“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.
Couples Facing Fertility Treatments Should Beware of This
When Jane Stein and her husband used in-vitro fertilization in 2001 to become pregnant with twins, her fertility clinic recommended using a supplemental procedure called intracytoplasmic sperm injection (ICSI), known in fertility lingo as "ix-see."
'Add-on' fertility procedures are increasingly coming under scrutiny for having a high cost and low efficacy rate.
During IVF, an egg and sperm are placed in a petri dish together with the hope that a sperm will seek out and fertilize the egg. With ICSI, doctors inject sperm directly into the egg.
Stein, whose name has been changed to protect her privacy, agreed to try it. Her twins are now 16, but while 17 years have gone by since that procedure, the efficacy of ICSI is still unclear. In other words, while Stein succeeded in having children, it may not have been because of ICSI. It may simply have been because she did IVF.
The American Society for Reproductive Medicine has concluded, "There are no data to support the routine use of ICSI for non-male factor infertility." That is, ICSI can help couples have a baby when the issue is male infertility. But when it's not, the evidence of its effectiveness is lacking. And yet the procedure is being used more and more, even when male infertility is not the issue. Some 40 percent of fertility treatments in Europe, Asia and the Middle East now use ICSI, according to a world report released in 2016 by the International Committee for Monitoring Assisted Reproductive Technologies. In the Middle East, the figure is actually 100 percent, the report said.
ICSI is just one of many supplemental procedures, or 'add-ons,' increasingly coming under scrutiny for having a high cost and low efficacy rate. They cost anywhere from a couple of hundred dollars to several thousand – ICSI costs $2,000 to $3,000 -- hiking up the price of what is already a very costly endeavor. And many don't even work. Worse, some actually cause harm.
It's no surprise couples use them. They promise to increase the chance of conceiving. For patients who desperately want a child, money is no object. The Human Fertilization and Embryology Authority (HFEA) in the U.K. found that some 74 percent of patients who received fertility treatments over the last two years were given at least one type of add-on. Now, fertility associations in the U.S. and abroad have begun issuing guidance about which add-ons are worth the extra cost and which are not.
"Many IVF add-ons have little in the way of conclusive evidence supporting their role in successful IVF treatment," said Professor Geeta Nargund, medical director of CREATE Fertility and Lead Consultant for reproductive medicine at St George's Hospital, London.
The HFEA has actually rated these add-ons, indicating which procedures are effective and safe. Some treatments were rated 'red' because they were considered to have insufficient evidence to justify their use. These include assisted hatching, which uses acid or lasers to make a hole in the surrounding layer of proteins to help the embryo hatch; intrauterine culture, where a device is inserted into the womb to collect and incubate the embryo; and reproductive immunology, which suppresses the body's natural immunity so that it accepts the embryo.
"Fertility care is a highly competitive market. In a private system, offering add-ons may discern you from your neighboring clinic."
For some treatments, the HFEA found there is evidence that they don't just fail to work, but can even be harmful. These procedures include ICSI used when male infertility is not at issue, as well as a procedure called endometrial scratching, where the uterus is scratched, not unlike what would happen with a biopsy, to stimulate the local uterine immune system.
And then for some treatments, there is conflicting evidence, warranting further research. These include artificial egg activation by calcium ionophore, elective freezing in all cycles, embryo glue, time-lapse imaging and pre-implantation genetic testing for abnormal chromosomes on day 5.
"Currently, there is very little evidence to suggest that many of the add-ons could increase success rates," Nargund said. "Indeed, the HFEA's assessment of add-on treatments concluded that none of the add-ons could be given a 'green' rating, due to a lack of conclusive supporting research."
So why do fertility clinics offer them?
"Fertility care is a highly competitive market," said Professor Hans Evers, editor-in-chief of the journal Human Reproduction. "In a private system, offering add-ons may discern you from your neighboring clinic. The more competition, the more add-ons. Hopefully the more reputable institutions will only offer add-ons (for free) in the context of a randomized clinical trial."
The only way for infertile couples to know which work and which don't is the guidance released by professional organizations like the ASRM, and through government regulation in countries that have a public health care system.
The problem is, infertile couples will sometimes do anything to achieve a pregnancy.
"They will stand on their heads if this is advocated as helpful. Someone has to protect them," Evers said.
In the Netherlands, where Evers is based, the national health care system tries to make the best use of the limited resources it has, so it makes sure the procedures it's funding actually work, Evers said.
"We have calculated that to serve a population of 17 million, we need 13 IVF clinics, and we have 13," he said. "We as professionals discuss and try to agree on the value of newly proposed add-ons, and we will implement only those that are proven effective and safe."
Likewise, in the U.K., there's been a lot of squawking about speculative add-ons because the government, or National Health Service, pays for them. In the U.S., it's private insurers or patients' own cash.
"The [U.K.] government takes a very close look at what therapies they are offering and what the evidence is around offering the therapy," said Alan Penzias, who chairs the Practice Committee of the ASRM. It wants to make sure the treatments it is funding are at least worth the money.
ICSI is a case in point. Originally intended for male infertility, it's now being applied across the board because fertility clinics didn't want couples to pay $10,000 to $15,000 and wind up with no embryos.
"It is so disastrous to have no fertilization whatsoever, clinics started to make this bargain with their patients, saying, 'Well, listen, even though it's not indicated, what we would like to do is to take half of your eggs and do the ICSI procedure, and half we'll do conventional insemination just to make sure,'" he said. "It's a disaster if you have no embryos, and now you're out 10 to 12 thousand dollars, so for a small added fee, we can do the injection just to guard against that."
In the Netherlands, the national health care system tries to make the best use of its limited resources, so it makes sure the procedures it's funding actually work.
Clinics offer it where they see lower rates of fertilization, such as with older women or in cases where induced ovulation results in just two or three eggs instead of, say, 13. Unfortunately, ICSI may result in a higher fertilization rate, but it doesn't result in a higher live birth rate, according to a study last year in Human Reproduction, so couples wind up paying for a procedure that doesn't even result in a child.
Private insurers in the U.S. are keen to it. Penzia, who is also an associate professor of obstetrics, gynecology and reproductive biology at Harvard Medical School and works as a reproductive endocrinology and infertility specialist at Boston IVF, said Massachusetts requires that insurers cover infertility treatments. But when he submits claims for ICSI, for instance, insurers now want to see two sperm counts and proof that the man has seen a urologist.
"They want to make sure we're doing it for male factor (infertility)," he said. "That's not unreasonable, because the insurance company is taking the burden of this."
How exactly does your DNA make you who you are?
It's because of epigenetics that identical twins can actually look different and develop different diseases.
Just as software developers don't write apps out of ones and zeros, the interesting parts of the human genome aren't written merely in As, Ts, Cs and Gs. Yes, these are the fundamental letters that make up our DNA and encode the proteins that make our cells function, but the story doesn't end there.
Our cells possess amazing abilities, like eating invading bacteria or patching over a wound, and these abilities require the coordinated action of hundreds, if not thousands, of proteins. Epigenetics, the study of gene expression, examines how multiple genes work at once to make these biological processes happen.
It's because of epigenetics that identical twins – who possess identical DNA -- can actually look different and develop different diseases. Their environments may influence the expression of their genes in unique ways. For example, a research study in mice found that maternal exposure to a chemical called bisphenol A (BPA) resulted in drastic differences between genetically identical offspring. BPA exposure increased the likelihood that a certain gene was turned on, which led to the birth of yellow mice who were prone to obesity. Their genetically identical siblings who were not exposed to BPA were thinner and born with brown fur.
These three mice are genetically identical. Epigenetic differences, however, result in vastly different phenotypes.
(© 1994 Nature Publishing Group, Duhl, D.)
This famous mouse experiment is just one example of how epigenetics may transform medicine in the coming years. By studying the way genes are turned on and off, and maybe even making those changes ourselves, scientists are beginning to approach diseases like cancer in a completely new way.
With few exceptions, most of the 1 trillion cells that make up your body contain the same DNA instructions as all the others. How does each cell in your body know what it is and what it has to do? One of the answers appears to lie in epigenetic regulation. Just as everyone at a company may have access to all the same files on the office Dropbox, the accountants will put different files on their desktop than the lawyers do.
Our cells prioritize DNA sequences in the same way, even storing entire chromosomes that aren't needed along the wall of the nucleus, while keeping important pieces of DNA in the center, where it is most accessible to be read and used. One of the ways our cells prioritize certain DNA sequences is through methylation, a process that inactivates large regions of genes without editing the underlying "file" itself.
As we learn more about epigenetics, we gain more opportunities to develop therapeutics for a broad range of human conditions, from cancer to metabolic disorders. Though there have not been any clinical applications of epigenetics to immune or metabolic diseases yet, cancer is one of the leading areas, with promising initial successes.
One of the challenges of cancer treatments is that different patients may respond positively or negatively to the same treatment. With knowledge of epigenetics, however, doctors could conduct diagnostic tests to identify a patient's specific epigenetic profile and determine the best treatment for him or her. Already, commercial kits are available that help doctors screen glioma patients for an epigenetic biomarker called MGMT, because patients with this biomarker have shown high rates of success with certain kinds of treatments.
Other epigenetic advances go beyond personalized screening to treatments targeting the mechanism of disease. Some epigenetic drugs turn on genes that help suppress tumors, while others turn on genes that reveal the identity of tumor cells to the immune system, allowing it to attack cancerous cells.
Direct, targeted control of your epigenome could allow doctors to reprogram cancerous or aging cells.
The study of epigenetics has also been fundamental to the field of aging research. The older you get, the more methylation marks your DNA carries, and this has led to the distinction between biological aging, or the state of your cells, and chronological aging, or how old you actually are.
Just as our DNA can get miscopied and accumulate mutations, errors in DNA methylation can lead to so-called "epimutations". One of the big hypotheses in aging research today is that the accumulation of these random epimutations over time is responsible for what we perceive as aging.
Studies thus far have been correlative - looking at several hundred sites of epigenetic modifications in a person's cell, scientists can now roughly discern the age of that person. The next set of advances in the field will come from learning what these epigenetic changes individually do by themselves, and if certain methylations are correlated with cellular aging. General diagnostic terms like "aging" could be replaced with "abnormal methylation at these specific locations," which would also open the door to new therapeutic targets.
Direct, targeted control of your epigenome could allow doctors to reprogram cancerous or aging cells. While this type of genetic surgery is not feasible just yet, current research is bringing that possibility closer. The Cas9 protein of genome-editing CRISPR/Cas9 fame has been fused with epigenome modifying enzymes to target epigenetic modifications to specific DNA sequences.
A therapeutic of this type could theoretically undo a harmful DNA methylation, but would also be competing with the cell's native machinery responsible for controlling this process. One potential approach around this problem involves making beneficial synthetic changes to the epigenome that our cells do not have the capacity to undo.
Also fueling this frontier is a new approach to understanding disease itself. Scientists and doctors are now moving beyond the "one defective gene = one disease" paradigm. Because lots of diseases are caused by multiple genes going haywire, epigenetic therapies could hold the key to new types of treatments by targeting multiple defective genes at once.
Scientists are still discovering which epigenetic modifications are responsible for particular diseases, and engineers are building new tools for epigenome editing. Given the proliferation of work in these fields within the last 10 years, we may see epigenetic therapeutics emerging within the next couple of decades.