noticed a tiny streak of brown running through the thumbnail of his right hand. It slowly grew wider and the skin underneath began to deteriorate before he went to a local dermatologist in 2013. The doctor thought it was a wart and tried scooping it out, treating the affected area for three years before finally removing the nail bed and sending it off to a pathology lab for analysis.
I have some bad news for you; what we removed was a five-millimeter melanoma, a cancerous tumor that often spreads, Jamie recalls being told on his return visit. "I'd never heard of cancer coming through a thumbnail," he says. None of his doctors had ever mentioned it either. "I just thought I was being treated for a wart." But nothing was healing and it continued to bleed.
A few months later a surgeon amputated the top half of his thumb. Lymph node biopsy tested negative for spread of the cancer and when the bandages finally came off, Jamie thought his medical issues were resolved.
Melanoma is the deadliest form of skin cancer. About 85,000 people are diagnosed with it each year in the U.S. and more than 8,000 die of the cancer when it spreads to other parts of the body, according to the Centers for Disease Control and Prevention (CDC).
There are two peaks in diagnosis of melanoma; one is in younger women ages 30-40 and often is tied to past use of tanning beds; the second is older men 60+ and is related to outdoor activity from farming to sports. Light-skinned people have a twenty-times greater risk of melanoma than do people with dark skin.
"It was pretty weird, I was totally blasted away. Who had thought of this?"
Jamie had a follow up PET scan about six months after his surgery. A suspicious spot on his lung led to a biopsy that came back positive for melanoma. The cancer had spread. Treatment with a monoclonal antibody (nivolumab/Opdivo®) didn't prove effective and he was referred to the Hillman Cancer Center at the University of Pittsburgh Medical Center, a four-hour drive from his home in western Ohio.
An alternative monoclonal antibody treatment brought on such bad side effects, diarrhea as often as 15 times a day, that it took more than a week of hospitalization to stabilize his condition. The only options left were experimental approaches in clinical trials.
"When I graduated from medical school, in 2005, melanoma was a death sentence" with a cure rate in the single digits, says Dr. Diwakar Davar, 39, an oncologist at Hillman who specializes in skin cancer. That began to change in 2010 with introduction of the first immunotherapies, monoclonal antibodies, to treat cancer. The antibodies attach to PD-1, a receptor on the surface of T cells of the immune system and on cancer cells. Antibody treatment boosted the melanoma cure rate to about 30 percent. The search was on to understand why some people responded to these drugs and others did not.
At the same time, there was a growing understanding of the role that bacteria in the gut, the gut microbiome, plays in helping to train and maintain the function of the body's various immune cells. Perhaps the bacteria also plays a role in shaping the immune response to cancer therapy.
One clue came from genetically identical mice. Animals ordered from different suppliers sometimes responded differently to the experiments being performed. That difference was traced to different compositions of their gut microbiome; transferring the microbiome from one animal to another in a process known as fecal transplant (FMT) could change their responses to disease or treatment.
When researchers looked at humans, they found that the patients who responded well to immunotherapies had a gut microbiome that looked like healthy normal folks, but patients who didn't respond had missing or reduced strains of bacteria.
Davar knew that FMT had a very successful cure rate in treating the gut dysbiosis of C. difficile infection and he wondered if a fecal transplant from a patient who had responded well to cancer immunotherapy treatment might improve the cure rate of patients who did not originally respond to immunotherapies for melanoma.
"It was pretty weird, I was totally blasted away. Who had thought of this?" Jamie first thought when the hypothesis was explained to him. But Davar's explanation that the procedure might restore some of the beneficial bacterial his gut was lacking, convinced him to try. He quickly signed on in October 2018 to be the first person in the clinical trial.
Fecal donations go through the same safety procedures of screening for and inactivating diseases that are used in processing blood donations to make them safe for transfusion. The procedure itself uses a standard hollow colonoscope designed to screen for colon cancer and remove polyps. The transplant is inserted through the center of the flexible tube.
Most patients are sedated for procedures that use a colonoscope but Jamie doesn't respond to those drugs: "You can't knock me out. I was watching them on the TV going up my own butt. It was kind of unreal at that point," he says. "There were about twelve people in there watching because no one had seen this done before."
A test two weeks after the procedure showed that the FMT had engrafted and the once-missing bacteria were thriving in his gut. More importantly, his body was responding to another monoclonal antibody (pembrolizumab/Keytruda®) and signs of melanoma began to shrink. Every three months he made the four-hour drive from home to Pittsburgh for six rounds of treatment with the antibody drug.
"We were very, very lucky that the first patient had a great response," says Davar. "It allowed us to believe that even though we failed with the next six, we were on the right track. We just needed to tweak the [fecal] cocktail a little better" and enroll patients in the study who had less aggressive tumor growth and were likely to live long enough to complete the extensive rounds of therapy. Six of 15 patients responded positively in the pilot clinical trial that was published in the journal Science.
Davar believes they are beginning to understand the biological mechanisms of why some patients initially do not respond to immunotherapy but later can with a FMT. It is tied to the background level of inflammation produced by the interaction between the microbiome and the immune system. That paper is not yet published.
It has been almost a year since the last in his series of cancer treatments and Jamie has no measurable disease. He is cautiously optimistic that his cancer is not simply in remission but is gone for good. "I'm still scared every time I get my scans, because you don't know whether it is going to come back or not. And to realize that it is something that is totally out of my control."
"It was hard for me to regain trust" after being misdiagnosed and mistreated by several doctors he says. But his experience at Hillman helped to restore that trust "because they were interested in me, not just fixing the problem."
He is grateful for the support provided by family and friends over the last eight years. After a pause and a sigh, the ruggedly built 47-year-old says, "If everyone else was dead in my family, I probably wouldn't have been able to do it."
"I never hesitated to ask a question and I never hesitated to get a second opinion." But Jamie acknowledges the experience has made him more aware of the need for regular preventive medical care and a primary care physician. That person might have caught his melanoma at an earlier stage when it was easier to treat.
Davar continues to work on clinical studies to optimize this treatment approach. Perhaps down the road, screening the microbiome will be standard for melanoma and other cancers prior to using immunotherapies, and the FMT will be as simple as swallowing a handful of freeze-dried capsules off the shelf rather than through a colonoscopy.
In Sydney, Australia, in the basement of an inner-city high-rise, lives a mass of unexpected inhabitants: millions of maggots. The insects are far from unwelcome. They are there to feast on the food waste generated by the building's human residents.
Goterra, the start-up that installed the maggots in the building in December, belongs to the rapidly expanding insect agriculture industry, which is experiencing a surge of investment worldwide.
The maggots – the larvae of the black soldier fly – are voracious, unfussy eaters. As adult flies, they don't eat, so the young fatten up swiftly on whatever they can get. Goterra's basement colony can munch through 5 metric tons of waste in a day.
"Maggots are nature's cleaners," says Bob Gordon, Head of Growth at Goterra. "They're a great tool to manage waste streams."
Their capacity to consume presents a neat response to the problem of food waste, which contributes up to 8% of global greenhouse gas emissions each year as it rots in landfill.
"The maggots eat the food fairly fresh," Gordon says. "So, there's minimal degradation and you don't get those methane emissions."
Alongside their ability to devour waste, the soldier fly larvae hold further agricultural promise: they yield an incredibly efficient protein. After the maggots have binged for about 12 days, Goterra harvests and processes them into a protein-rich livestock feed. Their excrement, known as frass, is also collected and turned into soil conditioner.
"We are producing protein in a basement," says Gordon. "It's urban farming – really sustainable, urban farming."
Goterra's module in the basement at Barangaroo, Sydney.
Supplied by Goterra
Goterra's founder Olympia Yarger started producing the insects in "buckets in her backyard" in 2016. Today, Goterra has a large-scale processing plant and has developed proprietary modules – in shipping containers – that use robotics to manage the larvae.
The modules have been installed on site at municipal buildings, hospitals, supermarkets, several McDonald's restaurants, and a range of smaller enterprises in Australia. Users pay a subscription fee and simply pour in the waste; Goterra visits once a fortnight to harvest the bugs.
Insect agriculture is well established outside of the West, and the practice is gaining traction around the world. China has mega-facilities that can process hundreds of tons of waste in a day. In Kenya, a program recently trained 2000 farmers in soldier fly farming to boost their economic security. French biotech company InnovaFeed, in partnership with US agricultural heavyweight ADM, plans to build "the world's largest insect protein facility" in Illinois this year.
"The [maggots] are science fiction on earth. Watching them work is awe-inspiring."
But the concept is still not to everyone's taste.
"This is still a topic that I say is a bit like black liquorice – people tend to either really like it or really don't," says Wendy Lu McGill, Communications Director at the North American Coalition of Insect Agriculture (NACIA).
Formed in 2016, NACIA now has over 100 members – including researchers and commercial producers of black soldier flies, meal worms and crickets.
McGill says there have been a few iterations of insect agriculture in the US – beginning with worms produced for bait after World War II then shifting to food for exotic pets. The current focus – "insects as food and feed" – took root about a decade ago, with the establishment of the first commercial farms for this purpose.
"We're starting to see more expansion in the U.S. and a lot of the larger investments have been for black soldier fly producers," McGill says. "They tend to have larger facilities and the animal feed market they're looking at is potentially quite large."
InnovaFeed's Illinois facility is set to produce 60,000 metric tons of animal feed protein per year.
"They'll be trying to employ many different circular principles," McGill says of the project. "For example, the heat from the feed factory – the excess heat that would normally just be vented – will be used to heat the other side that's raising the black soldier fly."
Although commercial applications have started to flourish recently, scientific knowledge of the black soldier fly's potential has existed for decades.
Dr. Jeffery Tomberlin, an entomologist at Texas A&M University, has been studying the insect for over 20 years, contributing to key technologies used in the industry. He also founded Evo, a black soldier fly company in Texas, which feeds its larvae the waste from a local bakery and distillery.
"They are science fiction on earth," he says of the maggots. "Watching them work is awe-inspiring."
Tomberlin says fly farms can work effectively at different scales, and present possibilities for non-Western countries to shift towards "commodity independence."
"You don't have to have millions of dollars invested to be successful in producing this insect," he says. "[A farm] can be as simple as an open barn along the equator to a 30,000 square-foot indoor facility in the Netherlands."
As the world's population balloons, food insecurity is an increasing concern. By 2050, the UN predicts that to feed our projected population we will need to ramp up food production by at least 60%. Insect agriculture, which uses very little land and water compared to traditional livestock farming, could play a key role.
Insects may become more common human food, but the current commercial focus is animal feed. Aquaculture is a key market, with insects presenting an alternative to fish meal derived from over-exploited stocks. Insect meal is also increasingly popular in pet food, particularly in Europe.
While recent investment has been strong – NACIA says 2020 was the best year yet – reaching a scale that can match existing agricultural industries and providing a competitive price point are still hurdles for insect agriculture.
But COVID-19 has strengthened the argument for new agricultural approaches, such as the decentralized, indoor systems and circular principles employed by insect farms.
"This has given the world a preview – which no one wanted – of [future] supply chain disruptions," says McGill.
As the industry works to meet demand, Tomberlin predicts diversification and product innovation: "I think food science is going to play a big part in that. They can take an insect and create ice cream." (Dried soldier fly larvae "taste kind of like popcorn," if you were wondering.)
Tomberlin says the insects could even become an interplanetary protein source: "I do believe in that. I mean, if we're going to colonize other planets, we need to be sustainable."
But he issues a word of caution about the industry growing too big, too fast: "I think we as an industry need to be very careful of how we harness and apply [our knowledge]. The black soldier fly is considered the crown jewel today, but if it's mismanaged, it can be relegated back to a past."
Goterra's Gordon also warns against rushing into mass production: "If you're just replacing big intensive animal agriculture with big intensive animal agriculture with more efficient animals, then what's the change you're really effecting?"
But he expects the industry will continue its rise though the next decade, and Goterra – fuelled by recent $8 million Series A funding – plans to expand internationally this year.
"Within 10 years' time, I would like to see the vast majority of our unavoidable food waste being used to produce maggots to go into a protein application," Gordon says.
"There's no lack of demand. And there's no lack of food waste."