Last month, a Philadelphia biotech company began clinical trials that could revolutionize our understanding of what it means to be dead. With ethical approval from the Independent Ethics Committee, Bioquark has treated twenty patients at Anupam Hospital in India, whose brains were presumed to be clinically dead after severe traumatic brain injury. With an arsenal of cutting-edge but so far cryptic therapies - stem cells, bioactive molecules, brain and spinal cord stimulation - the team hopes to resurrect parts of patients' basic brain functions, with the intention of achieving the best possible outcome: regaining their ability to breathe on their own.
The results should become known in an extremely short time - 15 days.
If your first reaction was surprise, you are not alone. What is it: the Lazarus effect, Frankenstein effect, The Walking Dead? Or maybe some kind of viral campaign for an upcoming horror movie?
Not really. Bioquark's job is to cheat death. This is what will be done within the incredibly ambitious project ReAnima. Let's see how this will proceed.
This is an amazing word: death
More often than not, we imagine death as a kind of switch: here you are, and in a minute there is nothing, the light has gone out.
But this is just a caricature of the process of dying: even after the heartbeat and breathing stop, sparks of brain activity can flare up for a long time. In some cases, even deeply comatose patients - unable to breathe on their own - can maintain simple reflex responses. Their brain waves, erratic or weak, are still monitored on the EEG.
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Brain death, by contrast, is everything, finish. Such a diagnosis signals the complete and irreversible destruction of the brain, including the brain stem. People with brain dead are not in a coma or in a vegetative state. They have no hope of spontaneous recovery. They are dead.
In many countries around the world, such subjects are classified as "living corpses" (cadavers), says Ira Pastor, CEO of Bioquark (to avoid confusion, this is a man). But this definition has a problem.
In theory, brain death is a highly objective and strictly defined medical condition with enormous legal implications. Doctors see brain death in patients as the final signal - it's time to pull the cord, think about organ donation, and invite relatives to say goodbye.
In practice, brain death is not at all so simple. The pastor says there is a large gray area between deep coma and brain death. One of the reasons for the "irreversibility" of such death is dependence on technology. For centuries, lack of breath and pulse were signs of death, but the invention of life-supporting machines and resuscitation techniques blurred that line.
Given such a historical precedent, is it really possible to talk about the irreversibility of brain death?
While brain death may seem like a medically-grounded definition of death, its criteria were first formed in the late 1960s, long before neuroscientists dived into serious research on consciousness and personality. Therefore, brain death does not take into account the latest advances in neurosurgery, the latest technologies and methods, such as measuring the release of neurotransmitters.
The process of diagnosing brain death is very old-fashioned. A doctor can prick a patient with a needle to check pain receptors, see if carbon dioxide causes spontaneous breathing, try to detect signs of electrical activity in the brain using electroencephalography (EEG). But none of these measures can conclusively say that the patient will not return.
While brain death is irreversible, it is not measurable, Pastor says. In rare cases, doctors are wrong. Over the past few decades, there have been several dozen cases of spontaneous "resurrection" of brain-dead patients, mainly children and young adults. One young woman even gave birth successfully after being diagnosed with brain death.
“While these cases are controversial and the result of poor diagnosis, we believe they highlight the absence of white and black in the realm of serious impairment of consciousness,” says Pastor. This is the main incentive for scientists to pursue this niche program.
Lazarus Tools
How to get a dead brain?
The subjects in our study suffer from severe and extensive neuronal death, Pastor explains. The integrity of axons - long projections that neurons use to communicate with each other - decays and normal signal processing no longer works.
Alternatively, you can try to salvage what's left, like fixing broken headphones by tying up the remaining wires. But any attempt to repair a dead brain will likely require replacement parts - newly grown brain cells to replace those lost during the trauma. Moreover, cells need favorable conditions to grow and integrate into existing brain circuits.
Bioquark will do both.
The team's "secret sauce" is a combination of bioactive molecules and mesenchymal stem cells (MSC). MSCs are found in virtually all tissues and have been used in cell replacement therapy for ten years. Although no such trials have been conducted in humans, preliminary studies in rodents with traumatic brain injury have shown that transplanted MSCs integrate into the brain and help improve motor and cognitive recovery.
By studying the extreme stages of brain death, Pastor and scientists hope to find unique insights into the dying brain. Stem cell transplantation is nothing new, but Bioquark wants to go one step further: armed with bioactive molecules, the researchers hope to establish a microenvironment in the brain that will facilitate "epimorphic regeneration," the process of regrowing a missing body part.
When an adult is physically injured, such as losing a finger, our body responds by forming scar tissue. The default answer is healing, not regeneration. But during early embryonic development, tissue damage triggers a massive and highly coordinated response that keeps the body from inflammation and scarring. Instead of getting a nasty scar, a human fetus can repair lost tissue, much like flatworms can regenerate severed heads (and maybe even retain memories from a previous head!).
Much of this process involves recruiting massive amounts of local cells to help the tissue repair itself. And not just stem cells. In many cases, adult cells lose their identity and return to the state of stem cells. Thus, the body “recycles” these cells to support tissue regeneration.
This process is quite natural in the body of the fetus, says Pastor. Why not take and imitate this process by forcing the adult brain to abandon the scar in favor of regeneration? Previous research by Bioquark found that this recovery process relies on bioactive molecules that can be extracted from amphibian eggs.
The extracted bioactive components, mainly microRNAs and proteins, can reprogram damaged cells into a state of stem cells, as the scientists wrote in a 2014 patent. Stem cells are even somewhat secondary players. There are concerns that their role may be exaggerated, Pastor said. They also place greater emphasis on morphogenetic extracts. However, relatively little work has been published on the lead chemical extract, a mixture of bioactive molecules with the exotic name BQ-A, in animal models of brain death.
The problem is that there are few such models, and they are all far from each other, and some are completely exotic, like the poisoning of pigs with carbon monoxide, Pastor explains. "We steer clear of such models and instead focus on models of traumatic brain and spinal cord injury in preliminary studies."
First of all, scientists will test the strength of these extracts, whether they can reset the human brain. The pastor emphasizes that the study should show the most basic function of the brain stem after treatment - an electrical whisper here, a neurotransmitter cloud there.
In addition to cell therapy, Bioquark also plans to use brain stimulation techniques to turn on BQ-A. These techniques, including median nerve stimulation and transcranial laser stimulation, are often used to treat coma and other disorders of consciousness with varying degrees of success.
Why use so many different methods? Well, Bioquark wants to know right away what works and what doesn't.
The pastor sees two major flaws in current models of disease treatment and prevention. First, they are more focused on treating late-stage symptoms rather than the underlying cause. Secondly, the approach of reducing any disease to one cause, and as a consequence, to one drug, is often used.
“Epimorphic regeneration is inherently multifaceted and involves many mechanisms that work in synergy,” says Pastor. "In order to carry out such a complex initiative, it is obviously worth abandoning the notion of the 'magic silver bullet' (which will never be) in favor of the notion of a combination."
ReAnimation
“While full recovery is indeed our long-term vision, it is not the primary focus or primary endpoint of the first study,” says Pastor. The first plan on the schedule will be to resume independent breathing. We'll hardly see a dead brain awakening anytime soon.
But if the treatment works, we may be faced with a thorny philosophical question about personal identity. According to bioethicist Dr. Anders Sandberg, "It is not hard to imagine that such treatment will not completely restore the brain: memories, personality and functions can be lost, closed or replaced with the newly grown tissue."
In this case, the person will obviously not benefit from the treatment - he will be replaced by someone similar, but different. Yet this is a scenario for the distant future, which may not happen at all. After all, the proposed treatments are experimental and the regenerative capacity of the brain can be prohibitively limited.
But the Pastor sees value in his endeavors, even if they fail.
“It goes without saying that this is a pristine area of discovery and development. Even if you look into the broader class of “mental disorders,” this is an area where there is little or no interventional research going on,”says Pastor. This is especially evident when considering more "traditional" neurodegenerative disorders such as Alzheimer's or Parkinson's.
“We believe that any research we do along these lines will be invaluable for all of these diseases,” says the scientist. Lazarus or Frankenstein?
ILYA KHEL