Neural cryobiology and the legal recognition of cryonics

It has been said that if you want to persuade someone, you need to find common ground. But one of the defining characteristics of cryonics is that proponents and opponents cannot even seem to agree on the criteria that should be employed in discussing cryonics. The cryonics skeptic will argue that the idea of cryonics is dead on arrival because cryonics patients are dead. The response of the cryonics advocate is that death is not a state but a process and there is good reason to believe that a person who is considered dead today may not be considered dead by a future physician. In essence, the cryonics advocate is arguing that his skeptical opponent would agree with him if he would just embrace his conception of death….

Cryonicists have named their favorite conception of death “information-theoretic death.” In a nutshell, a person is said to be dead in the information-theoretic sense of the word if no future technologies are capable of inferring the original state of the brain that encodes the person’s memories and identity. There are a lot of good things to be said about substituting this more rigorous criterion of death for our current definitions of death. However, in this brief paper I will argue that our best response does not necessarily need to depend on skeptics embracing such alternative definitions of death and that we may be able to argue that opponents of cryonics should support legal protection for cryonics patients or risk contradicting conventional definitions of death.

In contemporary medicine, death can be pronounced using two distinct criteria; cardiorespiratory arrest or brain death. A lot of ink has been spilled over the co-existence of those criteria and its bioethical implications but I think that most people would agree that the practice of medicine requires this kind of flexibility. What is interesting for us is that clinical brain death (or brain stem death) is defined as “the stage at which all functions of the brain have permanently and irreversibly ceased.” There are a number of ways how such a diagnosis can be made, but in this context I want to focus on the absence of organized electrical activity in the brain.

We first should note the use of the word “irreversible.” After all, if a patient is cooled down to a low core temperature to permit complicated neurosurgical procedures most of us would not say that this person is “temporarily brain dead.” As a matter of fact, one could argue that cryonics is just an experimental extension of clinical hypothermic circulatory arrest in which there is a temporal separation of stabilization and treatment. Now, we could argue that what may be irreversible by today’s standards may not be irreversible by future standards but then, again, we are trying to persuade the other person to accept our view of future medicine. It would be much better, and I hope much easier, to argue that contemporary cryopreservation techniques can preserve organized electrical activity in the brain. The advantage of this approach is obvious. Instead of arguing in favor of our own criterion of death we can argue that, according to mainstream criteria for determination of death, cryonics patients are not dead. This is an interesting case in which a scientist (i.e., a cryobiologist) may be able to make a major contribution to the legal recognition and protection of cryonics patients.

So where are we standing right now? How good are our preservation techniques? If we aim for reversible whole brain cryopreservation a cryoprotective agent should have two properties: (1) elimination of ice formation, and (2) negligible toxicity. In the early days of cryonics, we were not able to satisfy both criteria at once. Using just a little bit of glycerol would not be toxic but it would still allow massive ice formation. Using a lot of a strong glass former such as DMSO would eliminate ice formation but at the price of severe toxicity. Mostly due to the groundbreaking work of cryobiologists Gregory Fahy and Brian Wowk, in the year 2000 the Alcor Life Extension Foundation introduced a vitrification agent called B2C that eliminated ice formation and had a more favorable toxicity profile. In the year 2005, the separation between the state of the art in experimental cryobiology and cryonics practice was further narrowed when Alcor introduced M22 as their new vitrification agent. M22 is the least toxic vitrification agent in the academic cryobiology literature that permits vitrification of complex mammalian organs at a realistic cooling rate.

M22 and other solutions derived from the same cryobiological principles have been validated in the brain as well. Former Cryonics Institute researcher Yuri Pichugin and collaborators used a related vitrification solution for the preservation of rat hippocampal brain slices without loss of viability after vitrification and rewarming. At a cryonics conference in 2007, 21st Century Medicine announced that the use of M22-based solutions permitted the maintenance of organized electrical activity in rabbit brain slices. So, at this stage we can argue that our existing vitrification solutions have a reasonable chance of maintaining organized electrical activity in brain slices. The next challenge is to demonstrate this property in whole brains.

Whole brain cryopreservation is not just the cryopreservation of a great number of individual brain slices. Brain slices can be cryopreserved by (step-wise) immersion in the vitrification solution. Vitrification of whole brains (even small brains such as rodent brains) requires the introduction of the vitrification solution through the circulatory system. This aspect of whole brain vitrification presents a number of technical challenges. Electron micrographs of vitrified tissue from whole brains, however, indicate that these challenges can be overcome. The current research objective is to perfect perfusion techniques and optimize vitrification solutions to maintain organized electrical activity in whole brains. We know that this objective is possible in principle because the famous surgeon Robert White demonstrated retention of electrical activity in whole isolated brains after cooling them to ~2-3°C. Isolated brain perfusion is a complicated surgical procedure, but the current writer and cryobiologist Brian Wowk have recognized that validation of whole brain activity is also feasible in situ.

Reversible cryopreservation of the whole brain without losing organized electrical activity is not a trivial research objective but it should be easier to achieve than reversible cryopreservation of the whole body and, perhaps, some other organs. If and when we accomplish this, we will no longer be dependent on “rationalist” arguments that appeal to logic and optimism about the future. We can argue that our patients should not be considered dead by the most rigorous criterion for determination of death in current medical practice. We can then even mount some smart legal challenges to seek better protection for cryonics patients. If we can make this step forward we should also aim at improved protection of existing cryonics patients, which will allow them, among other things, to own assets and bank accounts. This is how science can be employed in legal strategies for asset preservation.

This article is a slightly revised version of a paper that accompanied a recent presentation on neural cryobiology and the legal recognition of  cryonics at the 5th Asset Preservation Meeting in Benicia, California.

David J. Chalmers on the Singularity, mind uploading and cryonics

If I would make an argument in favor of mind uploading (or substrate independent minds) it would not be a logical deduction from what we know about neuroscience but from what we don’t know.  As one of the leading philosophers of mind David J. Chalmers has argued in this insightful paper about the Singularity and mind uploading:

Can an upload be conscious? The issue here is complicated by the fact that our understanding of consciousness is so poor. No-one knows just why or how brain processes give rise to consciousness. Neuroscience is gradually discovering various neural correlates of consciousness, but this research program largely takes the existence of consciousness for granted. There is nothing even approaching an orthodox theory of why there is consciousness in the first place. Correspondingly, there is nothing even approaching an orthodox theory of what sorts of systems can be conscious and what systems cannot be….

It is true that we have no idea how a nonbiological system, such as a silicon computational system, could be conscious. But the fact is that we also have no idea how a biological system, such as a neural system, could be conscious. The gap is just as wide in both cases. And we do not know of any principled di differences between biological and nonbiological systems that suggest that the former can be conscious and the latter cannot. In the absence of such principled di differences, I think the default attitude should be that both biological and nonbiological systems can be conscious

One can argue with this derivation of what the “default position” should be, but his more skeptical approach has a degree of modesty in its favor that is often lacking in transhumanist circles.

David J. Chalmers also discusses cryonics in a favorable context:

Cryonic technology off ers the possibility of preserving our brains in a low-temperature state shortly after death, until such time as the technology is available to reactivate the brain or perhaps to upload the information in it. Of course much information may be lost in death, and at the moment, we do not know whether cryonics preserves information sufficient to reactivate or reconstruct anything akin to a functional isomorph of the original. But one can at least hope that after an intelligence explosion, extraordinary technology might be possible here

On his blog he also writes that “for the last couple of weeks I have been in Oxford giving the John Locke Lectures on Constructing the World.  The title is an homage to Rudolf Carnap’s 1928 book Der Logische Aufbau Der Welt. The lectures are based on a book I have been writing for the last couple of years, trying to execute a project that is reminiscent of Carnap’s in certain respects.”

A person who discusses mind uploading in a meaningful context, gives cryonics a fair hearing, and has a work in progress that is inspired by Rudolf Carnap’s The Logical Structure of the World should not be ignored, let alone be ridiculed.

Promoting cerebral blood flow in cryonics patients

It has been shown that perfusability of the brain is significantly compromised after long-term (>5 min) ischemic events (the “no reflow” phenomenon). Improving cerebral blood flow after circulatory arrest is one of the fundamental objectives of human cryopreservation stabilization protocol.  To that end, cryonics organizations administer the resuscitation fluid Dextran-40 and the drug Streptokinase to dilute the blood (and inhibit  red cell aggregation / cold aggulination) and  break up blood clots, thereby improving macro and microvascular circulation. Research by Fischer and Ames, who investigated the effects of perfusion pressure, hemodilution, and anticoagulation (i.e., the use of heparin) on post-ischemic brain perfusion, indicated that hemodilution is the most effective component of the post-ischemic perfusion protocol for enhancing brain perfusability. However, a later study by Lin, et al. (1978) reported significant improvement of cerebral function and blood flow with combined dextran and Streptokinase administration after cardiac arrest in dogs.

In their study, the researchers measured regional cerebral blood flow and cardiac output as well as EEG (i.e., brain wave activity) during five hours of post-resuscitation physiological maintenance following 12-16 minutes of cardiac arrest. Animals were divided into three groups as follows:

Group I:   no treatment

Group II: 1 g/kg dextran 40 in 10% saline following arrest and 10 mg/kg/minute during the five hour maintenance period

Group III: combined therapy of dextran-40 and Streptokinase — same dose of dextran as Group II and 5,000 u/kg rapid infusion and 25 u/kg/minute during the five hour maintenance period

The duration of flat EEG was significantly shorter in Group III animals (20 to 45 minutes with a mean of 28.8 +/- 2.8) than in Groups I (20 to 120 minutes with a mean of 59.5 =/- 10.8) or II (20 to 62 minutes with a mean of 46.9 +/- 4.8) and showed a faster recovery pattern than in Group I (significant difference was reached at three hours). Group II also showed a faster EEG recovery than Group I, reaching significance at five hours.

Cerebral blood flow, particularly in the hippocampus and grey matter (the areas most detrimentally affected by ischemia) in Group III was significantly improved as compared to Group I as early as three hours post-arrest, and was greater than that in Group II (significantly better only in the hippocampus). There was no difference in cardiac output found between the treated and untreated groups. All groups suffered a decrease in cardiac output of nearly 50% of baseline level (measured at 3 and 5 hours post-arrest).

Hematocrit — the proportion of blood volume occupied by red blood cells — was measured in each group and was found to be significantly increased during the post-arrest period in Group I, decreased to 25% of the baseline measurement in Group III (at both 3 and 5 hours post-arrest), and unchanged in Group II.

The authors speculate that “the improvement in cerebral circulation at the microvascular level after infusion of low molecular weight dextran was thought to be 1) related to the rapid increase in plasma volume with resultant lowering of hematocrit and reduction in blood viscosity, 2) a direct effect on the RBC [red blood cell] which increases its negativity and reduces the tendency to cellular aggregation.” They also note that though some doubt had been cast by the Fischer and Ames paper on the hypothesis of vascular endothelial cell swelling as a cause of no reflow, they did observe a higher proportion of smaller diameter capillaries in ischemic brains as compared to controls, and that “if capillary narrowing does play a role in microvascular deterioration, then hemodilution and prevention of cellular aggregates such as occurs with dextran would be beneficial in minimizing poor flow in narrow capillaries.”

Taken together, these findings indicate that combined dextran-40 and Streptokinase therapy improve brain perfusion after cardiac arrest — at least for arrest periods of up to 16 minutes.– supporting the choice for these agents in cryonics. One limitation of this study, however, is that the experiments did not include a group which received only Streptokinase. Including a Streptokinase group would have given more  precise data about the individual effects of the two agents in improving post-ischemic cerebral blood flow. Recent clinical trials with clot busting agents in cardiac arrest have failed and some contemporary authors question the phenomenon of post-arrest blood clotting. Perhaps streptokinase is useful in the treatment of circulatory arrest but its efficacy is dependent upon other blood flow improving interventions such as hemodilution. The case for post-ischemic hemodilution (and interventions to reduce RBC aggregation) is strong but the case for antithrombotic therapy in cryonics (and resusctation medicine) remains to be made.