Connectome (37 page)

 

Alcor's procedures are based on a field of science known as cryobiology. You probably know that fertility doctors freeze sperm, eggs, and embryos for later use. Blood banks freeze rare blood types for transfusion years later. The classic method is to lower the temperature slowly, say one degree per minute, after immersing cells in glycerol or other cryoprotective agents that increase their survival rate. The method is far from perfect. Sperm survive the best;
eggs and embryos do less well. Cryobiologists would like to freeze entire organs, since it is wasteful to discard them just because immediate transplantation is not possible.

Slow freezing was discovered mainly by trial and error. To improve on the method, cryobiologists have tried to understand why it works. It's not easy to sort out the complex phenomena happening inside cells during cooling. One thing is certain: The formation of ice inside cells is lethal.
It's not known why intracellular ice kills, but cryobiologists know to avoid it at all costs. Slow freezing is intended to cool cells so that the water outside freezes to ice while the water inside does not.

How is that possible? If you live in a cold climate, you've probably seen people scattering salt on the sidewalk during a winter snow. This prevents ice from forming (and people from falling), because salt water freezes at a lower temperature than pure water. The higher the concentration of salt, the lower the freezing point. When cells are cooled slowly, water is gradually sucked out of them owing to a force known as osmotic pressure. The water remaining in the cell becomes saltier and saltier, and hence resists icing. If cells are cooled too rapidly, however, their contents don't become salty enough, and they freeze, with deadly consequences.

Slow freezing is not completely benign, because it replaces ice with saltiness. The latter, though not as deadly, is still damaging to cells,
and additives like glycerol can protect only so much. Some researchers have therefore given up on slow freezing. Instead, they cool cells under special conditions that turn liquid water into an exotic state of matter that is said to be glassy or “vitrified,” from the Latin word for glass. The vitrified state is solid but not crystalline. Its water molecules remain disorganized; they're not arranged into the orderly lattice you see in ice crystals.

Under normal circumstances, vitrification requires extremely rapid cooling, which is feasible for cells but not entire organs. Alternatively, you can get water to vitrify even at slow cooling rates if you add extremely high concentrations of cryoprotectants. Fertility researchers are already applying this method to oocytes and embryos,
with some success.

Greg Fahy, who works at a company called 21st Century Medicine, has worked for decades on the problem of cryopreserving organs. Fahy has used an electron microscope to examine vitrified tissues. The process appears to protect cellular structures, with relatively little damage to membranes. But disappointingly, vitrified organs failed the acid test repeatedly over the years: They didn't survive and function after rewarming and transplantation. In a remarkable advance, Fahy's team has at last succeeded, demonstrating recently that a previously vitrified kidney
functioned for weeks after transplantation into a rabbit. Inspired by Fahy's research, Alcor now uses vitrification to preserve the corpses of its members.

So how long can those corpses stay frozen without damage? You've probably noticed that items in your freezer do not last indefinitely. This has no bearing on cryonics, because the –196 degrees of liquid nitrogen is far colder than your freezer gets. It is closer to the lowest temperature possible—“absolute zero,” or –273 degrees. Cold temperatures preserve because they slow down chemical reactions, the transformations that alter the atomic structure of molecules. The extreme cold of liquid nitrogen halts chemical reactions almost completely. The molecules in the corpses do not change, except when they are hit by cosmic rays or other types of ionizing radiation. Since such collisions are rare, the physicist Peter Mazur
has estimated that cells should last for thousands of years in liquid nitrogen. The clock may be ticking for Alcor members, but they have at least a few millennia before their time runs out.

There's a more fundamental problem, though. The Alcor members were all
dead
before they were vitrified, for hours or sometimes even days. Isn't death irreversible, by definition? If so, how could reanimation ever succeed?

Irreversibility is indeed a central aspect of our definition of death. This makes the definition problematic. Irreversibility is not a timeless concept; it depends on currently available technology. What is irreversible today might become reversible in the future. For most of human history, a person was dead when respiration and heartbeat stopped. But now such changes are sometimes reversible. It is now possible to restore breathing, restart the heartbeat, or even transplant a healthy heart to replace a defective one.

Conversely, even if the heartbeat and respiration continue, a person with sufficiently severe brain damage is now regarded as legally dead. This redefinition was spurred by the introduction of mechanical ventilators in the 1960s. These kept accident victims alive so that the heart still pumped, even though the patient never regained consciousness. Eventually the heart stopped, or family members requested removal of the ventilator. At autopsy, the organs of the body looked perfectly normal to the naked eye or under a microscope. But the brain was discolored, soft or partially liquefied, and often disintegrated as it was removed. From this condition, nicknamed “respirator brain,”
pathologists concluded that the brain had died well before the rest of the body.

In the 1970s the United States and United Kingdom began to institute new laws governing the determination of death.
To the traditional criterion of respiratory/circulatory failure, the United States added an alternative criterion: death of the entire brain, including the brainstem. In the United Kingdom, the death of the brainstem alone was considered sufficient. The U.S. definition is sometimes called “whole-brain death,” while the U.K. one is known as “brainstem death.”

The brainstem is critical for both respiration and consciousness. Its neurons generate signals that control the breathing muscles. If they fall inactive, breathing stops, and the patient cannot live without a mechanical ventilator. It is the brainstem's role in breathing that gives brainstem death its close tie to the traditional notion of respiratory/circulatory death. Another role played by the brainstem, perhaps even more important, is that it arouses the rest of the brain to consciousness. Our level of arousal goes up and down all the time, most dramatically in the sleep–wake cycle. Several populations of brainstem neurons, collectively called the reticular activating system, send their axons widely over the brain. These neurons secrete special neurotransmitters known as neuromodulators, chemicals that “wake up” the thalamus and cerebral cortex. Without them the patient cannot be conscious, even if the rest of the brain is intact.

The situation can be summarized this way: “If the brainstem is dead,
then the brain is dead, and if the brain is dead, the person is dead.” That's the rationale for the U.K. notion of brainstem death, and it makes sense because the brainstem typically functions longer than any other part of the brain. Damage to the brain causes cerebral edema, an abnormal buildup of fluid. This raises the pressure in the skull, causing blood flow to stagnate. Even more cells die, causing more edema and further shutting down the blood flow. The vicious cycle continues,
and culminates with the brainstem being crushed by the pressure. So if the brainstem no longer functions, it's likely that the rest of the brain has already been destroyed.

This is the normal course of events. But sometimes—rarely—the entire brainstem is destroyed while the rest of the brain is left intact. The patient will never breathe without a mechanical ventilator, and will never regain consciousness. Yet one could argue that the patient still lives, assuming that memories, personality, and intelligence are preserved in the cerebrum. These properties seem more fundamental to personal identity than respiration, circulation, or brainstem function.

Today this distinction is merely theoretical, because no patient with complete brainstem damage has ever regained consciousness. But imagine a future medicine in which physicians can induce neurons in the brainstem to regenerate, reversing the damage. Then it might be possible for the patient to become conscious and functional again. The idea that the failure of the brainstem means that the person has died could eventually seem as outmoded as considering someone dead after respiratory/circulatory failure that is reversible.

Such future developments may seem far-fetched, but prognostication is not the real goal here. Rather, these thought experiments should motivate us to find a definition of death that is more fundamental. Ideally, the definition should remain valid no matter how far medicine progresses in the future. In this book I've talked about various ways of testing the hypothesis “You are your connectome.” If this hypothesis is true, a fundamental definition of death follows immediately: Death is the destruction of the connectome. Of course, we don't know yet whether a connectome contains a person's memories, personality, or intellect. Testing these ideas will occupy neuroscientists for a very long time.

In the near term, all we can do is speculate. It's possible that a connectome contains most of the information in a person's memories. But even if that's the case, a connectome might not contain
all
of the information. Like any kind of summary, a connectome leaves out some details. Some of that discarded information
could be relevant to personal identity. I conjecture that
connectome death
implies loss of a person's memories. However, the converse may not be true. Some of the information in a person's memories might be lost even if the connectome is perfectly preserved. (I'll tackle the issue of
completeness
in the next chapter.)

In its emphasis on brain
structure,
connectome death departs from conventional definitions based on brain function. The legal definition of death is the irreversible loss of
function
of the whole brain or of the brainstem. But as we've seen, the term
irreversible
is problematic. Snakebites and certain drugs can mimic brainstem death, but this loss of function is reversible. After mechanical ventilation
for a short period, the patient recovers completely. So even for an expert, it can be tricky to decide when loss of function is permanent.

On the other hand, connectome death is based on a structural criterion that implies a truly irreversible loss of function (assuming that it implies the loss of memories). Alas, this definition is practically useless in a hospital. Currently, in live patients we can measure brain function through reflexes mediated by the brainstem, brain waves (EEG), or functional MRI. But we know of no way to find neuronal connectomes of living brains.

I can think of only one practical application of the idea of connectome death. Perhaps it's not really
that
practical, but I find it fascinating nonetheless. Why not use connectomics to critically examine the claims of cryonics? I've described at length the ways in which the brains of Alcor members have been damaged by circulatory/respiratory death and vitrification. Is there any chance that this damage could be reversed, as Alcor claims? To find out, I propose that we attempt to find the connectome of a vitrified brain. If the information in the connectome turns out to be erased, then we can declare connectome death. Resurrection by an advanced civilization of the future might be possible, but only for the body, not for the mind. If, however, the information is still intact, then we cannot rule out the possibility of resurrecting memories and restoring personal identity.

I suppose we should not conduct this experiment on a vitrified human brain. But Alcor has also vitrified the brains of some dogs and cats, at the request of pet-loving members. Perhaps some of these members would be willing to sacrifice their pets' brains in the name of science?

Until this scientific test is conducted, we can only speculate about what it might find. It's well-known that the brain is extremely sensitive to oxygen deprivation. Loss of consciousness follows in seconds, permanent brain damage after a few minutes. This is why disruption of blood flow to the brain can be so deadly, as happens in a stroke. At first glance, this seems like bad news for Alcor members. By the time Alcor receives the corpse, the brain has been deprived of oxygen for hours at least, and no living cells may remain. (Of course, it can be as difficult to define life and death for a cell as for the whole body.) Whether dead or alive, the cells have been badly damaged. Electron microscope (EM) studies have characterized the types of damage present
in brain tissue a few hours after respiratory/circulatory death. Among other changes, mitochondria look damaged, and the DNA in the nucleus is abnormally clumped.

But these and other cellular abnormalities are irrelevant for connectome death. What matters is the integrity of synapses and “wires.” Synapses seem less of a problem; they are still intact in the EM images,
so they appear to be stable even in a dead brain. The status of axons and dendrites is harder to judge. Their cross-sections look largely intact in the published two-dimensional images, but there are some damaged locations. The big question is whether the damage has actually broken the “wires” of the brain. This can be answered by attempting to trace the neurites in three-dimensional images. If there are few breaks, tracing might still be possible. One could deal with an isolated break by bridging the gap between two free ends that were obviously once joined. But if there are clusters of many adjacent breaks, it might be impossible to figure out which free ends were once joined together. This would be true connectome death, a loss of information about connectivity that can never be recovered, no matter how advanced the technology.