13. February 2015 · Comments Off on Though She Isn’t Really Ill, There’s a Little Yellow Pill… · Categories: Health, Neuroscience, Society

Humans have been ingesting mindand mood-altering substances for millennia, but it has only rather recently become possible to begin to elucidate drug mechanisms of action and to use this information, along with our burgeoning knowledge of neuroscience, to design drugs intended to have a specific effect. And though most people think of pharmaceuticals as “medicine,” it has become increasingly popular to discuss the possibilities for the use of drugs in enhancement, or improvement of “human form or functioning beyond what is necessary to sustain or restore good health” (E.T. Juengst; in Parens, 1998, p 29).

Some (transhumansits) believe that enhancement may not only be possible, but that it may even be a moral duty. Others (bioconservatives) fear that enhancement may cause us to lose sight of what it means to be human altogether. It is not the intention of this article to advocate enhancement or to denounce it. Instead, let’s review some of the drugs (and/or classes of drugs) that have been identified as the most promisingly cognitive- or mood-enhancing. Many of the drugs we will cover can be read about in further depth in Botox for the brain: enhancement of cognition, mood and pro-social behavior and blunting of unwanted memories (Jongh, R., et al., Neuroscience and Biobehavioral Reviews 32 (2008): 760-776).

Of most importance in considering potentially cognitive enhancer drugs is to keep in mind that, to date, no “magic bullets” appear to exist. That is, there are no drugs exhibiting such specificity as to have only the primary, desired effect. Indeed, a general principle of trade-offs (particularly in the form of side effects) appears to exist when it comes to drug administration for any purpose, whether treatment or enhancement. Such facts may constitute barriers to the practical use of pharmacological enhancers and should be taken into consideration when discussing the ethics of enhancement.

Some currently available cognitive enhancers include donepezil, modafinil, dopamine agonists, guanfacine, and methylphenidate. There are also efforts underway to develop memory-enhancing drugs, and we will discuss a few of the mechanisms by which they are proposed to act. Besides cognitive enhancement, the enhancement of mood and prosocial behavior in normal individuals are other types of enhancement that may be affected pharmacologically, most usually by antidepressants or oxytocin. Let’s briefly cover the evidence for the efficacy of each of these in enhancing cognition and/or mood before embarking on a more general discussion of the general principles of enhancement and ethical concerns.

One of the most widely cited cognitive enhancement drugs is donepezil (Aricept®), an acetylcholinesterase inhibitor. In 2002, Yesavage et al. reported the improved retention of training in healthy pilots tested in a flight simulator. In this study, after training in a flight simulator, half of the 18 subjects took 5 mg of donepezil for 30 days and the other half were given a placebo. The subjects returned to the lab to perform two test flights on day 30. The donepezil group was found to perform similarly to the initial test flight, while placebo group performance declined. These results were interpreted as an improvement in the ability to retain a practiced skill. Instead it seems possible that the better performance of the donepezil group could have been due to improved attention or working memory during the test flights on day 30.

Another experiment by Gron et al. (2005) looked at the effects of donepezil (5 mg/day for 30 days) on performance of healthy male subjects on a variety of neuropsychological tests probing attention, executive function, visual and verbal short-term and working memory, semantic memory, and verbal and visual episodic memory. They reported a selective enhancement of episodic memory performance, and suggested that the improved performance in Yesavage et al.’s study is not due to enhanced visual attention, but to increased episodic memory performance.

Ultimately, there is scarce evidence that donepezil improves retention of training. Better designed experiments need to be conducted before we can come to any firm conclusions regarding its efficacy as a cognitive-enhancing.

The wake-promoting agent modafinil (Provigil®) is another currently available drug that is purported to have cognitive enhancing effects. Provigil® is indicated for the treatment of excessive daytime sleepiness and is often prescribed to those with narcolepsy, obstructive sleep apnea, and shift work sleep disorder. Its mechanisms of action are unclear, but it is supposed that modafinil increases hypothalamic histamine release, thereby promoting wakefulness by indirect activation of the histaminergic system. However, some suggest that modafinil works by inhibiting GABA release in the cerebral cortex.

In normal, healthy subjects, modafinil (100-200 mg) appears to be an effective countermeasure for sleep loss. In several studies, it sustained alertness and performance of sleep-deprived subjects(up to 54.5 hours) and has also been found to improve subjective attention and alertness, spatial planning, stop signal reaction time, digit-span and visual pattern recognition memory. However, at least one study (Randall et al., 2003) reported “increased psychological anxiety and aggressive mood” and failed to find an effect on more complex forms of memory, suggesting that modafinil enhances performance only in very specific, simple tasks.

The dopamine agonists d-amphetamine, bromocriptine, and pergolide have all been shown to improve cognition in healthy volunteers, specifically working memory and executive function. Historically, amphetamines have been used by the military during World War II and the Korean War, and more recently as a treatment for ADHD (Adderall®). But usage statistics suggest that it is commonly used for enhancement by normal, healthy people—particularly college students.

Interestingly, the effect of dopaminergic augmentation appears to have an inverted U-relationship between endogenous dopamine levels and working memory performance. Several studies have provided evidence for this by demonstrating that individuals with a low workingmemory capacity benefit from greater improvements after taking a dopamine receptor agonist, while high-span subjects either do not benefit at all or show a decline in performance.

Guanfacine (Intuniv®) is an α2 adrenoceptor agonist, also indicated for treatment of ADHD symptoms in children, but by increasing norepinephrine levels in the brain. In healthy subjects, guanfacine has been shown to improve visuospatial memory (Jakala et al., 1999a, Jakala et al., 1999b), but the beneficial effects were accompanied by sedative and hypotensive effects (i.e., side effects). Other studies have failed to replicate these cognitive enhancing effects, perhaps due to differences in dosages and/or subject selection.

Methylphenidate (Ritalin®) is a well-known stimulant that works by blocking the reuptake of dopamine and norepinephrine. In healthy subjects, it has been found to enhance spatial workingmemory performance. Interestingly, as with dopamine agonists, an inverted U-relationship was seen, with subjects with lower baseline working memory capacity showing the greatest improvement after methylphenidate administration.

Future targets for enhancing cognition are generally focused on enhancing plasticity by targeting glutamate receptors (responsible for the induction of long-term potentiation) or by increasing CREB (known to strengthen synapses). Drugs targeting AMPA receptors, NMDA receptors, or the expression of CREB have all shown some promise in cognitive enhancement in animal studies, but little to no experiments have been carried out to determine effectiveness in normal, healthy humans.

Beyond cognitive enhancement, there is also the potentialfor enhancement of mood and pro-social behavior. Antidepressants are the first drugs that come to mind when discussing the pharmacological manipulation of mood, including selective serotonin reuptake inhibitors (SSRIs). Used for the treatment of mood disorders such as depression, SSRIs are not indicated for normal people of stable mood. However, some studies have shown that administration of SSRIs to healthy volunteers resulted in a general decrease of negative affect (such as sadness and anxiety) and an increase in social affiliation in a cooperative task. Such decreases in negative affect also appeared to induce a positive bias in information processing, resulting in decreased perception of fear and anger from facial expression cues.

Another potential use for pharmacological agents in otherwise healthy humans would be to blunt unwanted memories by preventing their consolidation.Thismay be accomplished by post-training disruption of noradrenergic transmission (as with β-adrenergic receptor antagonist propranolol). Propranolol has been shown to impair the long-term memory of emotionally arousing stories (but not emotionally neutral stories) by blocking the enhancing effect of arousal on memory (Cahill et al., 1994). In a particularly interesting study making use of patients admitted to the emergency department, post-trauma administration of propranolol reduced physiologic responses during mental imagery of the event 3 months later (Pitman et al., 2002). Further investigations have supported the memory blunting effects of propranolol, possibly by blocking the reconsolidation of traumatic memories.


Reviewing these drugs and their effects leads us to some general principles of cognitive and mood enhancement. The first is that many drugs have an inverted U-shaped dose-response curve, where low doses improve and high doses impair performance.This is potentially problematic for the practical use of cognition enhancers in healthy individuals, especially when doses that are most effective in facilitating one behavior simultaneously exert null or detrimental effects on other behaviors.

Second, a drug’s effect can be “baseline dependent,” where low-performing individuals experience greater benefit from the drug while higher-performing individuals do not see such benefits (which might simply reflect a ceiling effect), or may, in fact, see a deterioration in performance (which points to an inverted U-model). In the case of an inverted U-model, low performing individuals are found on the up slope of the inverted U and thus benefit from the drug, while high-performing individuals are located near the peak of the inverted U already and, in effect, experience an “overdose” of neurotransmitter that leads to a decline in performance.

Trade-offs exist in the realm of cognitive enhancing drugs as well. As mentioned, unwanted “side effects” are often experienced with drug administration, ranging from mild physiological symptoms such as sweating to more concerning issues like increased agitation, anxiety, and/or depression.

More specific trade-offs may come in the form of impairment of one cognitive ability at the expense of improving another. Some examples of this include the enhancement of long-term memory but deterioration of working memory with the use of drugs that activate the cAMP/protein kinase A (PKA) signaling pathway. Another tradeoff could occur between the stability versus the flexibility of long-term memory, as in the case of certain cannabinoid receptor antagonists which appear to lead to more robust long-term memories, but which also disrupt the ability of new information to modify those memories. Similarly, a trade-off may exist between stability and flexibility of working memory. Obviously, pharmacological manipulations that increase cognitive stability at the cost of a decreased capacity to flexibly alter behavior are potentially problematic in that one generally does not wish to have difficulty in responding appropriately to change.

Lastly, there is a trade-off involving the relationship between cognition and mood. Many mood-enhancing drugs, such as alcohol and even antidepressants, impair cognitive functioning to varying degrees. Cognition-enhancing drugs may also impair emotional functions. Because cognition and emotion are intricately regulated through interconnected brain pathways, inducing change in one area may have effects in the other. Much more research remains to be performed to elucidate these interactions before we can come to any firm conclusions.


Again, though it is not the place of this article to advocate or denounce the use of drugs for human enhancement, obviously there are considerable ethical concerns when discussing the administration of drugs to otherwise healthy human beings. First and foremost, safety is of paramount importance. The risks and side-effects, including physical and psychological dependence, as well as long-term effects of drug use should be considered and weighed heavily against any potential benefits.

Societal pressure to take cognitive enhancing drugs is another ethical concern, especially in light of the fact that many may not actually produce benefits to the degree desired or expected. In the same vein, the use of enhancers may give some a competitive advantage, thus leading to concerns regarding fairness and equality (as we already see in the case of physical performance-enhancing drugs such as steroids). Additionally, it may be necessary, but very difficult, to make a distinction between enhancement and therapy in order to define the proper goals of medicine, to determine health-care cost reimbursement, and to “discriminate between morally right and morally problematic or suspicious interventions” (Parens, 1998). Of particular importance will be determining how to deal with drugs that are already used off-label for enhancement. Should they be provided by physicians under certain conditions? Or should they be regulated in the private commercial domain?

There is an interesting argument that using enhancers might change one’s authentic identity—that enhancing mood or behavior will lead to a personality that is not really one’s own (i.e., inauthenticity), or even dehumanization—while others argue that such drugs can help users to “become who the really are,” thereby strengthening their identity and authenticity. Lastly, according to the President’s Council on Bioethics, enhancement may “threaten our sense of human dignity and what is naturally human” (The President’s Council, 2003). According to the Council, “the use of memory blunters is morally problematic because it might cause a loss of empathy if we would habitually ‘erase’ our negative experiences, and because it would violate a duty to remember and to bear witness of crimes and atrocities.” On the other hand, many people believe that we are morally bound to transcend humans’ basic biological limits and to control the human condition. But even they must ask: what is the meaning of trust and relationships if we are able to manipulate them?

These are all questions without easy answers. It may be some time yet before the ethical considerations of human cognitive and mood enhancement really come to a head, given the apparently limited benefits of currently available drugs. But we should not avoid dealing with these issues in the meantime; for there will come a day when significant enhancement, whether via drugs or technological means, will be possible and available. And though various factions may disagree about the morality of enhancement, one thing is for sure: we have a moral obligation to be prepared to handle the consequences of enhancement, both positive and negative.

Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, December, 2013

27. January 2015 · Comments Off on Brain Fitness · Categories: Health, Neuroscience

Book Review: The SharpBrains Guide to Brain Fitness: How to Optimize Brain Health and Performance at Any Age by Alvero Fernandez

Of all the organs in the human body, a cryonicist should be most concerned about the health and integrity of his or her brain. Thousands of books have been written about physical health and fitness, but very few address the topic of how to keep the brain fit and healthy. Happily, interest in brain fitness, once relegated to academics and gerontologists, is now taking root across America and the world.

The importance of lifelong learning and mental stimulation as a component of healthy aging has long been recognized and touted as a way to stay mentally alert and to stave off dementia in old age. As with physical exercise, “use it or lose it” appears to apply to our brains too. And now that scientists are learning more about neuroplasticity and how brains change as a result of aging, they have begun to test the effects of various factors on brain health and cognitive ability across the lifespan.

Unfortunately, like much health-related research, the results reported by the media have often been convoluted, confusing, and even contradictory. Products developed by overzealous entrepreneurs make outlandish claims and frequently don’t deliver the purported results. Consumers and professionals alike are left wondering what works and what doesn’t when it comes to maintaining our brains in optimal working condition.

To aid all those navigating the murky waters of brain fitness, enter SharpBrains—a company dedicated to tracking news, research, technology, and trends in brain health and to disseminating information about the applications of brain science innovation. In so doing, they “maintain an annual state-of-the-market consumer report series, publish consumer guides to inform decision-making, produce an annual global and virtual professional conference,” and maintain SharpBrains.com, a leading educational blog and website with over 100,000 monthly readers.

Most recently, SharpBrains has published a book on brain fitness called The SharpBrains Guide to Brain Fitness: How to Optimize Brain Health and Performance at Any Age. A compilation and condensation of information accumulated over the lifespan of the company, The SharpBrains Guide to Brain Fitness emphasizes credible research and goes to great lengths to provide the most up-to-date research results in specific areas of brain fitness, followed by interviews with scientists doing work in those fields. The goal of the guide is to help the reader begin to “cultivate a new mindset and master a new toolkit that allow us appreciate and take full advantage of our brain’s incredible properties…[by] providing the information and understanding to make sound and personally relevant decisions about how to optimize your own brain health and performance.”

The Guide begins by emphasizing that the brain’s many neuronal networks serve distinct functions including various types of memory, language, emotional regulation, attention, and planning. Plasticity of the brain is defined as its lifelong capacity to change and reorganize itself in response to the stimulation of learning and experience—the foundation upon which “brain training” to improve cognitive performance at any age, and to maintain brain health into old age, is predicated.

The difficulty of making sense of the scientific findings on brain health and neuroplasticity is discussed at length, with the finger of blame pointed squarely at the media for reporting only fragments of the research and for often reporting those results which are not most meaningful. The authors stress that “it is critical to complement popular media sources with independent resources, and above all with one’s own informed judgment.”

The following chapters go on to review what is known today about how physical exercise, nutrition, mental challenge, social engagement, and stress management can positively affect brain health. Along the way they provide dozens of relevant research results (as well as the design of each study) to support their recommendations. Reporting on all of those experiments is beyond the scope of this review, so if you are interested in examining them (and you should be!) please obtain a copy of the Guide for yourself or from your local library.

Physical exercise is discussed first because of the very strong evidence that exercise—especially aerobic, or “cardio,” exercise slows atrophy of the brain associated with aging, actually increasing the brain’s volume of neurons (i.e., “gray matter”) and connections between neurons (i.e., “white matter”). While much of the initial research supporting the effects of exercise on the brain came from animal studies, the authors report that “several brain imaging studies have now shown that physical exercise is accompanied by increased brain volume in humans.”

Staying physically fit improves cognition across all age groups, with particularly large benefits for so-called “executive” functions such as planning, working memory, and inhibition. A 2010 meta-analysis by the NIH also concluded that physical exercise is a key factor in postponing cognitive decline and/or dementia, while other studies have found physical exercise to lower the risk of developing Parkinson’s disease, as well.

But don’t think that just any moving around will do the trick. When it comes to providing brain benefits, a clear distinction is drawn between physical activity and physical exercise. Only exercise will trigger the biochemical changes in the brain that spur neurogenesis and support neuroplasticity. It doesn’t need to be particularly strenuous, but to be most beneficial it should raise your heart rate and increase your breathing rate.

Of course, adequate nutrition is also imperative in obtaining and maintaining optimal brain health. The SharpBrains Guide to Brain Fitness primarily highlights the well-known benefits of the Mediterranean diet, which consists of a high intake of vegetables, fruit, cereals, and unsaturated fats, a low intake of dairy products, meat, and saturated fats, a moderate intake of fish, and regular but moderate alcohol consumption. But I think it is safe to say that the jury is still out on the best diet for the brain, as evidenced by the recent popularity of the Paleo diet among life extentionists. And, of course, ethnicity and genetics are important, too. The authors do stress the importance of omega-3 fatty acids and antioxidants obtained from dietary sources, stating firmly that “to date, no supplement has conclusively been shown to improve cognitive functioning, slow down cognitive decline, or postpone Alzheimer’s disease symptoms beyond placebo effect.” This includes herbal supplements such as Ginko biloba and St. John’s wort.

Beyond what we normally do to keep our bodies healthy, the Guide also discusses the relative effectiveness of different forms of “mental exercise.” Perhaps you’ve heard that doing crossword or Sudoku puzzles will keep you sharp and alert into old age, or that speaking multiple languages is associated with decreased risk of Alzheimer’s disease. The good news is that these things are true—to a degree. The part that is often left out is that it’s the challenge of these activities that is important. As with physical activity vs. physical exercise, mental exercise refers to the subset of mental activities that are effortful and challenging.

Puzzles and games may be challenging at first, but they (and other mental exercises) can quickly become routine and unchallenging. In order to reap the most benefit from mental exercise, the goal is to be exposed to novelty and increasing levels of challenge. Variety is important for stimulating all aspects of cognitive ability and performance, so excessive specialization is not the best strategy for maintaining long-term brain health. If you are an artist, try your hand at strategybased games. If you’re an economist, try an artistic activity. Get out of your comfort zone in order to stimulate skills that you rarely use otherwise.

The SharpBrains Guide states that “lifelong participation in cognitively engaging activities results in delayed cognitive decline in healthy individuals and in spending less time living with dementia in people diagnosed with Alzheimer’s disease.” This is hypothesized to be because doing so builds up one’s “cognitive reserve”—literally an extra reservoir of neurons and neuronal connections—which may be utilized so that a person continues to function normally even in the face of underlying Alzheimer’s or other brain pathology. This observation raises another important point on which neuroscientists and physiologists do not yet fully agree. Will we all eventually get dementia if we live long enough without credible brain rejuvenation biotechnologies? This is a topic I would like to return to in a future installment of Cooler Minds Prevail.

Social engagement also appears to provide brain benefits. The NIH meta-analysis mentioned earlier concluded that higher social engagement in mid- to late life is associated with higher cognitive functioning and reduced risk of cognitive decline. Brain imaging studies indicate an effect of social stimulation on the volume of the amygdala, a structure that plays a major role in our emotional responses and which is closely connected to the hippocampus, which is important for memory.

Yet again, not all activity is equal. When it comes to social stimulation, “you can expect to accrue more benefits within groups that have a purpose (such as a book club or a spiritual group) compared to casual social interactions (such as having a drink with a friend to relax after work).” To keep socially engaged across the lifespan, seek out interactions that naturally involve novelty, variety, and challenge such as volunteering and participating in social groups.

“The lifelong demands on any person have changed more rapidly in the last thousand years than our genes and brains have,” The SharpBrains Guide explains in the intro to the chapter on stress management. The result? It has become much more difficult to regulate stress and emotions. It is great that we have such amazing and complex brains, but humans are among the few animals that can get stressed from their own thoughts. And while there are some (potentially) beneficial effects of short bursts of stress, high and sustained levels of stress can have a number of negative consequences. Those of note include: increased levels of blood cortisol which can lead to sugar imbalances, high blood pressure, loss of muscle tissue and bone density, lower immunity, and cause damage to the brain; a reduction of certain neurotransmitters, such as serotonin and dopamine, which has been linked to depression; and a hampering of our ability to make changes to reduce the stress, resulting in General Adaption Syndrome (aka “burnout”).

Research-based lifestyle solutions to combat stress include exercise, relaxation, socialization, humor and laughter, and positive thinking. In particular, targeted, capacity-building techniques such as biofeedback and meditation are recommended to manage stress and build resilience. Mindfulness Based Stress Reduction (MBSR) programs have provided evidence that meditative techniques can help manage stress and research shows that MBSR can lead to decreases in the density of an area of the amygdala which is correlated with reduction in reported stress.

So it appears that multiple approaches are necessary to develop a highly fit brain capable of adapting to new situations and challenges throughout life. “Consequently,” The SharpBrains Guide to Brain Fitness states, “we expect cross-training the brain to soon become as mainstream as cross-training the body is today, going beyond unstructured mental activity in order to maximize specific brain functions.”

There is growing evidence that brain training can work, but in evaluating what “works” we are mostly looking at two things: how successful the training program is (i.e., does it actually improve the skill(s) being trained?) and the likelihood of transfer from training to daily life. Building on an analysis of documented examples of brain training techniques that “work” or “transfer,” SharpBrains suggests the following five conditions need to be met for brain training to be likely to translate into meaningful real world improvements (condensed excerpt):

  1. Training must engage and exercise a core brain-based capacity or neural circuit identified to be relevant to real-life outcomes.
  2. The training must target a performance bottleneck.
  3. A minimum “dose” of 15 hours total per targeted brain function, performed over 8 weeks or less, is necessary for real improvement.
  4. Training must be adaptive to performance, require effortful attention, and increase in difficulty.
  5. Over the long-term, the key is continued practice for continued benefits.

Meditation, biofeedback, and/or cognitive therapy in concert with cognitive training to optimize targeted brain functions appear to be winning combinations in terms of successful techniques facilitating transfer from training to real life benefits. Top brain training software programs, based on SharpBrains’ analysis and a survey of their users, include Lumosity, Brain games, brainHQ, Cogmed, and emWave.

In the end, brain fitness needs are unique to each individual and brain fitness claims should be evaluated skeptically. SharpBrains recommends asking several questions when evaluating brain fitness claims, particularly whether there is clear and credible evidence of the program’s success documented in peer-reviewed scientific papers published in mainstream scientific journals that analyze the effects of the specific product.

Of course, your own individual experience with the product is ultimately the most important evaluation of all. If you are ready to take the plunge into the emerging brain fitness market, The SharpBrains Guide to Brain Fitness is a good place to start, and I’m sure they’d appreciate your feedback as this field continues to develop.

Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, August, 2013

26. January 2015 · Comments Off on HIV, Immunosenescence, and Accelerated Aging · Categories: Health, Neuroscience, Science

After a few articles considering Alzheimer disease from several angles, I would like to switch gears this month and talk more generally about the interaction between the immune system and aging.

In his 2012 paper[1], Caleb E. Finch documents the evolution of life expectancy in the course of human history. The life expectancy at birth of our shared ape ancestor 6 millions years ago is hypothesized to approximate that of a chimpanzee, 15 years. The first Homo species appeared 1-2 million years ago and had a life expectancy of ~20 years, while H. sapiens came onto the scene ~100,000 years ago and could expect about 30 years of life. But starting around 200 years ago, concurrent with industrialization, human life expectancy jumped rapidly, to somewhere between 70 and 80 years today.

As many readers are likely aware, the huge recent increases in life expectancy are commonly attributed to improvements in hygiene, nutrition, and medicine during the nineteenth and twentieth centuries that reduced mortality from infections at all ages. Finch hypothesizes, generally, that early age mortality over the course of human history is primarily due to (acute) infection, while old age mortality is primarily due to (chronic) inflammation. Further analysis of mortality rates over the last several hundred years leads him to further hypothesize that aging has been slowed in proportion to the reduced exposure to infections in early life. These hypotheses are supported by twentieth century examples which strongly demonstrate influences of the early life environment on adult health, such as the effects of prenatal and postnatal developmental influences (e.g., nutrition, exposure to infection) on adult chronic metabolic and vascular disorders as well as physical traits and mental characteristics. This leads Finch to suggest “broadening the concept of ‘developmental origins’ to include three groups of factors: nutritional deficits, chronic stress from socioeconomic factors, and direct and indirect damage from infections.”

Finch also considers the effects of inflammation and diet on human evolution, proposing several environmental and foraging factors that may have been important in the genetic basis for evolving lower basal mortality through interactions with chronic inflammation, in particular: dietary fat and caloric content; infections from pathogens ingested from carrion and from exposure to excreta; and noninfectious inflammagens such as those in aerosols and in cooked foods. He hypothesizes that exposure to these proinflammatory factors, which one would expect to shorten life expectancy, actually resulted in humans evolving lower mortality and longer lifespans in response to highly inflammatory environments.

A means for this, he argues, was the development of the apoE4 genotype. Noting that the apoE4 allele favors advantageous fat accumulation and is also associated with enhanced inflammatory responses, Finch argues that heightened inflammatory response and more efficient fat storage would have been adaptive in a pro-inflammatory environment and during times of uncertain nutrition. As has been discussed in prior articles in Cooler Minds Prevail, the apoE alleles also influence diverse chronic non-infectious degenerative diseases and lifespan. “Thus,” Finch concludes, “the apoE allele system has multiple influences relevant to evolution of brain development, metabolic storage, host defense, and longevity.”

With the general relationship between inflammation and the evolution of human aging and life expectancy in mind, let us now consider immune system involvement in more detail, and the relationship between HIV and immunosenescence more specifically.

Immunosenescence refers to the ageassociated deterioration of the immune system. As an organism ages it gradually becomes deficient in its ability to respond to infections and experiences a decline in long-term immune memory. This is due to a number of specific biological changes such as diminished self-renewal capacity of hematopoietic stem cells, a decline in total number of phagocytes, impairment of Natural Killer (NK) and dendritic cells, and a reduction in B-cell population. There is also a decline in the production of new naïve lymphocytes and the functional competence of memory cell populations. As a result, advanced age is associated with increased frequency and severity of pathological health problems as well as an increase in morbidity due to impaired ability to respond to infections, diseases, and disorders.

It is not hard to imagine that an increased viral load leading to chronic inflammatory response may accelerate aging and immunosenescence. Evidence for this is accumulating rapidly since the advent of antiretroviral therapies for treatment of HIV infection. An unforeseen consequence of these successful therapies is that HIV patients are living longer but a striking number of them appear to be getting older faster, particularly showing early signs of dementia usually seen in the elderly. In one study, slightly more than 10% of older patients (avg = 56.7 years) with wellcontrolled HIV infection had cerebrospinal fluid (CSF) marker profiles consistent with Alzheimer disease[2] – more than 10 times the risk prevalence of the general population at the same age. HIV patients are also registering higher rates of insulin resistance and cholesterol imbalances, suffer elevated rates of melanoma and kidney cancers, and seven times the rate of other non-HIV-related cancers. And ultimately, long-term treated HIV-infected individuals also die at an earlier age than HIV-uninfected individuals[3].

Recent research is beginning to explore and unravel the interplay between HIV infection and other environmental factors (such as co-infection with other viruses) in the acceleration of the aging process of the immune system, leading to immunosenescence. In the setting of HIV infection, the immune response is associated with abnormally high levels of activation, leading to a cascade of continued viral spread and cell death, and accelerating the physiologic steps associated with immunosenescence. Despite clear improvements associated with effective antiretroviral therapy, some subjects show persistent alterations in T cell homeostasis, especially constraints on T cell recovery, which are further exacerbated in the setting of co-infection and increasing age.

Unsurprisingly, it has been observed that markers of immunosenescence might predict morbidity and mortality in HIV-infected adults as well as the general population. In both HIV infection and aging, immunosenescence is marked by an increased proportion of CD28- to CD57+, and memory CD8+ T cells with reduced capacity to produce interleukin 2 (IL-2), increased production of interleukin 6 (IL-6), resistance to apoptosis, and shortened telomeres. Levels of markers of inflammation are elevated in HIV infected patients, and elevations in markers such as high-sensitivity C-reactive protein, D-dimer, and interleukin 6 (IL-6) have been associated with increased risk for cardiovascular disease, opportunistic conditions, or all-cause mortality[4].

But even as we are beginning to identify markers that appear to be associated with risk of poor outcome in HIV infection, it is still unclear how patients should be treated on the basis of this information. To that end, several trials are underway to evaluate the effects of modulation of immune activation and inflammation in HIV infection. At the same time, clinicians at the forefront of advancing knowledge and clinical care are performing research aimed at optimizing care for aging HIV patients.

The implications for such research may be far-reaching. In fact, many HIV clinicians and researchers think that HIV may be key to understanding aging in general. Dr. Eric Verdin states, “I think in treated, HIV-infected patients the primary driver of disease is immunological. The study of individuals who are HIV-positive is likely to teach us things that are really new and important, not only about HIV infection, but also about normal aging.”

Dr. Steven Deeks stresses the collaborative efforts of experts across fields. “I think there is a high potential for tremendous progress in understanding HIV if we can assemble a team of experts from the world of HIV immunology and the world of gerontology,” he says. “Each field can dramatically inform the other. I believe HIV is a well described, well studied, distinct disease that can be used as
a model by the larger community to look at issues of aging.”


[1] Finch, C (2012). Evolution of the Human Lifespan, Past, Present, and Future: Phases in the Evolution of Human Life Expectancy in Relation to the Inflammatory Load. Proceedings of the American Philosophical Society, 156:1, 9-44.

[2] Mascolini, M (2013). Over 10% in Older HIV Group Fit Alzheimer’s Biomarker Risk Profile. Conference Reports for NATAP: 20th Conference on Retroviruses and Opportunistic Infections, March 3-6, 2013.

[3] Aberg, X (2012). Aging, Inflammation, and HIV Infection. Topics in Antiviral Medicine, 20:3, 101-105.

[4] Deeks, S, Verdin, S. and McCune, JM (2012). Immunosenescence and HIV. Current Opinion in Immunology, 24: 1-6.

Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, June, 2013

23. January 2015 · Comments Off on Apolipoprotein E Genotype and Viral Infections · Categories: Neuroscience, Science

Last month this column considered current and future progress in Alzheimer Disease (AD) diagnosis, management, and treatment. Because AD is a terrible brain disease with an increasing rate of prevalence with age, and because it represents one of – if not the – worst conditions that can afflict a person with cryopreservation arrangements, I would like to continue our consideration of this well-known and widely-feared neurodegenerative disease. Specifically, our focus will be on apolipoprotein E (apoE) and research regarding its role in the modulation of physiological responses to certain viral infections.

ApoE protein is primarily synthesized peripherally in the liver and mediates cholesterol metabolism systemically, but it is also made in the central nervous system by astroglia and microglia (non-neuronal cell types) where it transports cholesterol to neurons. In the CNS, neurons express receptors for apoE that are part of the low density lipoprotein receptor gene family. Historically, apoE has been recognized for its role in lipoprotein metabolism and its importance in cardiovascular disease. Of course, apoE carrier status is also widely known as the major factor determining one’s risk of developing late-onset Alzheimer disease (AD). But more recent research has indicated that the various isoforms of apoE may also have significant immunological impact by conferring different susceptibilities to other diseases, as well.

The human apoE gene is located on chromosome 19 and is composed of 79 individual single nucleotide polymorphisms (SNPs). The three major alleles of apoE, named Epsilon-2 (Ɛ2), Epsilon-3 (Ɛ3), and Epsilon-4 (Ɛ4), are determined by differences in SNPs s429358 and rs7412. The products of these alleles are the protein isoforms apoE2, apoE3, and apoE4, which differ only by a single amino acid at two residues (amino acid 112 and amino acid 158). These amino acid substitutions affect noncovalent “salt bridge” formation within the proteins, which ultimately impacts on lipoprotein preference, stability of the protein, and receptor binding activities of the isoforms (see Table 1).

Isoform Amino acid 112 Amino acid 158 Relative charge Lipoprotein preference LDL receptor binding ability

















VLDL, chylomicrons


Table 1. ApoE isoform amino acid differences and resulting chemical and physiological changes.

There are also two minor alleles, Epsilon-1 (Ɛ1) and Epsilon-5 (Ɛ5), which are present in less than 0.1% of the population. The three major alleles are responsible for three homozygous (Ɛ2/Ɛ2, Ɛ3/Ɛ3, Ɛ4/Ɛ4) and three heterozygous (Ɛ2/Ɛ3, Ɛ2/Ɛ4, Ɛ3/Ɛ4) genotypes. [I will pause to mention here that it is now quite easy to determine one’s genotype through services such as 23andme.com.]

An interesting document in the field is the literature review by Inga Kuhlman, et al. (Lipids in Health and Disease 2010, 9:8) which assesses hepatitis C, HIV and herpes simplex disease risk by ApoE genotype. An important finding is that the Ɛ4 allele is found less frequently in populations as they age (e.g., 14% of the general German population vs. 5% in centenarians), indicating that Ɛ4 is a major mortality factor in the elderly. This is assumed to be a result of the Ɛ4 allele’s well-known predisposition to Alzheimer and cardiovascular diseases.

The authors explain that “apoE4 carriers have a tendency for 5-10% higher fasting total cholesterol, LDL-cholesterol and triglyceride levels relative to homozygote Ɛ3/Ɛ3” and that this tendency towards higher lipid levels is probably responsible for the 40-50% greater cardiovascular disease risk in Ɛ4 carriers. They also point out that “although the molecular basis of the pathology is poorly understood, and likely to be in part due to apoE genotype associated differences in brain lipid metabolism, an apoE4 genotype has been highly consistently associated with the risk of an age-related loss of cognitive function, in an allele dose fashion.” This means, of course, that Ɛ4/Ɛ4 carriers are at greatest risk for cognitive dysfunction with increasing age.

In the field of immune regulation, a growing number of studies point to apoE’s interaction with many immunological processes. In their article, Kuhlman, et al., summarize the impact of the Ɛ4 allele on the susceptibility to specific infectious viral disease. The authors review a number of studies of the effects of apoE4 genotype on hepatitis C (HCV), human immunodeficiency virus (HIV), and herpes simplex (HSV) infection and outcome in humans.

In general, apoE4 was found to be protective against hepatitis C infection vs. (Ɛ3/Ɛ3) controls. Though the exact mechanisms of apoE genotype-specific effects on HCV life cycle remain uncertain, apoE seems to be involved because “available data indicate that the outcome of chronic HCV infection is better among Ɛ4 carriers due to slower fibrosis progression.”

Concerning the possible influence of apoE genotype on HIV infection and HIV-associated dementia, the authors call attention to the fact that “cholesterol is a crucial component of the HIV envelope and essential for viral entry and assembly.” Given that apoE is essential for cholesterol transport, they hypothesize that apoE genotype influences HIV-induced effects on neurological function. Subsequent review of available research suggests that the 4 allele is associated with higher steady-state viral load and faster disease progression due to accelerated virus entry in 4 carriers, but a correlation between apoE4 and HIV-associated dementia “remains controversial and needs to be clarified by further studies.”

Lastly, a review of the literature regarding the effects of apoE4 genotype on herpes simplex virus (HSV)-1 infection and outcome in humans indicates that apoE4 enhances the susceptibility for HSV-1 “as well as the neuroinvasiveness of HSV-1 compared to other apoE variants” (i.e., HSV-1 is found in more frequently in the CNS of 4 carriers). Importantly, the authors also note that “the combination of apoE4 and HSV-1 may lead to a higher risk of Alzheimer disease (AD) than either factor in isolation.”

Due to its generally being associated with higher risk of cardiovascular disease, dementia, and increased susceptibility to and/or accelerated progression of various viral infections, one may wonder why the 4 allele has not been eliminated by evolutionary selection. This may be explained, in part, by the protective and beneficial effects it exhibits in certain harmful infectious diseases, as demonstrated for hepatitis C.

The exact mechanisms of apoE influence on susceptibility to and course of viral infection remain shrouded. Because the mechanisms of HCV, HIV, and HSV infection are quite similar (i.e., all three viruses compete with apoE for cell attachment and receptor binding), it is interesting to find differences in receptor binding among them.

Involvement or interaction between the immune system, cognition, and brain diseases such as AD is an as-yet widely untouched field of inquiry. Further elucidation of the mechanisms by which apoE may influence the pathogenesis of infectious viral diseases can lead to new developments in the treatment of disease based on an individual’s apoE genotype.

Aside from the role that ApoE plays in susceptibility and progression of infectious disease, there is growing interest in the role that infection or a compromised immune system plays in the development of dementia. For example, despite the successful management of HIV with antiretroviral drugs, some patients are showing signs of memory impairment and dementia at a relatively young age. Interestingly, these people seem to show accelerated aging, too, which raises important questions about the relationship between the immune system, immunosenescence, and aging.

Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, May, 2013

14. November 2014 · Comments Off on Alzheimer Disease in 2020 · Categories: Health, Neuroscience

Any terminal illness is a terrible thing; but to a cryonics member, a brain-destroying neurodegenerative disease is the worst contemporary medical “death sentence” one can receive. There are several flavors of neurodegenerative disorders, many of which primarily affect the patient’s movement, strength, coordination, or the peripheral nervous system. And there are numerous contributory mechanisms in the causation of neurodegeneration, including prion infection and toxin related disease. But the most common – and the most feared – neurodegenerative disease is one that affects not movement, but cognition.

Of course, I am speaking of Alzheimer disease (AD). Originally described in a 51- year old woman by the Bavarian psychiatrist Alois Alzheimer in 1906, neuropathologists have increasingly recognized that AD is also the most common basis for latelife cognitive failure. Culminating in neuronal dystrophy and death leading to the progressive loss of memory and other cognitive functions (i.e., dementia), and affecting individuals of both sexes and of all races and ethnic groups at a rate of occurrence in the U.S. ranging from approximately 1.3% (age 65-74) to 45% (age 85-93), it is easy to see why AD has generated so much intense scientific interest in recent years.

In the recently published work “The Biology of Alzheimer Disease” (2012), most of what is known about AD today is described in detail in the various chapters covering topics such as the neuropsychological profile and neuropathological alterations in AD, biomarkers of AD, the biochemistry and cell biology of the various proteins involved in AD, animal models of AD, the role of inflammation in AD, the genetics of AD, and treatment strategies. The editors’ selection of contributions has resulted in the most up-to-date compendium on Alzheimer disease to date.

The book culminates in a chapter called Alzheimer Disease in 2020, where the editors extol “the remarkable advances in unraveling the biological underpinnings of Alzheimer disease…during the last 25 years,” and yet also recognize that “we have made only the smallest of dents in the development of truly disease-modifying treatments.” So what can we reasonably expect over the course of the next 7 years or so? Will we bang our heads against the wall of discovery, or will there be enormous breakthroughs in identification and treatment of AD?

Though a definitive diagnosis of AD is only possible upon postmortem histopathological examination of the brain, a thorough review of the book leads me to believe that the greatest progress currently being made is in developing assays to diagnose AD at earlier stages. It is now known that neuropathological changes associated with AD may begin decades before symptoms manifest. This, coupled with the uncertainty inherent in a clinical diagnosis of AD, has driven a search for diagnostic markers. Two particular approaches have shown the most promise: brain imaging and the identification of fluid biomarkers of AD.

Historically, imaging was used only to exclude potentially surgically treatable causes of cognitive decline. Over the last few decades, imaging has moved from this minor role to a central position of diagnostic value with ever-increasing specificity. The ability to differentiate AD from alternative or contributory pathologies is of significant value now, but the need for an earlier and more certain diagnosis will only increase as disease-modifying therapies are identified. This will be particularly true if these therapies work best (or only) when initiated at the preclinical stage. Improvements in imaging have also greatly increased our understanding of the biology and progression of AD temporally and spatially. Importantly, the clinical correlations of these changes and their relationships to other biomarkers and to prognosis can be studied.

The primary modalities that have contributed to progress in AD imaging are structural magnetic resonance imaging (MRI), functional MRI, fluorodeoxyglucose (FDG) positron emission tomography (PET), and amyloid PET. Structural MRI, which is used to image the structure of the brain, has obvious utility in visualizing the progressive cerebral atrophy characteristic of AD. Such images can be used as a marker of disease progression and as a means of measuring effective treatments (which would slow the rate of atrophy). Functional MRI, on the other hand, measures changes in blood oxygen leveldependent (BOLD) MR signal. This signal, which can be acquired during cognitive tasks, may provide the clinician with a tool to compare brain activity across conditions in order to assess and detect early brain dysfunction related to AD and to monitor therapeutic response over relatively short time periods.

FDG PET primarily indicates brain metabolism and synaptic activity by measuring glucose analog fluorodeoxyglucose (which can be detected by PET after labeling it with Fluorine-18). A large body of FDG-PET work has identified an endophenotype of AD – that is, a signature set of regions that are typically hypometabolic in AD patients. FDG hypometabolism parallels cognitive function along the trajectory of normal, preclinical, prodromal, and established AD. Over the course of three decades of investigation, FDG PET has emerged as a robust marker of brain dysfunction in AD. Imaging of β-amyloid (Aβ) – the peptide that makes up the plaques found in the brains of AD patients – is accomplished via amyloid PET to determine brain Aβ content. Historically, this has only been possible upon postmortem examination, so the utility of amyloid imaging is in moving this assessment from the pathology laboratory to the clinic. Because amyloid deposition begins early on, however, amyloid PET is not useful as a marker of disease progression.

The well-known hallmarks of AD, the plaques and neurofibrillary tangles first described by Alouis Alzheimer in 1906, were discovered in 1985 to be composed primarily of β-amyloid and hyperphosphorylated tau protein, respectively. Advances in our knowledge of Aβ generation and tau protein homeostasis have led to substantial research into disease-modifying drugs aimed at decreasing overall plaque and tangle load in an effort to halt neurodegeneration. Such treatments will likely be most effective if started early in the disease process, making sensitive and accurate fluid biomarkers of Aβ and tau especially important.

Outside of imaging, progress in AD diagnostics stems primarily from the assessment of fluid biomarkers of AD. These biomarkers are generally procured from the cerebrospinal fluid (CSF) and blood plasma and include total tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid form of of β-amyloid (Aβ42). These core biomarkers reflect AD pathology and have high diagnostic accuracy, which is especially useful in diagnosing AD in prodromal and mild cognitive impairment cases.

Because the CSF is in direct contact with the extracellular space of the brain, biochemical changes in the brain can be detected in the CSF. Assays to detect Aβ42 led to the discovery that Aβ42 in AD is decreased to approximately 50% of control levels, making the measurement of Aβ42 a useful clinical tool. Measurements of T-tau (around 300% of control in AD patients) and P-tau biomarkers (a marked increase in AD patients) in combination with Aβ42, however, provide an even more powerful diagnostic assay.

Fluid biomarkers for AD other than Aβ and tau have been posited, but positive results have been difficult to replicate. Novel biomarkers with the most promise inlcude the amyloid precursor proteins sAPPβ and sAPPα, β-site APP cleaving enzyme-1 (BACE1), Aβ oligomers, and other Aβ isoforms. Additionally, neuronal and synaptic proteins as well as various inflammatory molecules and markers of oxidative stress may prove valuable as CSF biomarkers. Studies of plasma biomarkers such as those investigating plasma Aβ have yielded contradictory results, but promising novel blood biomarkers for AD may be found in certain signaling and inflammatory proteins.

Taken together, progress in brain imaging and identification of fluid biomarkers hold great promise in improved diagnosis of AD cases. When combined with expected drug therapies we may be able to delay the onset of neurodegeneration and associated cognitive impairment significantly. In the meantime, early diagnosis is helpful in stratifying AD cases, monitoring potential treatments for safety, and monitoring the biochemical effect of drugs. For cryonicists, early diagnosis can help guide treatment and end-of-life care decisions in order to optimize cryopreservation of the brain.

So – back to the original question. What can we predict about the AD landscape in 2020?

Besides continued progress in early diagnosis through brain imaging and fluid biomarkers, the authors anticipate that advances in whole-genome and exome sequencing will lead to a better understanding of all of the genes that contribute to overall genetic risk of AD. Additionally, improved ability to sense and detect the proteins that aggregate in AD and to distinguish these different assembly forms and to correlate the various conformations with cellular, synaptic, and brain network dysfunction should be forthcoming in the next few years. Lastly, we will continue to improve our understanding of the cell biology of neurodegeneration as well as cell-cell interactions and inflammation, providing new insights into what is important and what is not in AD pathogenesis and how it differs across individuals, which will lead, in turn, to improved clinical trials and treatment strategies.

Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, April, 2013

10. November 2014 · Comments Off on Ancient Brains · Categories: Cryonics, Neuroscience, Science

Cryonics seeks to preserve terminally ill humans in anticipation of future medical advances that may restore these patients to youthful vigor, cure their devastating diseases, and resuscitate them from cryopreservation itself. At the core of this mission lies the goal of preserving that which we know to be most important to continuity of the person him/herself: the brain.

Absent reversible cryopreservation of the brain (i.e., maintenance of viability), a cryonicist’s best hope for eventual resuscitation lies in preserving brain ultrastructure with as much fidelity as possible. Improvements in cryopreservation solutions, methodologies, and protocols from the field to the operating room have greatly enhanced our ability to meet this objective, as evidenced by microscopic evaluations of tissues vitrified in the lab. More recently, CT scans of patients after neuropreservation have provided valuable feedback as to the efficacy of cryoprotective perfusion in actual Alcor cases. Such progress bodes well for good patient outcomes.

But even our greatest attempts at optimal preservation are thwarted by issues such as long ischemic periods resulting in significant perfusion impairment or even the inability to perfuse at all. So how do we evaluate these patients in light of our objective?

Perhaps the best place to start is the extreme. Let us consider, for example, a prehistoric human brain discovered in 2008 at a construction site in York, UK. A paper published in 2011 in the Journal of Archaeological Science (“Exceptional preservation of a prehistoric human brain from Heslington, Yorkshire, UK”) provides gross and histological observations as well as preliminary results of chemical assays in order to determine the extent and cause of preservation of the brain. Low-powered reflected light microscopy and electron microscopy were performed to explore the surviving morphology and histology of the brain, while highly sensitive neuroimmunological techniques and proteomic analyses were employed to explore brain chemistry.

Examination of the skull indicated death by an abrupt trauma to the neck followed by deliberate dismemberment of the head between veretebrae C2 and C3. Significantly, the authors report “no trace of microbial activity, bacterial or fungal, with none of the porosity or ‘tunneling’ that is characteristic of putrefactive microorganisms.” Examination of the brain masses revealed recognizable sulci and gyri, but neither macroscopic nor CT evaluation could differentiate between grey and white matter.

Histological examination of the brain masses showed “a homogenous, amorphous substance that had not retained any cellular or matrix structure.” Transmission electronic microscopy (TEM) also did not detect any surviving cellular structure, although it did reveal what appeared to be “numerous morphologically degraded structures characteristic of the myelin sheath of nerve fibres.”

Preliminary biomolecular analysis found only 5% of the brain was detectable as hydrolysable amino acids, in contrast to fresh brain tissue of which proteins represent more than 1/3 of dry weight. When compared with a fresh brain, the Heslington brain was also depleted in polar amino acids and enriched in hydrophobic amino acids. Very little undegraded solventsoluble brain lipid was preserved (0.8%- 1.1% wet weight compared with 17.1% for rat brain). In addition, there was an almost complete absence of phospholipids and only a trace of cholesterol, while degradation products of a wide range of lipids were found in abundance.

Ultimately, the authors determined that the preservation of this brain was due to decapitation (thus eliminating the movement of putrefying bacteria from the gut to the brain) followed by inhibition of postmortem putrefaction achieved through rapid burial into fine-grained wet sediment. They go on to argue that this type of preservation is not as unusual as one might think, citing several similar examples of preserved prehistoric human brains, almost always found in wet burial environments.

While interesting in its own right, few would argue that the Heslington brain represents a state of preservation amenable to resuscitation. The ability to infer anything beyond gross macro structure has been obliterated and the normal chemical constituents of the brain have dissolved almost completely into the surrounding environment. Clearly, much of the look of a brain can be retained while none of the person’s identity remains (or is recoverable).

Let us then look at a situation that hits a little closer to home. Published in Forensic Science International in 2007, an article entitled “Autopsy at 2 months after death: Brain is satisfactorily preserved for neuropathology” provides us with considerable food for thought. In this example, a 77-year-old woman’s whole body was stored postmortem in a 3°C cooling chamber for 2 months prior to chemical fixation of her brain at autopsy.

The authors describe moderate autolysis of internal organs of the body, indicating the start of decomposition and putrefaction, as well as reduced tissue consistency and superficial areas of disintegration of the brain. Overall gross morphology was sufficiently preserved to allow macroscopic examination and application of neuropathological methods for diagnosis of neurological disorders. Importantly, they also report that “histologically, normal brain structures including all major parenchymal cell types (neurons, astrocytes, oligodendrocytes, microglia), neuropil, axons, and myelin sheaths were preserved.”

In this case, the use of cold temperatures (3°C) drastically slowed, but did not stop, deterioration of the brain. However, enough of the brain’s chemical constituents and physical structure remained to provide the basis for possible future resuscitation. And while this woman’s brain was preserved by chemical diffusion over the course of 9 weeks (allowing for continued degradation of subcortical tissues during the course of fixation), the use of cryogenic temperatures to quickly preserve her brain would also have been possible, as has been the situation for many “straight frozen” Alcor patients who were received in similar condition.

Exactly where the line between recoverability and non-recoverability — resulting in information-theoretic death — exists is yet to be determined. And while we push, rightfully, for ever greater preservation methods, we do well to remember that those preserved under lessthan- optimal conditions are by no means lost causes. Preserved information, even in fractured and distorted form, may well be adequate to infer the original state.

Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, March, 2013

20. October 2014 · Comments Off on Consciousness, Natural Selection, and Knowledge · Categories: Neuroscience, Science

Cryonics Magazine, February 2013

This is the first entry in a new series of short articles about neuroscience and its implications for the field of human cryopreservation and life extension. In this article I discuss the relationship of the brain to consciousness and knowledge acquisition before venturing into more specific and practical topics

What is consciousness? Most of us understand the word in context, but when asked to define it we are suddenly at a loss for words or at best we offer a description that seems wholly inadequate. Scientists, philosophers, and religious scholars have debated the source, meaning, and nature of consciousness for all of recorded history. But with the rise of neuroscience over the past few decades, it now seems as though explaining the nature and mechanisms of conscious experience in neurobiological terms may be an attainable goal.

The recent work on consciousness by neuroscientists has left certain philosophers more frustrated than ever before, including the likes of Thomas Nagel and David Chalmers. They suspect that consciousness may be quite different and separate from the brain circuitry proposed to underlie it.

Consciousness has appeared to be a strange and undefinable phenomenon for a very long time. Daniel Dennett captured the feeling very nicely in the 1970s:

“Consciousness appears to be the last bastion of occult properties, epiphenomena, immeasurable subjective states — in short, the one area of mind best left to the philosophers. Let them make fools of themselves trying to corral the quicksilver of “phenomenology” into a respectable theory.”(1)

Consciousness no longer appears this strange to many researchers, but the philosophers just mentioned continue to hold that it may not be reduced to brain processes active in cognition. A common philosophical complaint is that any neurobiological theory of consciousness will always leave something out. What it will always leave out is the feeling itself — the feeling of what it is like to be aware, to see green, to smell flowers, and so on (Nagel 1974; Chalmers, 1996). These are so-called qualia — the experiences themselves — and these are what are important about consciousness. The philosopher making this argument may go on to conclude that no science can ever really explain qualia because it cannot demonstrate what it is like to see green if you have never seen green. Ultimately, they argue, consciousness is beyond the reach of scientific understanding.

By contrast, neuroscientists take for granted that consciousness will be domesticated along with the rest of cognition. Indeed, this work tends to assume that neuroscience will not only identify correlates of consciousness, but will eventually tell us what consciousness is. By and large, these neuroscientific efforts have been directed toward cortical regions of the brain, cortical pathways, and cortical activity. This is due, in part, to the prevalence of clinical studies of human patients with region-specific cortical lesions that are correlated with deficits in specific kinds of experiences. This tendency to focus on the cortex may also reflect the common knowledge that humans possess the highest level of consciousness of all animals and have proportionally more cortex than our closest relatives (and — so the supposition goes — therein lies the difference in levels of consciousness).

Another theory of consciousness, offered by Dr. Gerald M. Edelman, aims to resolve this “divorce” between science and the humanities over theories of consciousness. The premise of Edelman’s theory is that the field of neuroscience has already provided enough information about how the brain works to support a scientifically plausible understanding of consciousness. His theory attempts to reconcile the two positions described earlier by examining how consciousness arose in the course of evolution.

In his book on the topic, Second Nature: Brain Science and Human Knowledge, Edelman says:

“An examination of the biological bases of consciousness reveals it to be based in a selectional system. This provides the grounds for understanding the complexity, the irreversibility, and the historical contingency of our phenomenal experience. These properties, which affect how we know, rule out an all-inclusive reduction to scientific description of certain products of our mental life such as art and ethics. But this does not mean that we have to invoke strange physical states, dualism, or panpsychism to explain the origin of conscious qualia. All of our mental life, reducible and irreducible, is based on the structure and dynamics of our brain.

In essence, Edelman has attempted to construct a comprehensive theory of consciousness that is consistent with the latest available neuroanatomical, neurophysiological, and behavioral data. Calling his idea Neural Darwinism, Edelman explains that the brain is a selection system that operates within an individual’s lifetime. Neural Darwinism proposes that, during neurogenesis, an enormous “primary repertoire” of physically connected populations of neurons arises. Subsequently, a “secondary repertoire” of functionally defined neuronal groups emerges as the animal experiences the world. A neural “value system,” developed over the course of evolution and believed to be made up of small populations of neurons within deep subcortical structures, is proposed to assign salience to particular stimuli encountered by the animal in order to select patterns of activity.

For example, when the response to a given stimulus leads to a positive outcome the value system will reinforce the synaptic connections between neurons that happened to be firing at that particular moment. When a stimulus is noxious, the value system will similarly strengthen the connections between neurons that happened to be firing at the time the stimulus was encountered, thus increasing the salience of that stimulus. When a stimulus has no salience, synaptic connections between neurons that fired upon first exposure to that stimulus will become weaker with successive exposures.

Importantly, the mapping of the world to the neural substrate is degenerate; that is, no two neuronal groups or maps are the same, either structurally or functionally. These maps are dynamic, and their borders shift with experience. And finally, since each individual has a unique history, no two individuals will express the same neural mappings of the world.

This brings us to the three tenets of Edelman’s theory:

1. Development of neural circuits leads to enormous microscopic anatomical variation that is the result of a process of continual selection;

2. An additional and overlapping set of selective events occurs when the repertoire of anatomical circuits that are formed receives signals because of an animal’s behavior or experience;

3. “Reentry” is the continual signaling from one brain region (or map) to another and back again across massively parallel fibers (axons) that are known to be omnipresent in higher brains.

Edelman thus believes that consciousness is entailed by reentrant activity among cortical areas and the thalamus and by the cortex interacting with itself and with subcortical structures. He suggests that primary consciousness appeared at a time when the thalmocortical system was greatly enlarged, accompanied by an increase in the number of specific thalamic nuclei and by enlargement of the cerebral cortex — probably after the transitions from reptiles to birds and separately to mammals about a quarter of a billion years ago. Higherorder consciousness (i.e., consciousness of consciousness), on the other hand, is due to reentrant connections between conceptual maps of the brain and those areas of the brain capable of symbolic or semantic reference — and it only fully flowered with hominids when true language appeared. Regarding language and its relationship to higher-order consciousness, Edelman explains:

“We do not inherit a language of thought. Instead, concepts are developed from the brain’s mapping of its own perceptual maps. Ultimately, therefore, concepts are initially about the world. Thought itself is based on brain events resulting from the activity of motor regions, activity that does not get conveyed to produce action. It is a premise of brain-based epistemology that subcortical structures such as the basal ganglia are critical in assuring the sequence of such brain events, yielding a kind of presyntax. So thought can occur in the absence of language….

The view of brain-based epistemology is that, after the evolution of a bipedal posture, of a supralaryngeal space, of presyntax for movement in the basal ganglia, and of an enlarged cerebral cortex, language arose as an invention. The theory rejects the notion of a brainbased, genetically inherited, language acquisition device. Instead, it contends that language acquisition is epigenetic. Its acquisition and its spread across speech communities would obviously favor its possessors over nonlinguistic hominids even though no direct inheritance of a universal grammar is at issue. Of course, hominids using language could then be further favored by natural selection acting on those systems of learning that favor language skills.”

Such a theory is attractive because it does not simply concentrate on conscious perception, but it also includes the role of behavior. We do well to keep in mind that moving, planning, deciding, executing plans, and more generally, keeping the body alive, is the fundamental business of the brain. Cognition and consciousness are what they are, and have the nature they have, because of their role in servicing behavior.

An important element of Edelman’s theory that consciousness is entailed by brain activity is that consciousness is not a “thing” or causal agent that does anything in the brain. He writes that “inasmuch as consciousness is a process entailed by neural activity in the reentrant dynamic core it cannot be itself causal.” This process causes a number of “useful” illusions such as “free will.”

Edelman’s theory of consciousness has further implications for the development of brain-based devices (BBDs), which Edelman believes will be conscious in the future as well. His central idea is that the overall structure and dynamics of a BBD, whether conscious or not, must resemble those of real brains in order to function. Unlike robots executing a defined program, the brains of such devices are built to have neuroanatomical structures and neuronal dynamics modeled on those known to have arisen during animal evolution and development.

Such devices currently exist — such as the “Darwin” device under development by The Neurosciences Institute. Darwin devices are situated in environments that allow them to make movements to sample various signal sequences and consequently develop perceptual categories and build appropriate memory systems in response to their experiences in the real world.

And though Edelman recognizes that it is currently not possible to reflect the degree of complexity of the thalmocortical system interacting with a basal ganglia system, much less to have it develop a true language with syntax as well as semantics, he nevertheless suggests that someday a conscious device could probably be built.

More ambitiously, Edelman also thinks that contemporary neuroscience can contribute to a naturalized epistemology. The term “naturalized epistemology” goes back to the analytical philosopher Willard Quine and refers to a movement away from the “justification” (or foundations) of knowledge and emphasizes the empirical processes of knowledge acquisition. Edelman is largely sympathetic towards Quine’s project, but provides a broader evolutionary framework to epistemology that also permits internal states of mind (consciousness).

1 Daniel C. Dennett, “Toward a Cognitive Theory of Consciousness,” in Brainstorms: Philosophical Essays on Mind and Psychology (Montgomery, VT: Bradford Books, 1978).

13. October 2014 · Comments Off on Can You Build a Locomotive out of Helium? · Categories: Cryonics, Neuroscience, Science

First published in Cryonics, 4th Quarter 2011

Robert Ettinger on Substrate-Independent Minds

Introduction and Afterword by Aschwin de Wolf


Robert Ettinger, the “father of cryonics,” was cryopreserved on July 23, 2011. While Ettinger’s book Man into Superman (1972) is considered an important contribution to transhumanism, he increasingly came to recognize that most people do not desire a hard break with the past and resist radical transformation. During the last years of his life he became a vocal critic of ‘mind uploading’ as a means of personal survival and spent a considerable amount of time refining his arguments why mind uploading is not likely to work. This document organizes excerpts from his last book Youniverse and mailing list messages on the topic of substrate-independent minds. In the afterword, I make a brief attempt to place his contributions in a broader philosophical context.

The title of this document refers to a message that Robert Ettinger sent to the Cryonics Institute mailing list on July 21, 2011. In response to the claim that the human mind is a machine, and that the function of any machine can be duplicated by a machine built of another material, Ettinger asked, “Can you build a locomotive out of helium?”

Mind Uploading

“A large and burgeoning group of scientists, including some of the brightest, believe that—in principle—computers will fairly soon be able to think in the fullest sense of the word. They will be living, conscious entities with feelings and subjective experiences.

“A corollary—many believe—is that your persona could be uploaded into a computer and you could then live an incomparably bigger and better life as a simulation or emulation.

“I think the uploading thesis is probably wrong, although (as usual) it’s too soon to be sure. But the issue is a significant part of modern philosophy, and potentially has enormous practical importance.

“…I am among the radicals in the expectations for AI. But intelligence is not life. It is by no means proven that life as we know it with subjective experience can exist on an arbitrary substrate, such as silicon.” (Youniverse)


“One extreme school of thought holds that information and its processing constitute everything that is important. In particular, you are essentially just a collection of information, including a program for processing that information. Your ‘hardware’—the nervous tissue that embodies and handles the information—is only secondary.

“My conclusion will be that it is not necessarily possible—even in principle—for consciousness to exist on an inorganic substrate, and in fact that it is unlikely.

“Sometimes the doubters are accused of dualism—the increasingly discredited belief that the living and inanimate worlds, or the material and the spiritual worlds, are separate.

“This certainly is not true of me or of many others who question the information paradigm. I am a thoroughgoing materialist and reductionist. I will not feel in the least dehumanized if it turns out the information paradigm is right…I have strong doubts, but they are based entirely on the evidence, or lack thereof.

“The most radical of the ‘strong AI’ people believe that all thinking is information processing, and all information processing is thinking; and they appear to believe that consciousness is just an expression of complexity in thinking.

“People who talk this way must be admired for boldness and strength of conviction, but I think not for clarity of thought.

“The point is, all physical phenomena, all interactions, involve information processing in some sense. But that isn’t all they do. A computer, or a person with pencil and paper, could figure out—describe or predict—what the atoms do, and that would be an analog of the information processing part of the phenomenon; but only the actual, physical atoms can form an oxygen molecule. And to anthropomorphize or analogize ‘feelings’ and ‘thoughts’ into these phenomena is simply unjustified. It amounts to declaring, by fiat, that thinking and feeling are inherent in information processing; but saying so doesn’t make it so.” (Youniverse)

Turing Tests and Zombies

“Alan Turing was a brilliant mathematician and computer pioneer. He played an extraordinary part in winning World War II through his work in cryptography for British Intelligence. He also showed many of the potential capabilities of general computers. But one of the works for which he is most famous is badly flawed or has been badly misused—the ‘Turing test’ for intelligence/- consciousness.

“Again, I am a firm materialist and reductionist: I readily concede the possibility that a machine could (conceivably) have life and consciousness. But I deny that we can assume that (inorganic) machines have this potential; and with still more help from Turing I think I can make the case persuasive.

“‘Uploaders’ or ‘upmorphists’ or patternists generally maintain that our identity resides in our information content. Their most extreme position is patently absurd—that ‘we’ literally persist, in some degree, if any of the information about us is preserved, even our writings or biographical data. (Shades of Woody Allen! ‘I don’t want to live on in my works; I want to live on in my apartment.’) Anyone who believes this needs more help than I can provide.

“Turing ingeniously showed that a strip of paper tape marked in squares, with zeroes or ones marked on the squares according to certain rules, along with a simple mechanism for moving the tape and making or erasing marks, could be a universal information processor—i.e., it could accomplish any information processing task that any digital computer (serial or parallel) could do, given enough time. It could even produce any result that a quantum computer might, albeit at a teeny-tiny fraction of the speed.

“You certainly can’t claim that a paper tape (even when it is moving) is alive or conscious! Yet that tape, in theory, could produce any response that a person could to a particular stimulus—if by ‘response’ we mean a signal sent to the outside world, suitably coded. It could converse with perfect fidelity to an individual’s character, and over a teletype could fool that person’s husband or wife.

“My original objection to the uploading assumption was simply that we don’t know anything about consciousness or feeling, hence it is premature to assume that it can exist other than where we know it exists, viz., in organic brains. It is entirely possible that meat machines (as opposed to machines of silicon or metal etc.) have some unique quality that allows the emergence of feeling and consciousness. Until we can isolate and define the mechanisms of feeling—of the subjective condition—we must reserve judgment as to the possibility of inorganic people. (Youniverse)

“Uploaders tend to put faith in the Turing Test  for human intelligence, and to believe that zombies cannot exist. Let’s  take a quick look.

“Communicating (say) by email, a testor tries to determine whether the testee is a human or a computer program. Passing the test supposedly proves the  testee is human or equivalent. But the test is clearly worthless, since it  produces both false positives and false negatives. As much as 50 years  ago Eliza, a program pretending to be a psychiatrist, fooled many people—false positives. And of course a child or a retarded person could perform below par and produce a false negative. The Turing test is baloney.

“In similar vein, uploaders tend to believe that something which outwardly behaves like a person must be a person. They reject the possibility of zombies, systems that by their actions appear to be sentient but are not. Yet it  is often easy to fool people, and, as already noted, programs have fooled  people even though no one claims the programs were alive.” (Cryonics Institute Mailing List, September 9, 2010).”

Imperfect Simulations

“..any simulation created in the foreseeable future will be imperfect, because it will necessarily reflect current theories of physics, and these are known to be incomplete and almost certainly in error to some extent or in some domains. Whether this would necessarily result in material deviations of the simulation from the course of nature, and in particular whether it would preclude feeling, we don’t yet know. But we do know that the simulation would be wrong, which in itself is enough to justify withholding judgment on the possibility of living computers.” (Youniverse)

Analog Failures

“The uploading thesis depends on the assumption that any organic process in the brain can be duplicated by analog in some other medium but this not only isn’t obvious; it’s nonsense.

“For example, suppose a certain process depends on magnetism, and all you have to work with are the mechanical forces transmitted by rigid bodies. Can you make an electric motor out of tinker toys? Can you build a synchrotron out of wooden boards and nails? Uploaders think a computer (of the electronic variety) can be a person: how about a Babbage mechanical computer made of rods and gears? Presumably, any kind of information processing and storage can be done by a collection of rods and gears but could rods and gears conceivably be conscious? I doubt it; not all media are created equal. So it is entirely possible that organic brains have potentialities not realizable anywhere else in the universe.” (Youniverse)

“Just ask yourself what consciousness is—what physical condition or process constitutes consciousness. You don’t know, hence you cannot know that a simulation  fills the bill.” (Cryonics Institute Mailing List, September 16, 2010)

Petitio Principii

“It seems to me that all the computer-metaphor people… keep making the same error over and over again—assuming as a premise the very hypothesis they are trying to establish. When the premise is the same as the conclusion, naturally the conclusion follows from the premise. They refer repeatedly to ‘all computational devices’ etc., implying that the brain is just that—another computational device—when in fact that is precisely what is at issue: Is the brain possibly something more than a computational device? The computer metaphor is plausible (and I am not in the least uncomfortable with it) but plausibility isn’t proof.” (Youniverse)

The Map is not the Territory

“Adherents of the ‘information paradigm,’ I believe, are deceived in part by glibness about  ‘information’ and hasty ways of looking at it.

“Apprently it needs to be said again and again: a description of a thing or a process—no matter how accurate and how nearly complete—is not the same as the thing or the process itself. To assume that isomorphism is enough is just that—an assumption, not self-evidently permissible.

“Even though (for example) a computer program can in principle describe or predict the behavior of a water molecule in virtually all circumstances, a water molecule for most purposes cannot be replaced by its description or program. If you pile up 6.02 x 1023 computers with their programs, you will not have 18 grams of water, and you will have a hard time drinking it or watering your plants.” (Youniverse)

“Eliezer Yudkowsky (and other uploaders) claim that mapping a system results in a map that effectively has the same properties as the original. Well, look again at one of my counter-examples. I write down with pencil and paper the quantum description of a hydrogen atom in its ground state. It could hardly be more obvious that the marks on paper do not constitute a hydrogen atom. And if you put side by side two papers describing two hydrogen atoms, they will not combine to form a hydrogen molecule. In principle, of course (the math is difficult) you could write down expressions corresponding to the formation of hydrogen molecules from hydrogen atoms, but you will still have just marks on paper.

Once more, a simulation is just a coded description of a thing, not the thing itself.” (Cryonics Institute Mailing List, September 18, 2010)


“The term ‘identical’ is used in different ways by different people. To  some, two systems are identical if they differ only in location, e.g. two  hydrogen atoms in ground state. But I have pointed out that a difference in location necessarily implies other differences as well, such as gravitational fields. Hence my position is that, if the question arises, are A and B  identical, then they are not.

“If two systems differ in spatial or temporal location, then they may be identical to most observers for most purposes, but survival of one does not  imply survival of the other. Suppose you, as you are now according to local  observation, also exist at a great distance in space or time (either past or  future), just by accident. I see no reason for the survival of B to imply the survival of A.” (Cryonics Institute Mailing List, September 16, 2010)


Robert Ettinger presented a number of distinct arguments (no fewer than fifteen, by his own count!) against mind uploading and I cannot pretend to have presented them all in this document. I think there are a number of core positions associated with Ettinger’s argument that can be stated quite succinctly, however.

  1. Whether mind uploading is possible is ultimately an empirical question and cannot be settled conclusively by analogies or thought experiments.
  2. A description of a material object is not necessarily the same as the object.
  3. A simulation must be erroneous because the program necessarily is based on our incomplete knowledge about physics.
  4. Consciousness may be substrate-dependent.
  5. A copy of a person may not constitute personal survival.

The common denominator that runs through Ettinger’s critique of substrate-independent minds is a thorough empiricism about knowledge. Ettinger does not categorically rule out the feasibility of mind uploading but takes people to task for dogmatic claims on these topics in absence of empirical corroboration.

Ettinger was particularly irritated by the claim that materialism commits a person to the acceptance of mind uploading. He could not see how a rejection of the soul excludes the view that certain materials are uniquely suitable, or even exclusively suitable, for a certain function. One might add that it is even conceivable that the mind is substrate-independent but that existing organic chemistry provides the most versatile basis for advanced consciousness and survival.

Most of the issues that Ettinger was concerned about may be resolved by the time he will be resuscitated but it is possible that some of the issues that are at stake in this debate are ultimately un-falsifiable or even pseudo-problems. For example, how could we settle the question of whether a copy is “really you?” Obviously, a copy of something will always confirm that (s)he is really him- or herself but that is of little help in resolving the question. Similarly, we may never be able to conclusively verify (or falsify) that a computer has consciousness or feelings. Is it even conceivable that new super-intelligent life forms will replace humans without being conscious or having feelings! Evolution selects for fitness, and whether this implies consciousness is an open question.

So who is right, Robert Ettinger or his critics? I think what captures Ettinger’s perspective the best is to say that if you expect an answer right now, you have not paid close attention to his argument.

11. October 2014 · Comments Off on Symposium on Cryonics and Brain-Threatening Disorders Report · Categories: Cryonics, Neuroscience

Cryonics MagazineSeptember-October 2012

On Saturday, July 7, 2012, I attended the Symposium on Cryonics and Brain-Threatening Disorders in Portland, Oregon. The symposium was the “brain child” of Aschwin de Wolf, who also kindly invited me to give a presentation on treatments to mitigate Alzheimer’s Disease (AD). The symposium was organized by the Institute for Evidence-Based Cryonics and Cryonics Northwest.

It has been said that cryonics arrangements are made by people who think about things other people would rather not think about – in this case, one’s personal mortality. Like the sun in the sky, we can be aware of its presence, but prefer not to look at it. Dementia is in the same category. Despite the fact that anyone who lives long enough (cryonicists are usually life-extensionists) is much more likely than not to get dementia, even cryonicists are often reluctant to plan for becoming demented. Aschwin deserves a lot of credit for not only being a cryonicist, but for organizing (with his wife Chana) the world’s first symposium/conference dealing with the subject of cryonics and dementia. It is all the more impressive because Aschwin is a man in his 30s.

The symposium required no registration, registration fee, or notification of attendance. One man attended because another attendee had informed his wife of the event while on an airplane to Portland. There were only about 30 people at the event, but the quality of the attendees and presenters was very high. The event was held at Kaos Softwear, a manufacturing company where Chana is a manager. All the talks were allotted one full hour.

Chana, who has a master’s degree in neuroscience, was the first presenter. Her topic was neurogenesis — the creation of new neurons. Although neurogenesis was discovered in 1965, because neurons are post-mitotic (are non-dividing cells), the discovery was viewed with skepticism until the discovery of neural stem cells in 1992. Neurogenesis only occurs in two discrete areas of the mammalian brain: in the olfactory system and in the hippocampus. The latter is more crucial, although the exclusion of the cerebral cortex is of great concern insofar as that is the probable location of memory, identity, and decision-making. The hippocampus prepares new memories for long-term storage in the cerebral cortex. Chana asked lots of questions for which there are yet no answers. Why does the hippocampus need to create new neurons in the creation of new memories? How is neurogenesis used? How is neurogenesis regulated? Neurogenesis declines with age, and is enhanced with exercise or ischemia. Ultimately, endogenous neurogenesis does not appear to hold much promise as a repair strategy for AD or other forms of dementia. However, it is a worthwhile endeavor to understand neurogenesis in order to guide our own attempts at neuronal repair and/or replacement.

Aubrey de Grey began his talk by acknowledging that none of the work being funded in the 2012 $4.5 million budget of his SENS (Strategies for Engineered Negligible Senescence) Foundation is focused on repairing the brain, although there is a project determining the rate of accumulation of epimutations, that is not focused on repair. He spent the first half-hour reviewing the SENS program, and the next 15 minutes explaining why 3 of the 7 SENS strategies are particularly applicable to dementia: (1) Neurofibrillary tangles and soluble amyloid in Alzheimer’s disease (AD), and their counterparts in other neurodegenerative diseases, are intracellular junk, (2) amyloid plaque in AD is extracellular junk, and (3) late-stage neurodegeneration involves cell loss. Dr. de Grey said that intracellular junk shows signs of failed autophagy. He said that most of the intracellular junk in dementia is protein. It should be easier to dispose of than the cholesterol degradation products which are the focus of SENS lysosome work on atherosclerosis, but which are not properly delivered to the lysosome. He outlined the circumstantial evidence that the main problem may be the same as in atherosclerosis, i.e. oxidized cholesterol poisoning the lysosome. He spoke of the current clinical trials for having microglia eliminate extracellular junk (amyloid plaques). The first human clinical trials had shown great promise, but were halted because 5% of the patients developed brain inflammations. The newer trials have apparently corrected that problem. Aubrey noted the widespread belief that the amyloid would be removed without being of much benefit – expressing his belief that this misses the point, because major postponement or reversal of AD will require fixing all three main problems, hence lack of benefit from fixing one is not evidence that that one need not be fixed. I am one of the skeptics because follow-up autopsies on the first trials showed that even when amyloid plaques had been completely removed, no reduction in degeneration had occurred [THE LANCET; Holmes,C; 372:216 (2008)]. By the time AD is diagnosed, neurodegeneration is too far along to be helped by removing amyloid (though there is rapid progress in improving very early diagnosis). Immunization to remove amyloid would be more effective if begun in the 20s or 30s, much like shots for measles or polio — as prevention rather than cure. Although amyloid may serve a positive function in repair or it would not have evolved. [Aubrey notes: who says it evolved? “Aging is a product of evolutionary neglect, not evolutionary intent” (Hayflick)]. Concerning cell loss, Aubrey was sanguine about Jean Hebert’s work exploiting the fact that certain neural progenitor cells are highly migratory, potentially facilitating widespread distribution of new neurons throughout the neocortex via stem cell therapies. Even if neurons can be replaced in the neocortex, I wonder how that would compensate for the loss of synaptic connections and strength of synaptic connections. Of the three approaches mentioned by Dr. de Grey, I would say that removal of intracellular junk has the best chance of being of benefit on its own, because it is the neurofibrillary tangles that tend to cause cell death rather than the amyloid plaques, which are an upstream event.

My talk was basically a summary of the “Alzheimer’s Disease: Molecular Mechanisms” page in the life extension section of my website BENBEST.COM. I wrote the page in 2003 between leaving my job as bond database support for Scotiabank in Toronto, Canada, and becoming president of the Cryonics Institute in Michigan. For the subsequent 9 years I have become increasingly displeased about how out-dated the webpage was becoming. So I was pleased at the opportunity to do the massive research required to update that webpage for this symposium. Unfortunately, it was all I could do to finish the updating before catching my flight to Portland. Aschwin and Chana allowed me to crash at their condominium. I missed the Friday evening social for those attending the symposium because I spent all evening and a couple of hours the next morning creating my PowerPoint. I was pleased with the result, however, and pleased with the presentation I was able to deliver.

I encourage anyone interested in the content of my talk to consult my Alzheimer’s webpage because that page has detailed linkable references which I could not include in my presentation. I believe that the most promising therapy is the targeting of copper with PBT2, which removes copper from amyloid without chelating essential element metals. Etanercept, which antagonizes the inflammatory cytokine TNF-alpha has also shown promising results. Possibly also, passive immunization with tau antibodies would be of greater benefit in stopping neurodegeneration than immunological approaches against amyloid. Concerning prevention, exercise, curcumin, pomegranate juice, and folic supplementation have shown good results. Seemingly conflicting results would indicate that ginko biloba can slow cognitive decline in Alzheimer’s patients, but is of no benefit in preventing the disease.

Mike Perry’s topic was Early Detection of Alzheimer’s Disease. On that subject he reported that the CerebroSpinal Fluid (CSF) is low in amyloid beta and high in phosphorylated tau protein. I had put much more detail on this subject into the biomarkers section of my webpage on Alzheimer’s Disease – which I showed to Mike later in the day. In his presentation Mike noted even for people who do not get AD, dementia of some kind is still very probable with aging. He commented that AD is not a terminal illness, which is defined as an illness in which two physicians have certified that the patient probably has no more than six months left to live. No AD patient dies of AD — the cause of death is usually infection (pneumonia, bedsores, urinary tract infection, etc.). I expressed concern that suicide by VSED (Voluntary Stopping of Eating and Drinking, as Mike calls it) by an AD victim could lead to autopsy. Mike denied that this was necessarily the case.  I was told that for anyone who had died by refusing food and water the cause of death would be obvious, and no autopsy would be required, though circumstances and policies will vary. Mike Darwin, however, noted that VSED could be harmful to the brain as cardiac arrest draws near, due to low respiration rates. Aschwin responded that this kind of brain damage is still relatively benign in comparison to the alternative (advanced dementia). James Swayze, who is a paraplegic with cryonics arrangements and was in attendance at this event, has expressed concerns that dehydration causes brain damage. Dehydration may reduce brain functionality, but brain dehydration is a key process in removing water from the brain in the vitrification point of view and is probably a benefit rather than a harm for cryonics purposes.  Alzeimer’s patients nearly always die of infection, and because infection may also occur early in the disease,  Mike Darwin recommended that anti-microbial treatment be refused by an Alzheimer’s victim as a way of hastening cryopreservation. If infection does not occur early in the disease, however, refusing antibiotics may not produce the desired result.

Keegan Macintosh, who recently graduated from a Canadian law school, presented on the subject of Thomas Donaldson’s 1988 lawsuit in California to be cryopreserved before his brain cancer destroyed too much of his brain to make cryonics a worthwhile effort. Keegan criticized the attorneys involved in the appeal for arguing that Donaldson’s right to “premortem cryopreservation” stemmed from a constitutionally-protected right to assisted suicide, rather than the right to pursue a risky, but potentially life-saving procedure. By framing the case this way, the Court was able to avoid having to consider Donaldson’s unique and crucially relevant motive, and thus the possibility of cryonics succeeding, for him or anyone else. Acknowledging, however, that options for assisted suicide could be of use to cryonicists with brain-threatening disorders, Keegan examined developments in American law on the issue, and then turned to Canadian jurisprudence. He pointed out a number of potentially significant differences between the U.S. Supreme Court’s substantive due process analysis in the more recent physician-assisted suicide cases, Washington v. Glucksberg and Vacco v. Quill, and Supreme Court of Canada’s approach to section 7 of Canada’s Charter Rights and Freedoms (right to life, liberty and security of the person) in Rodriguez v British Columbia, and cases since. The government’s position is presumably influenced by a desire to avoid a “slippery-slope” that disvalues human life. Keegan noted that although formerly other countries looked to the American Constitution for guidance, Canada’s constitution is now the world’s most popular role-model. Section 2 of Canada’s Charter of Rights and Freedoms emphasizes “freedom of conscience and religion.”

What would be the effect of someone acting on the belief that pre-mortem cremation is the road to salvation? “Freedom of conscience” implies that secular morality is as important as religious belief and there is some emerging jurisprudence to that effect. Would the belief that good-quality cryopreservation is necessary to live again at some future time not then receive equal protection to analogous beliefs and practices of religious origin? Keegan believes that an appeal such as Donaldson’s – and indeed any constitutional challenge against a law impeding access to cryonics – would have a better chance of success in Canada than in the United States.

Max More spoke without slides on the subject of “Survival, Identity, and Extended Mind.” The objective of Max’s talk was to consider how it could be possible to back-up personal identity-relevant information and then reintegrate that information to restore personality if cryopreservation has been imperfect. If cognitive processes and their inputs can be external to the brain, Max would like to take advantage of this to improve the chances of reviving people suffering from brain-threatening disorders. Andy Clark and David Chalmers wrote an authoritative paper entitled “The Extended Mind.” According to Max, for an outside object or process to be considered part of the mind, it has to produce results that are reasonably comparable to the components normally seen internally and biologically/neurologically. Clark and Chalmers propose three conditions for considering externally-located processes to be part of an individual’s cognitive processes: 1) constancy (the external component has to be there reliably); 2) accessibility (a natural ease of use of that component); and 3) automatic endorsement (the person must trust the component as they would trust any comparable part of their natural body). Max noted that a few years before the Clark/Chalmers paper he had considered the related issue of when an external technology could be considered part of the self (in chapter 4 of his dissertation: “Technological Transformation and Assimilation”). Although Max doubted Ray Kurzweil’s claim that an externally-convincing simulation of his father (made out of traces available) would actually have a self, Max did not argue that no well-simulated person could have a self. Max suggested that a notebook could be part of the thinking process, rather than just a tool. Nonetheless, he was dubious about the value of keeping lots of diaries, although it has been suggested that biographical information could assist in reconstruction of a cryonics patient and that cryonics organizations should take a more proactive role in fasciliting storage of identity- and memory relevant information. Max was also dubious that a computer that could convincingly simulate a person would have a self. He raised the question “What is self?” He referred to David Hume’s claim to introspectively only be able to discover thoughts and feelings, but no self. Dennett called self an illusion. This would lead me to believe that neither Hume nor Dennett should have much concern with their own survival (like most people?). Max said that he could lose a few memories without feeling his self was compromised — because he believes that personal identity is more than memory. It includes dispositions, values, and so on.

After the presentations there was a panel of all the presenters, plus Aschwin the host. I requested that each panelist explain what they would do if diagnosed with AD. Aschwin said he would immediately proceed to terminate his life under conditions favorable to cryopreservation provided that the diagnosis was credible and there are no short-term cures on the horizon. Keegan said that he would see first what, if any, time he had before symptoms such as apathy and denial would be expected to set in, and take some conservative portion of that time remaining to spend some quality time with family and friends. Keegan noted that, despite our best efforts, cryonics may not work, and thus it is rational to seek meaningful experiences in the moments one knows they have left, if such can be done without irreparably compromising one’s cryopreservation. I noted that Robert Ettinger also said he would terminate life by hypothermia in a cold bathtub at the end of a party with friends – but delayed such an action to the point where he lost consciousness and lost the ability to do any such thing at the age of 92 when he deanimated. I said that I would probably spend about a year attempting to confirm the diagnosis, and might delay further trying to determine if a cure was possible or forthcoming soon. Max said that he would want a second opinion, but like Keegan wanted to have some joyful time before self-termination. Chana said that she would be very concerned about how the decision to self-terminate would affect others, in particular how to explain to her family why she was ending her life while outwardly being in good health. Chana and Aschwin spoke of being sensitive to each other’s feelings about the matter. Aschwin noted that those who care for AD family members to a natural death often suffer from severe caregiver depression. Chana said that once she had decided to pull the plug that she would “find a way to take a bath in Agent Orange and take advantage of Oregon laws.” By this she meant she would find a way to give herself an aggressive form of cancer that would cause two Oregon physicians to declare that she is a terminal patient. Once this is done, an Oregon physician can write a prescription for phenobarbital which the patient can use for suicide by overdose at the time and place of their choosing. Aubrey said that he would delay the decision without worrying too much about loss of neurons. In addition to delaying because of diagnosis confirmation and evaluating hope for a cure within a short time period, Aubrey added evaluating the likelihood that cryopreservation procedures would be improved by waiting. Mike Perry said that he would try to confirm the diagnosis and if sure about it, “get it [deanimation] over with as soon as possible.”

I mentioned the case of a CI Member dying of cancer who, with her husband, called Suspended Animation, Inc., to be present at their suicide. Her 30-year-old husband was in good health, but did not want to live without his wife and planned to die along with her. CI terminated both their memberships and established a policy of reserving the right to cancel cryonics contracts in cases of suicide. Aschwin strongly disapproved of this CI policy. In his opinion, cryonics organizations should never encourage or condone suicide but should not refuse cryopreservation to those who have taken their own lives. I believe cryonics organizations cannot be seen as encouraging the hastening of death on the ground that cryonics may work, and must ensure that others do not get that impression. Not enough was said about what policies would be most appropriate for cryonics organizations.

I asked Aubrey if he thought that an AD patient would ever be so advanced that SENS could not save the self. Aubrey agreed that could happen, but it would be difficult to say when. The case is similar with straight frozen patients or patients with varying amounts of ischemic damage. The concept of “information theoretic death” is meaningful, but difficult to determine. Even if SENS methods could not recover enough memory and identity to save a person, some future molecular archeology might be able to do so.

There was some discussion about the most promising treatments for Alzheimer’s disease. Aschwin pointed out that both early-onset Alzheimer’s and late onset Alzheimer’s have a strong genetic component, which should favor the use of gene therapy.

Mike described the activities of the Venturists, which is offering to save Venturist Members who are being cryopreserved by a cryonics organization that fails. Another project of the Venturists is that they are seeking $50,000 for Mike Darwin, who lost his cryopreservation arrangements with Alcor due to financial difficulties.

04. October 2014 · Comments Off on Connectome: How the Brain’s Wiring Makes Us Who We Are · Categories: Cryonics, Neuroscience, Science

Connectome: How the Brain’s Wiring Makes Us Who We Are by Sebastian Seung, Houghton Mifflin Harcourt Trade, 384 pages, 2012.

[This review originally appeared in Venturist News and Views, June-July 2012, 6-7 and Cryonics, September-October 2012]

The scientific perspective that informs Sebastian Seung’s bestselling popular neuroscience book Connectome is so familiar to cryonicists that the bulk of this book could be mistaken for an extensive introduction to the philosophy of mind embodied in cryonics. His book offers a rigorous exposition of the view that our identity is encoded in the connections between neurons, the “connectome,” which itself is shaped by our genes and life experience. The strength of this book is not only its review of the empirical evidence that supports this outlook but its encouraging the reader to think about its implications.  Readers who are intimately familiar with the argument in favor of cryonics should not assume that there is little to learn from this book. As imaging and storage technologies evolve, cryonicists can do more now than in the past to learn about their individual connectome, strengthening the likelihood of successful resuscitation.

One important element of the connectionist premise that structures Seung’s book is that it does not completely resolve competing theories about how the brain works. For example, the recognition that long-term memory (and identity) does not depend on transient electrical activity but has a more robust long-term physical basis that persists during cessation of brain activity (examples are hypothermic circulatory arrest and short periods of cardiac arrest) does not imply a single perspective on how the genome provides the neurological bases for memory formation, retention, recollection, and re-prioritization. One interesting perspective, “neural Darwinism,” which was anticipated by the multi-talented classical-liberal economist Friedrich Hayek, proposes a theory of brain function in which a genetically determined wiring of the brain is subject to competing experiences that strengthen or weaken populations of synapses throughout life. One of the interesting implications of this theory is that consciousness can be treated as an emergent outcome of micro-events in the brain, instead of a mysterious, autonomous property of the brain (think of the curious concept of “free will”).

Seung devotes two chapters to the nature-nurture debate through a connectionist perspective. One of the unfortunate effects of the nature-nurture distinction is that it masks the obvious point that what we call “nurture” (upbringing, environment, etc.) is not exempt from biology but simply concerns the relationship between biological systems and between a biological system and its physical environment. Social scientists who have a strong “nurture”-bias should therefore not be exempted from describing “nurture” in verifiable physical terms, something that many of them do not feel the slightest obligation to do. Another unattractive feature of this debate is that it is routinely portrayed as one between genetic determinists and “environmentalists.” In reality, the debate is mostly between serious scholars who acknowledge that behavior and learning are shaped by both genetics and the environment and those who basically consider the mind a blank slate—a position that is clearly contradicted by existing science but remains popular as a premise in contemporary public policy and certain political ideologies. One of the interesting topics that Seung discusses in these chapters is whether the plasticity of the brain changes over time.

From the perspective of cryonics, the relationship between the genome and the connectome is of great importance. If some of the basic wiring of the brain that encodes personality and temperament is determined by genes and is fixed (or mostly fixed) at an early age, then some parts of the connectome might be inferred from a person’s genome, which opens up an exciting research program for cryonics. A systematic study of the field where genetics meets neurodevelopment might help in understanding the relationship between the genome and brain ultrastructure. This in turn could assist in future resuscitation attempts. To date, the assumption in cryonics has been that the complete ultrastructure of the patient must be preserved (or at least preserved in such a manner that it can be inferred), but if some of it can be inferred from the genome the repair requirements for resuscitation of cryonics patients may be relaxed. Looking for such invariable features in variable brains is an important element of a credible cryonics resuscitation research program.

The power of comparing connectomes is also recognized by Seung in a separate chapter (“Comparing”). There he reviews technologies and approaches to compare connectomes with the goal of understanding personality differences and understanding neuropathologies or “connectopathies.” This chapter is one of several in which the author reviews the existing and emerging technologies that are enabling us to produce a complete connectome, including the innovative equipment of cryonicist and Alcor member Kenneth Hayworth to perform serial electron microscopy. Also discussed are technologies such as diffusion MRI (dMRI), which allows for non-invasive mapping of the connectome at the macro scale using water as a probe. This technology may not be adequate to map the connectome at the cellular level but its contribution to comparative connectomics has already been recognized. It may also hold promise as a means to collect identity-critical information about an individual while alive, which again may lessen the computational challenges involved in cryonics resuscitation. One of the exciting prospects of the field of connectomics is that it can contribute to a further narrowing of the challenges involved in restoring cryonics patients to good health.

Seung closes his chapters on emerging technologies with a review of the prospects of connectomics for the treatment of neurological diseases. One of the potential treatments involves the re-programming of a person’s own (skin) cells to neurons, which can then be introduced in the brain to treat a disease or enhance brain function. Such an approach may also be used to fill the “missing gaps” in the brain of a cryonics patient (alternative technologies include molecular construction of neurons by advanced molecular nanotech­nology).

At this point, I think we can foresee a rather optimistic future for cryonics research and the prospect of resuscitation. Instead of conceptualizing cryonics as the preservation of clinically dead people in the hope that future medicine can restore these people to good health, we can envision a more complex, but more encouraging, path. The work of resuscitation and restoring identity is not something that is expected to occur exclusively in the future but rather will be an ongoing process that starts as soon as the patient is cryopreserved. And with the rise of advanced genomics and non-destructive imaging technologies, some of the initial work can be done while the person is still alive. One of the exciting aspects of being a cryonicist today is that you can take proactive steps to learn about your own connectome and other identity-relevant information.

Seung devotes no less than a whole chapter to human cryopreservation (and the associated idea of chemopreservation). The author recognizes that his own views about the connectome are so similar to the philosophy of mind that underpins cryonics that he needs to do some justice to the rationale of cryonics. One unfortunate aspect is that he situates his discussion of cryonics in the context of religion and immortality. It is undeniable that some cryonicists are motivated by visions of personal immortality but this idea is not intrinsic to cryonics (neither is mind uploading or transhumanism.) Properly conceived, cryonics is an experimental medical procedure that aims to stabilize patients at cryogenic temperatures in anticipation of future treatment. What really distinguishes cryonics from mainstream medicine is not uncertainty (which is a fact of life), but the temporal separation of stabilization and treatment. One regrettable implication of attributing religious motives to people who make cryonics arrangements is that it cheapens the use of the word ‘religious.’ Instead of referring to worship of a higher being, it is here used as a strong belief in something in the absence of conclusive evidence. But by putting the bar so low, Seung (unintentionally) classifies many aspects of life, including choosing novel experimental treatments in mainstream medicine, as “religious.”

At one point Seung writes that research aimed at demonstrating that contemporary vitrification technologies can preserve the connectome will “finally bring some science to Ettinger’s wager.” This is a remarkable statement because even the earliest arguments in favor of cryonics were never presented in the form of a pure wager. In his book The Prospect of Immortality, Robert Ettinger reviews existing evidence from cryobiology and neuroscience and argues that, combined with the expectation that medicine will continue to evolve, the choice to be cryopreserved is a rational decision. Since Ettinger’s book cryonics organizations and wealthy donors have expended a lot of money and time in perfecting preservation techniques and looking at the effects of new technologies on the structure and viability of the brain.  Compared to the state of, let’s say, interventive biogerontology, the scientific progress that has been made in cryonics is not trivial. For example, it is doubtful whether the widespread adoption of vitrification in mainstream cryobiology would have been possible without sustained research into using this approach for complex organs by cryonics supporters. To my knowledge, cryonicists have always been quite eager to generate experimental knowledge to inform their decision making. Now that more advanced technologies to map the human brain are becoming available, cryonics organizations are eager to use them instead of just passively maintaining their “faith.”

Ultimately, Seung still fails to recognize that cryonics inherently involves an element of uncertainty that cannot be eliminated without it not being cryonics anymore (i.e., elimination of uncertainty makes it suspended animation). For example, the author recognizes that it is not necessary for a preservation technology to perfectly preserve the connectome as long as it remains possible to infer the original state (or missing information) from what has been preserved. We can speculate what the limits of such “neural archeology” will be, but I do not think anyone can make conclusive arguments. In this sense, cryonics cannot be completely moved from the realm of informed decision making into the realm of indisputable fact. An element of uncertainty will always be associated with it, even if the experimental evidence in favor of this medical procedure keeps mounting.

The author also discusses alternative preservation approaches such as chemical fixation and plastination. One major disadvantage of existing chemical preservation technologies is that they are irreversible by contemporary techniques (literally a “dead end”) and they do not allow for viability assays to distinguish between worse and better preservation techniques. In contrast, in cryobiology, evidence of good ultrastructural preservation is often a starting point (or independent corroboration) to identify cryoprotectants that are able to store complex organs at cryogenic temperatures and restore them without loss of viability. There is one other formidable challenge that will inevitably arise if chemical preservation is offered as a means of personal survival. It is how to deal with the fact that if chemical fixation is delayed perfusion impairment will prevent complete cross-linking of biomolecules. Even more so than cryonics, chemopreservation requires that the procedure be started prior to, or immediately following, circulatory arrest. In absence of this, the fate of a person’s connectome is uncertain, and may even worsen during storage—a problem cryonics is exempt from.

The book ends with a chapter about mind uploading. One misconception about cryonics is that people seek it as a means to mind uploading, or that reviving the person in a computer is the aim of cryonics. In fact, the late Robert Ettinger became a vocal critic of mind uploading in his final years. He offered a lot of arguments for his skepticism but his main concern was that questions about the feasibility of mind uploading are ultimately empirical questions which cannot be settled by deductive reasoning and dogmatic claims about the nature of the mind or consciousness. One of the amusing aspects of the debate about mind uploading is that proponents and skeptics both accuse the other of not being consistent materialists. Interestingly enough, Seung makes an observation relevant to this debate when he writes how the idea that “information is the new soul” is implied in the mind uploading project.

Despite some misgivings about how Seung presents and conceptualizes cryonics, I am unaware of another book that offers such a clear exposition of the relationship between brain and identity that informs human cryopreservation (and chemopreservation). The most rewarding thing for me was a stronger recognition that the idea of the connectome is not just a premise but opens the door to multiple fruitful research programs aimed at personal survival.

About the Author: Sebastian Seung is Professor of Computational Neuroscience and Physics at MIT and Investigator at the Howard Hughes Medical Institute. He has made important advances in artificial intelligence and neuroscience. His research has been published in leading scientific journals and also featured in the New York Times, Technology Review, and the Economist. (From the dust jacket.)

Dr. Seung was also a speaker at the Alcor-40 conference in October 2012