About Josh Mitteldorf

Josh Mitteldorf studies evolutionary theory of aging using computer simulations. The surprising fact that our bodies are genetically programmed to age and to die offers an enormous opportunity for medical intervention. It may be that therapies to slow the progress of aging need not repair or regenerate anything, but only need to interfere with an existing program of self-destruction. Mitteldorf has taught a weekly yoga class for thirty years. He is an advocate for vigorous self care, including exercise, meditation and caloric restriction. After earning a PhD in astrophysicist, Mitteldorf moved to evolutionary biology as a primary field in 1996. He has taught at Harvard, Berkeley, Bryn Mawr, LaSalle and Temple University. He is presently affiliated with MIT as a visiting scholar. In private life, Mitteldorf is an advocate for election integrity as well as public health. He is an avid amateur musician, playing piano in chamber groups, French horn in community orchestras. His two daughters are among the first children adopted from China in the mid-1980s. Much to the surprise of evolutionary biologists, genetic experiments indicate that aging has been selected as an adaptation for its own sake. This poses a conundrum: the impact of aging on individual fitness is wholly negative, so aging must be regarded as a kind of evolutionary altruism. Unlike other forms of evolutionary altruism, aging offers benefits to the community that are weak, and not well focussed on near kin of the altruist. This makes the mechanism challenging to understand and to model. more at http://mathforum.org/~josh

Politics Influences the Science of COVID-19

Many of us are still shell-shocked by the changes in our lives that have been imposed this spring. We’re reacting to each unexpected event as it comes. But to anyone who has stepped back to make sense of this web of contradictory messages that pour out of our newsfeeds, it is clear that the government agencies and corporate news media are slanting their message toward fear. I am particularly concerned when they do this at the expense of honesty. This is a moment for the scientific community to be engaging in spirited dialog among diverse voices. Only with open debatei can we hope to shed light to guide the momentous public policy decisions that are being made, directing our culture and global economy into unexplored territory. But instead of robust debate, what I see is a monolithic message, and censorship of the few brave scientists who dissent from that message. I’m ashamed to say that the scientific community has been part of the problem.


I’m writing here about two issues: 

(1) Numbers reported by CDC have been gamed to make it appear that America is in the second wave of a pandemic. Instead of reporting COVID deaths, they began reported COVID cases. Then they conflated recovered individuals (who test positive for antibodies) with current cases (who test positive for the active virus). No wonder numbers are rising!

(2) A new report featured prominently in Nature purports to show that lockdowns have stemmed the spread of the virus and have saved lives. The article is by the same team whose flawed models produced apocalyptic predictions last March that justified lockdowns in Europe and the US. The new computer model assumes from the start that the number of COVID deaths would have expanded exponentially from their March levels, and that social distancing is the only factor responsible for lower death rates. That is, it assumes exactly what it purports to prove. Where is accountability? Why is this perspective promoted in the world’s most prestigious journal, while reasonable doubts are swept aside?


Part One—CDC reporting

The global death rate from COVID-19 is down to about 4,000 per day. It is not even among the top ten causes. COVID is lower than traffic deaths, lower than diarrhea. Even compared to other respiratory infections, COVID is now a minority.

In the US, daily COVID deaths peaked in April, and are now down to 1/10 the peak rate, at about 400/day. COVID is now the sixth leading cause of death in America, but it no longer registers as a bump in total mortality.

But the headlines claim we are in the midst of a “second wave”, based on reported numbers of cases.

Deaths from COVID are being over-reported. Hospitals are incentivized to diagnose COVID with Medicare reimbursement rates that are higher than other diseases, and guaranteed coverage from every major insurer. Doctors are being instructed to report COVID as a cause of death when no testing is done, and when chronic illnesses contributed to the outcome. And with all this, the number of deaths continues to fall, even as the reported number of cases is rising. Why is this?

In part, the lower fatality rate is real. Doctors are learning from experience how to treat the disease. More chloroquine and zinc, less intubation. Like all viruses, this one is evolving toward greater contagion and lower lethality. But the most important explanation is an artifact in the way COVID cases are being reported. Before May 18, the “case count” was based on tests for the live virus, and counted only sick people. Then the definition was changed to count both people who tested positive for the virus and for antibodies to the virus. The latter group is mostly people who have recovered from COVID, or who developed antibodies with exposure. As the number of recovered patients increases, of course the rate of positive tests will increase.

Part Two—Models that “prove” lockdown has saved lives

In the past, Neil Ferguson’s group at Imperial College of London has produced scary computer models that overestimated the epidemics of Mad Cow Disease, Avian Flu, Swine Flu, and the 2003 SARS outbreak. In March, his group’s computer model was justification for England, Europe and America to shut down economies, prevent people talking and meeting, prohibit concerts and theater and church and every kind of public gathering, throw tens of millions of people out of work, deny the rights to freedom of assembly that are fundamental to democratic governance. His manuscript was not even peer reviewed, but only posted on a university server. Even before its details and assumptions were made known, the integrity of the model was assailed by other experts, including Stephen Eubank (UVA Biocomplexity Institute) and Yaneer Bar-Yam (New England Complex Systems Inst). After details of the assumptions were revealed at the end of April, the model was widely scorned by real experts (e.g. Andrew Gelman) and self-appointed pundits (Elon Musk).

I have enough experience with computer models to know that results are often highly leveraged with respect to details of the input. Sensitivity analysis is essential for interpreting results, but is almost never done. Too often, the output is reported without the qualification that small changes to the input produce very different results.

Against this background, the high-profile publication in Nature of Ferguson’s recent work is suspicious. I would have thought he had no credibility left among serious modelers of epidemiology, but I have ceased to be surprised when politics trumps competence for access to the most prestigious publication venues.

The Ferguson Article Vindicating Lockdown

They analyze spread of COVID in 11 Eurpoean countries this Spring, averaging over different countries but not contrasting the different local strategies. They take death counts as surrogate for case counts because reports of case counts are even more unreliable than death counts. But (one of several crucial failures) they don’t apply a time lag between death counts and case counts.

They take as input for each country the dates on which each of three different isolation strategies was implemented. They assume that the virus would have spread exponentially but for these measures, and credit the isolation measures with the entire difference between reported death rates and the theoretical exponential curve.

They conclude that Europe has dodged a bullet, that less than 4% of people had been infected, and by implication the lockdown has saved the other 96%. They imply but don’t state explicitly that there would have been about 4 million deaths in Europe instead of ~150,000 reported when the paper was written.

It is obvious that lockdown and social isolation slow the spread of the disease, but not obvious that they affect the eventual reach of the disease. Thus it is an open question whether the public policy prevented or only delayed deaths from COVID. This question can be addressed most directly by comparing regions that were locked down with regions that remained open. Instead of doing this, the Ferguson group lumped all regions together and compared their results with an unrealistic scenario in which the exponential curve would have expanded to infect every susceptible person in Europe.

Two schools of thought

There are fundamentally two hypotheses about the epidemiological events of this spring: Either the number of people exposed has been high and the fatality rate low, or else the number of people exposed has been low and the fatality rate higher. People in the first camp argue that the exposed population is over 50% in Europe and America, approaching or exceeding herd immunity, and the population death rate is in the range 0.0005. In the second camp, people estimate the population exposure about ten times lower (5%) and the fatality rate correspondingly higher (0.005).

The story told by people in the first camp is that social distancing slowed but did not prevent transmission of the disease through the population. By now, the presence of the virus is waning because people in many places have already been exposed.

The story of Ferguson and others in the second camp is that social distancing actually stopped spread of the virus, so that most people in Europe and American have never been exposed. It follows that if we ease restrictions, there is another wave of infections ahead, potentially 20 times larger than the first wave.

The deep flaw of the recent Ferguson paper is that his team does not consider the first scenario at all. Built into their model, they assume that population level immunity is negligible, and the only thing that has slowed spread of the virus has been social distancing. This is where they put the rabbit in the hat.

If they had considered the alternative hypothesis, how would it have compared?

To choose between the two hypotheses, we might compare a region before and after lockdown, or we might compare regions that locked down with regions that didn’t.

In a preprint response to Ferguson, Homburg and Kuhbandner do a good job with the first approach. They take Ferguson to task for not considering the immunity that spreads through the population along with the disease. They show that exponential expansion had already slowed in England before the effect of the lockdown on mortality data could have been felt.

Lockdown went into effect in Britain on March 23. If lockdown had a benefit, it would be in preventing new cases, and its effect on the death rate would show up about 23 days later (April 14), because 23 days is the median time to fatality for those patients who die of COVID. In the graph, we see that the death rate had already leveled off by April 14.

On this log graph, an exponential increase would appear as a straight line sloping upward. It’s clear that the exponential expansion phase ended long before the lockdown could have had any effect. Not only weren’t the numbers expanding exponentially, but the death rate had already started to decline before April 14, when the effect of lockdown was expected to kick in. The authors state they performed the same analysis for 10 other countries in the Ferguson study with similar results, though they show the graph for Great Britain alone.

“We demonstrate that the United Kingdom’s lockdown was both superfluous and ineffective.”
[Homburg and Kuhbandner]

Here in the US, there was a natural experiment when people emerged into the streets to protest racism and police brutality at the end of May. Social distancing in this environment has been impossible. Allowing for a 23-day lag, we should have seen a surge in US mortality starting mid-June. In the plot below, there appears to be a leveling off of the death rate since mid-June, but no new disaster. This alone is strong evidence that US has substantial herd immunity, and that most of the population has already been exposed to the virus.

A second way to distinguish between the two hypotheses is to compare regions that locked down with regions that didn’t. One of their 11 European countries was Sweden, where the economy was kept open and quarantine was limited to people who were symptomatic with COVID. It is a glaring defect in the Nature paper that Sweden is lumped in with the other ten countries when it should have been contrasted. In fact, the mortality curve for Sweden was typical for the other ten countries, even as commercial and cultural institutions in Sweden continued normal operations. Sweden has had a higher death rate than Austria, Germany, France, and Denmark, but lower than Belgium, Italy, Spain, or UK. There is no evidence that Sweden’s COVID mortality was higher for having bucked the trend to remain open, but some indication that Germany and Austria had particularly effective containment policies.

We can ask the same question of the different states in the USA. Comparing death rates from COVID in the 42 states that locked down with 8 states that did not lock down, this article finds that the death rates in locked down states was 4 times higher. (Caveat: there was no correction for urban vs rural or for demographic differences.) The author concludes, “With the evidence coming in that the lockdowns were neither economically nor medically effective, it is going to be increasingly difficult for lockdown partisans to marshal the evidence to convince the public that isolating people, destroying businesses, and destroying social institutions was worth it.”

I’ve prepared a comparison of all states ranked by COVID mortality which you can view here.

The Politics of COVID

In 1933, Roosevelt told America we had nothing to fear but fear itself. It is common for government leaders to dispel panic because they know that a nation can better thrive when people feel confident and secure. Even G.W. Bush responded to the terror attacks of 9/11 by telling the American people, “keep shopping.” On the other side, despots sow fear in their subjects when they want to consolidate autocratic power, and when they want to stir up fervor for war.

It is clear from messaging in the corporate media that the COVID pandemic is being hyped to create more fear than is warranted.

  • The fatality rate was vastly overestimated initially, and even now is probably overestimated at 0.002 to 0.005
  • Doctors were told to report deaths from COVID without proof that COVID was the cause
  • Reimbursement incentives for hospitals to diagnose COVID
  • Repeated warnings of a second wave, etc, which has not materialized.
  • Suppression of tests for well-studied, cheap treatments (chloroquine) while jumping into large-scale tests of vaccines that have not yet been tested on animals.
  • No mention of vitamin D, which is a simple, cheap, and effective way people can lower their risk. [refrefref]. Our own CDC is silent, while the British equivalent agency actively discourages vitamin D for COVID prevention.
  • The biggest scandal of all is that lockdown has been authorized in the US and elsewhere based on hypothetical safety benefits with no consideration of costs. Our health is affected by our communities, our cultural lives, our social lives, and our livelihoods. [Yale epidemiologist David Katz politely makes this point.]

Shamefully, the scientific community has been complicit in the campaign of fear. A handful of courageous doctors and epidemiologists have been outspoken. In addition to Katz, John Ioannidis and Knut Wittkowski are best known to me. But the most trusted journals continue to publish articles that are based on politics rather than sound science.

Who is benefiting from the international panic? Who is behind the media campaign and the distortion of science, and what is their intention?

I invite people who are more politically astute than I to speculate on these questions.

Human Trials of Plasma Exchange

Animal experiments demonstrating the anti-aging effects of exchanging young blood plasma for old have been prominent in the last two months. Several groups are saying it’s time to translate their findings into human trials. But I’ve recently learned that others have been doing this for several years. What can we learn from their results to guide the next steps in experimentation?


I had never heard of Grifols, the Spanish pharmaceutical company that is the world’s largest supplier of albumin. Since 2005, Grifols has been quietly funding world leaders in plasma exchange research in humans. Albutein® is their brand-name solution of human albumin.

Last month, the first results of the Grifol’s AMBAR trial were released. (AMBAR stands for Alzheimer’s Modulation BAlbumin Replacement). It was a much larger-scale phase 2.5 trial, with 496 subjects recruited from sites in Spain and USA, and treated for 14 months. A single treatment consisted of removing 2.5 to 3 litres of blood (more than half the body’s inventory) and replacing it with Albutein. Patients began with 6 weekly treatments, and thereafter there were 12 monthly smaller plasma replacements (0.7 litres), again with Albutein.

Subjects were evaluated with two standard measures, one of cognitive ability and the other of ability to function independently. Most subjects got worse over the year, as AD is a progressive disease. But treated subjects progressed less than half as fast as sham-treated controls. There was enough variation among individuals that even this strong difference in averages was only marginally statistically significant.

Subjects were categorized as “mild” to “moderate” in their cognitive loss. “Moderate” subjects responded a little better than “mild”, within statistical limits.

In the Conboy paper which I recently reviewed, albumin was considered to be just a passive replacement of proteins that every mammal needs. Albumin was replaced in the blood because when harmful signaling proteins were diluted out of the blood, albumin was removed along with it. The body needs the albumin, while the protein signals were doing damage. Henced they replaced the albumin.

But in AMBAR, albumin is considered an active part of the therapy.

[P]lasma albumin from AD patients is more glycated and nitrotyrosinated than plasma from healthy subjects, reducing its ability to inhibit Aβ aggregation Grifols theorized that replacing AD patients’ albumin with therapeutic-grade albumin should overcome this problem. Further, therapeutic-grade albumin should more effectively bind plasma Aβ and sequester it than plasma albumin from AD patients. Albumin may protect neurons by additional mechanisms, including anti-oxidant and anti-inflammatory activities.  [review, referencing  this primary source].

In one branch of the AMBAR program, ¼ of subjects also received intravenous immunoglobulin (IVIG). This consists of antibodies which identify challenges to which the immune system can respond. Grifols has a proprietary IG product called Flebogamma®. The AMBAR trial was unable to detect a benefit from IVIG.

Plasma exchange has a long history for treatment of auto-immune disorders. Some of the diseases of old age are related to autoimmunity (e.g., diabetes, arthritis, chronic inflammation). Older persons have a higher generalized autoimmunity, but a lower incidence of explicitly autoimmune diseases. Presumably, there are antibodies to self that accumulate in the bloodstream with age, and in recent years this has been related to leaky gut disorders. It makes sense to me that blood dilution would be a downstream or stop-gap treatment for autoimmunity, but that better approaches would be directed at the source of the offending antibodies.

Dobri Kiprov was a co-author of the Conboys’ plasma dilution paper. Kiprov’s clinic has been a site in the AMBAR trials, with experience in plasma exchange going back 20 years. Kripov has studied plasma exchange for a variety of diseases. In these treatments, a patient’s blood is removed and separated. The patient’s own red and white blood are returned to him, but his plasma is replace with saline, albumin, and possibly other ingredients. When I spoke to him, he described work which is soon to be published in Alzheimer’s and Dementia involving a proprietary added ingredient in these plasma transfusions. Benefits last at least 6 months, he said, which suggests that there is some epigenetic re-programming of the cellular sources of blood constituents.

Kiprov claims that patients who receive frozen blood plasma for a variety of reasons have fewer adverse reactions when they receive plasma from young donors (18-24) compared to middle-aged donors (35-45). He has seen patients’ immune systems improve, and arthritis symptoms decrease. He’s eager to see formal trials proceed for these conditions (but someone has to fund them).

The bottom line

As a treatment for AD, these results are not impressive. Patients were already quite disabled, and the results were essentially to prolong their end-of-life institutional existence. There are no effective drugs for AD, so compared to any pharmaceutical, AMBAR looks good. But compare these results to Bredesen’s RECODE program, which aims to improve cognition, and in some cases has returned people to productivity from a non-functional state. RECODE works better the earlier you start it, whereas preliminary results suggests that AMBAR is more effective in late stages.

Inflammation is a driver of all the diseases of old age. Pro-inflammatory signals (cytokines) in the blood were among the elements diluted by AMBAR, and it may be that reduction in inflammation fully accounts for the program’s successes.

As a proof of principle, the results are quite informative. A benefit was demonstrated from plasma exchange in humans for the first time. Subjects did not become dramatically younger, despite much more dilution than in the Conboy mouse experiments (reviewed in this space earlier this month). They suggest that simple dilution as pioneered by the Conboys in mice might be effective in slowing senescence but not reducing biological age.


Two plasma exchange doctors were kind enough to help me with this column. I’m grateful to David Haase (TX) and Dobri Kiprov (CA) for offering background and providing direction to my readings.

Suppression of Chloroquine is Scandalous

It’s hardly newsworthy that medical science is distorted by money. But last week, a case arose that is so blatant, so extreme, and so suspiciously criminal that it should become a rallying point for all of us interested in reform. It involves the two best-respected medical journals in the world, and a finding that immediately affected the lives of thousands of patients around the globe. Two papers purported to be derived from a large, worldwide database, but they were quietly withdrawn when the data was requested by outside reviewers, and none could be produced. Where is the outrage? Where is the passion for reform?

Hydroxychloroquine is a cheap, out-of-patent drug that literally millions of travelers have been using for 65 years for prevention of malaria. It is also taken on a daily basis by hundreds of thousands of lupus patients. Its safety profile and side-effects are well established. Front-line doctors in Wuhan told us early that, in combination with zinc, it was the most effective COVID treatment they knew. It had previously been used with success during the SARS epidemic of 2003. European doctors reported anecdotal success with chloroquine/zinc, and it became standard treatment in France, the Netherlands, and elsewhere [review]. There were about 70 ongoing clinical trials before the two articles appeared.

HCQ has been discouraged by Anthony Fauci and segments of the American medical establishment, and I have wondered if they were compromised by their investments. Fauci is associated, ideologically and financially, with vaccines. The primary competitor for HCQ is Remdesivir, belonging to Gilead Sciences, and selling for $1,000 per dose. Billions of dollars have already been invested in developing a COVID vaccine. That COVID seems to be treatable and that the pandemic is fading with the spring weather is welcome news for world health, but it is devastating for investors in Gilead, Moderna, AstraZeneca, and 20 other companies that are racing to produce a COVID vaccine.

Last month, the two most prestigious medical journals in the world reported large studies by prominent researchers, based on a large COVID data set from Asia, Europe, and America. The lead author is from Harvard’s Brigham and Women’s teaching hospital. Here is the Lancet article, claiming that hydroxychloroquine is worse than useless. The data appear to show that people treated with HCQ are dying at 3 times the rate of other, similar patients. Here is the New England Journal article, which analyzes comorbidities but does not mention HCQ.

The Lancet paper had been duly peer-reviewed and rushed into print by editors. But seasoned researchers in the field immediately smelled that something must be wrong. How could this huge database of patients exist, crossing four continents and going back to the earliest days of the virus, when no one thought the records would be valuable? How could comparable conditions be established in hospitals from Capetown to Beijing to New York? And how could a drug in use for 65 years have such powerful lethal side-effects that no one had previously identified?

Questioned and challenged to produce the data behind the study, the authors quickly retracted the paper and refused further comment.

“Dr. Desai declined a request from The Times to be put in contact with a hospital or health care facility that provided its data to Surgisphere. He did not respond to inquiries after the retractions.” NYTimes

Nirav Desai is a physician and researcher from Surgisphere, a small Chicago company that claimed to have compiled the impressive database. Both retracted studies were led by Mandeep R. Mehra, a widely published and highly regarded professor of medicine at Harvard, who may end up being the fall guy for this scandal.

But no one is investigating Surgisphere as the source of a criminal fraud. No one is holding the Lancet journal or its editors or reviewers to account. Certainly no one is questioning the broad system funding and publishing the medical research on which the practice of Western medicine is based. To their credit, Science Magazine published this article, hinting at a scandal and beginning to ask the right questions.

This is happening at a time when the medical establishment is making the largest demands ever on our beliefs and our behaviors. We are locked down based on the computer simulation of a compromised researcher, who also did not document the basis of his computation, and whose predictions have proved spectacularly inflated. Why did we trust him, when he had cried wolf twice previously (EbolaAvian flu)? The liberal-intellectual press and the science journals speak with a unified voice. denouncing anyone who questions vaccines as ‘anti-science’. Every article in Wikipedia and every Google search is plastered with a message that tells us to trust the CDC. The head of Youtube goes on the air to explain why anyone who disagrees with the WHO must have their videos removed.

The largest of the studies evaluating HCQ were discontinued after the Lancet article raised the probability that the studies might be putting lives of experimental subjects at risk. Now they are being re-started, but a fresh scandal has arisen. Dr Meryl Nass has investigated details of the “Soldarity” and “Recovery” trials. She reports that these trials plan to use dosages that are at least 4 times larger than necessary, dosages that have been found to be unsafe in the past, in fact fatal to a few percent of sensitive patients. She does not mention that the trials are leaving out zinc supplementation, which doctors everywhere report to be an essential part of the treatment protocol. The studies have indirect ties to vaccine manufacturers, through the WHO and through the Gates Foundation.

It appears on its face that these trials are designed to fail, and will kill experimental subjects on the way to “proving” that HCQ is an ineffective treatment. These suspicions can only be amplified by an announcement today from FDA that chloroquine cannot be used for COVID cases. This intrusion into physician autonomy is unprecedented. For as long as FDA has existed, its policy has been to permit physicians to freely prescribe drugs off-label for any condition where the individual physician feels it might be useful.

The institutions in which Americans and Europeans have entrusted their health have betrayed our trust. There are narrow implications for the future of HCQ and treatment of COVID, and then there are broader implications about the need for overhauling the profit incentives in medical research.

Narrow perspective

For those of who dare to look beyond our own noses, a concerted campaign to discredit a good, cheap treatment for COVID is a hint that might help us make sense of the bizarre global events of the last five months. This is a real virus, a real pandemic, but it is being exploited for a political agenda far larger than the effects of the disease itself.

  • Why have death rates been consistently overestimated in public reports?
  • Why have hospitals been incentivized to over-report COVID deaths, and to treat patients with ventilators that don’t seem to be helping?
  • Why has CDC failed to recommend simple, inexpensive prevention measures (vitamin D, zinc, immune-enhancing herbs, special measures for nursing homes)?
  • Why have our government agencies encouraged shortcutting of safety tests in “warp-speed” vaccine development, while discrediting simple, cheap treatments (intravenous vitamin C, chloroquine/zinc, Artemisia) that work in other countries?
  • Why has COVID become cause for bailouts of the financial sector that have little to do with the disease, while working families and small businesses have been forced into bankruptcy?

Many geneticists, including two Nobel laureates, cite evidence that COVID seems to be man-made, the product of genetic engineering (excellent technical summary). But this idea is off the table for discussion, censored by both the scientific community and by the mainstream press (original articlesanitized rewrite). Could it be that the same powerful forces benefiting from the lockdown and social control have power to censor both the scientific establishment and the popular press? These may seem wild speculations, but perhaps they are justified by wild events.

The rules we are asked to follow have been maximally destructive to our economy, our institutions, and our culture, while providing far less life-saving benefit than simpler strategies. Maybe the cultural and social isolation were intended to serve a different purpose than the protection of public health.

Broad perspective

“Two major study retractions in one month have left researchers wondering if the peer review process is broken.” NYTimes

The Times calls them “big blunders” but this is far too charitable. A big blunder is when you publish an article without noticing that a plus sign is really a minus. But when you fail to notice that the database of patient cases you are analyzing doesn’t exist, that is a fraud and not a blunder.

We like to think that medical practice is following medical research as the tail follows the dog. But look at the two economies$3.5 trillion per year in health care revenues in America vs an NSF budget of only $8 billion spread over every kind of science. It may be too much to expect the dog to wag the tail when the tail is 500 times larger than the dog.

Meanwhile, medical consumers are voting with their feet. People flock to dietary supplements ($35 billion/year), acupuncturists, chiropractors, and alternative healers. 40% of Americans think that non-standard approaches to cancer are more likely to cure them than chemotherapy and radiation, while most of the purveyors of those alternatives have been driven overseas by aggressive FDA “oversight”.

If the medical science establishment wishes to regain the trust of the American public, they will have to demonstrate that the health of individual patients weighs more heavily in their calculations than the profit motive.

Out With the Old Blood

There is great promise in 2020 that we might be able to make our bodies young without having to explicitly repair molecular damage, but just by changing the signaling environment.

Do we need to add signals that say “young” or remove signals that say “old”?

Does infusion of biochemical signals from young blood plasma rejuvenate tissues of an old animal? Or are there dissolved signal proteins in old animals that must be removed?

For a decade, Irena and Mike Conboy have been telling us removal of bad actors is more important. But just last month, Harold Katcher reported spectacular success by infusing a plasma fraction while taking away nothing. Then, last week, the Conboys came back with a demonstration of the rejuvenating power of simple dilution. [Link to their new paper]

Dilution procedure

They simply replaced half of the blood plasma in 2-year-old mice with a saline solution containing 5% albumin. What is albumin? Blood plasma is chock full of dissolved proteins, about 10% by weight. About half of these are termed albumin. Albumin is the generic portion. It doesn’t change through the lifetime. It doesn’t carry information by itself. But albumin transports nutrients and minerals through the body.

The Conboys took care to show that albumin has no rejuvenation power on its own, and had nothing to do with their experimental results. Rather, they had to replenish albumin in diluting blood, because the animals would be sickened if half their albumin were removed. Replacing the albumin in a transfusion is akin to replacing the volume of water or maintaining the salinity.

In preparation for this experiment, the Conboys have invested years in miniaturizing the technology for blood transfusions, so that mice can be subjected to the same procedures that are commonplace in human hospitals.

Dose-Response

The Conboy lab replaced 50% of mouse blood plasma. They got spectacular results with a single treatment, based on a lucky guess. They have not yet experimented with 30% or 70%. They don’t know yet how long the treatment will last and how often it needs to be repeated.

Evidence of rejuvenation

As with previous papers from the Conboy lab, the group focused on repair and stem cell activity as evidence of a more youthful state. Three separate tissue samples were taken from liver, muscle, and brain.

“Muscle repair was improved, fibrosis was attenuated, and inhibition of myogenic proliferation was switched to enhancement; liver adiposity and fibrosis were reduced; and hippocampal neurogenesis was increased.”

  • They measured nerve growth factors in the brain, and detected a more robust response, typical of young mice
  • They lacerated muscles and showed repair rates typical of much younger animals
  • They examined microscope slides of liver tissue, and showed that it is less fatty and striated than is typical of older mice

Figure 2. Rejuvenation of adult myogenesis, and albumin-independent effects of TPE. One day after the NBE, muscle was injured at two sites per TA by cardiotoxin; 5 days later muscle was isolated and cryosectioned at 10 µm. (A) Representative H&E and eMyHC IF images of the injury site. Scale bar = 50 µm. (B) Regenerative index: the number of centrally nucleated myofibers per total nuclei. OO vs.ONBE p = 0.000001, YY vs ONBE non-significant p = 0.4014; Fibrotic index: white devoid of myofibers areas. OO vs ONBE p = 0.000048, YY vs YNBE non-significant p = 0.1712. Minimal Feret diameter of eMyHC+ myofibers is normalized to the mean of YY [9]. OO vs. ONBE p=3.04346E-05, YY vs. YNBE p=0.009. Data-points are TA injury sites of 4-5 YNBE and 5 ONBE animals. Young and Old levels (detailed in Supplementary Figure 1) are dashed lines. Representative images for YY versus YNBE cohorts are shown in Supplementary Figure 6. (C) Automated microscopy quantification of HSA dose response, as fold difference in BrdU+ cells from OPTI-MEM alone (0 HSA). There was no enhancement of myogenic proliferation at 1-16% HSA. N=6. (D) Meta-Express quantification of BrdU+ cells by automated high throughput microscopy for myoblasts cultured with 4% PreTPE versus PostTPE serum and (E) for these cells cultured with 4% of each: PreTPE serum + HSA or PostTPE serum + HSA. Significant increase in BrdU positive cells is detected in every subject 1, 2, 3, and 4 for TPE-treated serum (p=0.011, <0.0001, <0.0001, 0.0039, respectively), as well as for TPE-treated serum when 4%HSA is present (p<0.0001, <0.0001, <0.0001, =0.009 respectively). N=6. (F) Scatter plot with Means and SEM of all Pre-TPE, Post-TPE, +/- HSA cohorts shows significant improvement in proliferation in Pre TPE as compared to and Post TPE cohorts (p*=0.033), as well as Pre+HSA and Post+HSA cohorts (p*=0.0116). In contrast, no significant change was observed when comparing Pre with Pre+HSA (p=0.744) or Post with Post+HSA (p=0.9733). N=4 subjects X 6 independent assays for each, at each condition. (G) Representative BrdU IF and Hoechst staining in sub-regions of one of the 9 sites that were captured by the automated microscopy. Blood serum from old individuals diminished myogenic cell proliferation with very few BrdU+ cells being visible (illustrated by one positive cell in Pre-TPE and arrowhead pointing to the corresponding nucleus); TPE abrogated this inhibition but HSA did not have a discernable effect.

What’s missing? They did not test any measures of physical or cognitive performance at the level of the organism.

  • Evidence of behavioral changes (learning and memory, endurance, strength)
  • Inflammatory markers
  • Blood lipids
  • Methylation clock (Horvath, UCLA) or proteomic clock (Lehallier, Stanford)

Some of this is planned for future research. Mike and Irina plan to submit tissue samples for analysis by the Horvath mouse methylation clock.

Clock?

I am a committed enthusiast for the methylation and proteomic clocks that are the best surrogates we have for aging. These technologies can tell us whether anti-aging interventions have been effective without having to wait for animals (or humans) to die before reporting results. But the Conboys still regard these technologies as unproven, and they bristle at the word “clock”.  The closest they come is to catalog the entire proteome of treated mice, comparing it to untreated young and old mice.

Multi-dimensional t-SNE analyses and Heatmapping of these data revealed that the ONBE proteome became significantly different from OO and regained some similarities to the YY proteome. Supplementary Figure 4 confirms the statistical significance of this comparative proteomics through Power Analysis, and shows the YY vs. OO Heatmap, where the age-specific differences are less pronounced than those between OO vs. ONBE, again emphasizing the robust effect of NBE on the molecular composition of the systemic milieu.

Translation: As controls, they had mice that underwent plasma exchange with mice of similar age. YY were young, positive controls, and OO were old, negative controls. Treated mice were ONBE=”Old—Neutral Blood Exchange”. Rather than relying on “clock” algorithms that compute an age from the proteome, they compared the entire proteomes of test animals with those of old and young animals, and foud that they resembled the young animals more closely.

Aging and epigenetics

I was an early advocate of the theory that aging is driven primarily by changes in epigenetics. Other proponents include JohnsonRando, and Horvath. This theory is now mainstream, though its acceptance is far from universal. (The main reason people have difficulty with the idea is the question, “why would the body evolve to destroy itself?” I present a comprehensive answer in my popular book and my academic book.)

On the face of it, the new Conboy result is powerful evidence for the epigenetic theory. They have shown that there are proteins in the blood that actively retard growth and healing. Remove half theses proteins and the animals are able to grow youthful tissues and to heal better. The obvious conclusion is that, with age, there are signaling changes in the blood that weaken the animal and inhibit repair.

There are, however, other ways to interpret the changes. Aubrey de Grey has said (personal communication)

“When everything in the blood except the cells and the albumin is replaced by water, the body will definitely respond by synthesising and secreting everything that it detects a shortage of, whereas the bad stuff will not be so rapidly replaced, since by and large it was only there in the first place as a result of impaired excretion/degradation.”

The Conboys don’t embrace the programmed aging perspective, but neither is their understanding of what they see the same as Aubrey’s. The way Irina explained it to me is that the age of the biological of the body is simply a measure of how much damage has accumulated, but that cycles of epigenetics and catalysis are self-reinforcing.

“Epigenetic, mRNA, and protein are steps of one process, regulation of gene expression. And none of these steps are permanent they all actively and constantly respond to cell environment &mdash; tissue and systemic milieu…With aging there is a drift which is re-calibrated by a number of rejuvenation approaches…When an auto-inductive age-elevated ligand is diluted, it cannot activate its own receptor and induce its own mRNA, so ligand levels diminish to their younger states for prolonged time.”

The Conboys theorize that these harmful proteins are part of a positive feedback loop, in other words, a cycle that is self-sustaining

epigenetic state ⇒ gene expression ⇒ translation to circulating proteins ⇒ feedback that alters the epigenetic state

With age, the body has slipped into a dysfunctional, self-sustaining cycle, and with the shock of disruption, they are able to nudge it back into a more robust and youthful cycle, also self-sustaining.

Figure 6. Model of the dilution effect in resetting of circulatory proteome. System: A induces itself (A, red), and C (blue); A represses B (green), C represses A. A dilution of an age-elevated protein (A, at D1: initial dilution event), breaks the autoinduction and diminishes the levels of A (event 1, red arrow); the secondary target of A (B, at event 2 green arrow), then becomes de-repressed and elevated (B induces B is postulated); the attenuator of A (C, at event 3 blue arrow), has a time-delay (TD) of being diminished, as it is intracellular and was not immediately diluted, and some protein levels persist even after the lower induction of C by A. C decreases (no longer induced by A), and a re-boot of A results in the re-induction of C by A (event 4 blue arrow) leading to the secondary decrease of A signaling intensity/autoinduction, and a secondary upward wave of B (events 5 red arrow and 6 green arrow, respectively). alpha = 0.01, kc = 0.01, beta = 0.05, epsilon = 0.1, ka = 0.1. Protein removal rates from system: removalA = 0.01, removalB = 0.1, removalC = 0.01, Initial values: initialA = 1000, initialB = 400, initialC. = 700

For me, the surprising thing in Irina’s account is that there is no hysteresis in this system. The reprogramming responds to changes in the blood levels of signals within minutes. It is difficult for such a system to be homeostatic. I wonder how that can be. Life is all about homeostasis, and intuitively, we all imagine that negative feedback loops are more common than positive feedback loops. (Negative feedback loops lead to homeostasis; positive feedback loops lead to runaway, exponential change.)

Is there a clock somewhere? Is the brain special?

In the Conboy view, signals in the blood are emitted from all over the body, and not especially from the hypothalamus. If brain tissue responds in a seemingly exceptional way to proteins in the blood, it is because of selective passage of those proteins by the blood-brain barrier.

The authors remind us that in past parabiosis experiments (where blood is exchanged between old and young mice), the brain tissue of the young mice grew older but brains of the old mice didn’t get younger. This was an indication that brain aging is caused by affirmative action of “bad actors” in the plasma, and that these are able to penetrate the blood-brain barrier. This observation was part of the inspiration for the current experiments.

The corresponding procedure in humans is already FDA approved

Therapeutic Plasma Exchange (TPE) is a well-established medical procedure, and has already been performed on an experimental basis by co-author Dobri Kiprov. There is anecotal history of suggestive results, which I will write about in my next post.

Comparison with Katcher’s Elixir

This week’s announcement from the Conboys and last month’s preprint from Katcher/Horvath come from the same school of thought: that aging is coordinated through the body by signal molecules in the blood. Both demonstrated dramatic rejuvenation in rodents based on a short-term intervention, and both have plans for commercialization and human trials to begin ASAP.

So it is curious that in other ways, the programs of Katcher and Conboy are so different.

  • While both approaches are rooted in differing compositions of blood plasma between young and old, the Conboys focus exclusively on removing species that are inhibiting youthful regeneration, while Katcher’s approach is to add back the proteins that formerly kept the animal young.
  • The Conboys have fully disclosed all aspects of their experimental protocol, whereas the content of Katcher’s elixir remains a trade secret.
  • Katcher is on the fringe of academic research, and the Conboys’ lab is at one of the premier academic institutions in the world.
  • Katcher is a year further along, having experimented with different dosages and timings. Neither Katcher nor the Conboy lab has yet demonstrated life extension.
  • The Conboys demonstrate rejuvenation with wound healing, tissue structure, and renewal of nerve growth. Katcher’s claim is based on physiology (especially inflammation), cognitive performance, and methylation clock algorithms.
  • In fact, Katcher regards restoration of youthful methylation patterns as the best evidence he could offer for rejuvenation (I agree), while the Conboys are reserving judgment about the importance of methylation, and bristle at the language of a methylation “clock”.
  • Katcher understands the effects of plasma transfusions in terms of a broad theory (which I support). Aging is an epigenetic program, governed and enforced by a “clock” that operates via a feedback loop between circulating proteins that govern gene expression and gene expression that generate those proteins. The Conboys recognize they are working this feedback loop (their Fig 6) but they resist the theory that it is the essential cause of aging.

My guess is that a combination of their two approaches will be necessary for full remediation of aging, and that a combination of their resources, credibility, theoretical foundations, and contacts would be a transformative event for medical science, for biotech industry, and for biological theory. It is my fervent hope that Katcher and the Conboys might work together.

Age Reduction Breakthrough

If you eschew hyperbole and hang in for the long haul, maintaining a discipline of understatement in the midst of a flashy neon world, you may be offered a modicum of credence when you make an extraordinary announcement. No one is entitled to this courtesy twice. If the news that you trumpet to the moon does not pan out, your readers will be justified in discounting everything you say thereafter.  

Here goes.

I believe major rejuvenation has been achieved in a mammal, using a relatively benign intervention that shows promise of scaling up to humans. I’m going to stake my reputation on it.

Cartoon by Maddy Ballard

In the race to effect substantial, system-wide rejuvenation, Harold Katcher is a dark horse. He has the right academic credentials and a solid history of research. In fact, in earlier life he was part of a team that discovered the breast cancer genebrca1. I asked Harold for a biographical sketch, and have printed it in a box at the end of this posting.

But Katcher has no research grants or university lab or venture capital funding, no team of grad students mining databases and screening chemicals in the back room.

One thing Katcher has going for him is the correct theory. Most of the explosion in aging research (and virtually all the venture capital startups) are looking to treat aging at the cellular level. Their paradigm is that aging is an accumulation of molecular damage, and they see their job as engineering of appropriate repair mechanisms.

The truth, as Katcher understands it, is that, to a large extent, aging is coordinated system-wide via signal molecules in the blood. It was our common realization of this vision that brought Katcher and me together more than a decade ago. Katcher briefly describes his 2009 epiphany below. It was the source of his 2013 essay (it took a few years to get it into print) on the significance of parabiosis experiments for the future of aging science.

Of course, Katcher was not the only one to get the message about the power of signal molecules in the blood to reprogram tissues to a younger state throughout the body. The problem is that there are thousands of constituents represented in tiny concentrations in blood plasma, but conveying messages that cells read. Which of these are responsible for aging? A small number of labs, including the Conboys at Berkeley, Amy Wager at Harvard, and Tony Wyss-Coray at Stanford have been searching for the answer over the last decade and more.

Katcher has been able to guess or intuit or experimentally determine the answer to this question. With seed funding from Akshay Sanghavi, he set up a lab in Mumbai two years ago, and tried to rejuvenate old lab rats, using a fraction extracted from the blood of younger rats. The first round of experiments were encouraging, published in this space a year ago. He obtained the next round of funding from a reader of this blog, and had enough rats to titrate dosages experimentally, and to see if treated rats who aged again over time could be re-treated successfully.

There is a hole in this story that awaits the resolution of intellectual property rights. Katcher and Sanghvi have not applied for patents and have not yet found a suitable partner to provide financing for human trials. They have not revealed any details of the treatment, besides the fact that it is in four intravenous doses, and that it is derived from a fraction of blood plasma. Katcher thinks that the molecules involved will not be difficult to manufacture, so that when a product is eventually commercialized, it will not require extraction from the blood of live subjects, rodent or human.

We’re still waiting for longevity curves of these treated rats. In the meantime, the best available surrogate measure of age comes from methylation clocks, as developed by Steve Horvath at UCLA, and other scientists as well. Crucially, Katcher found an ally in Horvath, who didn’t just test his rejuvenated rats, but did the needed statistical analysis to develop a set of six methylation clocks specialized to rats. FIve of the clocks are optimized for different tissues, and one is calibrated across species, so that it can measure age in humans as well as corresponding age in “rat years” (about 1/40 human year). The two-species clock was a significant innovation, a first bridge for translating results from an animal model into their probable equivalent in humans.

In a paper posted to BioRxiv on Friday, Katcher and Horvath report results of the methylation measurements in rejuvenated rats. “Crucially, plasma treatment of the old rats [109 weeks] reduced the epigenetic ages of blood, liver and heart by a very large and significant margin, to levels that are comparable with the young rats [30 weeks]….According to the final version of the epigenetic clocks, the average rejuvenation across four tissues was 54.2%. In other words, the treatment more than halved the epigenetic age.”

Human-rat clock measure of relative age defined as age/maximum species lifespan.

Besides the methylation clock, the paper presents evidence of rejuvenation by many other measures. For example:

  • IL-6, a marker of inflammation, was restored to low youthful levels
  • Glutathione (GSH), superoxide dismutase (SOD), and other anti-oxidants were restored to higher youthful levels
  • In tests of cognitive function (Barnes maze), treated rats scored better than old rats, but not as well as young rats.
  • Blood triglycerides were brought down to youthful levels
  • HDL cholesterol rose to youthful levels
  • Blood glucose fell toward youthful levels

A major question in blood plasma rejuvenation experiments has been how often the cure must be administered. Many of the components of blood plasma are short-lived, secreted into the blood and absorbed continuously throughout the day. The good news from Katcher’s results is that it seems only four injections are needed in order to achieve rejuvenation.

A second question which these experiments resolve is whether rejuvenation requires both adding and removing molecular species from the blood plasma. For example, pro-inflammatory cytokines are found in old blood at much higher levels. Irina and Mike Conboy, people who I regard as most credible in the field, have said that removing bad actors from the blood is probably more important than restoring youthful levels of beneficial signals. They were grad students at Stanford 15 years ago, when the modern wave of parabiosis science was initiated, and have pursued the subject continuously ever since. Katcher’s experiments have achieved their results only by adding blood components, not by removing or even neutralizing others. This suggests that he has found the necessary formula for re-programming epigenetics, so that lower levels of the bad actors occur as a result. But it remains to be seen whether even better results can be obtained if some plasma constituents are removed.

A question that remains unresolved concerns the location and mechanism of the aging clock. I have been undecided over the years between two models:

  1. There is a central aging clock, perhaps in the hypothalamus, which keeps its own time and transmits signals throughout the body that coordinate methylation state of dispersed tissues
  2. Information about epigenetic age is dispersed through the body, and the body’s clock is a feedback loop that is continually updating methylation age locally in response to signals received about the methylation age globally.

There is a suggestion in the data that the hypothalamus may be more difficult to rejuvenate than other tissues. Does it play a more important role than other tissues in coordinating the age of the entire body? Horvath (personal communication) counsels caution in drawing this inference until measurements are corroborated and more experiments are done.

The Bottom Line

These results bring together three threads that have been gaining credibility over the last decade. Mutually reinforcing, the three have a strength that none of them could offer separately.

  • The root cause of aging is epigenetic progression = changes in gene expression over a lifetime.
  • Methylation patterns in nuclear DNA are not merely a marker of aging, but its primary source. Thus aging can be reversed by reprogramming DNA methylation.
  • Information about the body’s age state is transmitted system-wide via signal molecules in the blood. Locally, tissues respond to these signals and adopt a young or an old cellular phenotype as they are directed.

Harold Katcher, Biographical Sketch

So, you might consider me a late bloomer.  While I have thousands of citations in the literature, with publications ranging from the discovery of the human ‘breast cancer gene’, to protein structure, bacteriology, biotechnology, bioinformatics, and biochemistry, there was no center or direction to my work as I had given up my personal goal of solving/curing aging when I learned that ‘wear and tear’ was the cause of it.  Yet something happened in year 1985 when I was in California working with Michael Waterman and Temple Smith (fathers of bioinformatics) that is inexplicable: I found myself in Intensive Care with a tube inserted into my trachea and the knowledge that I might not live.   And then I had a dream: I dreamed that somehow in the far future (and on another world), I was being feted for ‘bringing immortality to mankind’. Clearly, I survived that incident (started with an infected tooth).    I lived a wonderful life – becoming a computer programmer (which I loved), leaving that for the University of Maryland’s Asian division, becoming a full professor and then the Academic Director for the Sciences, in Tokyo, Japan.  By the time I left Japan in 2004, (my daughter Sasha was a fourth-grader, (yonensei), in the Japanese school system), I was teaching for U of M online – somewhat retired, and looking forwards to writing computer programs for fun and profit. Yet I never ever forgot that dream. It was clearly impossible; I had no lab – and really, there was no way to repair all damaged cells – it’d be like sweeping back the ocean. And then, in 2009, I read an old paper from 2005, a paper written by the Conboys, (Michael and Irina), Tom Rando and others, coming from Irv Weisman’s lab, that completely changed my life; that showed me that everything I believed about aging was wrong – that aging occurred at the organismic level, not at the cellular level and could be reversed. Well, the rest of the story is about persistence and the blessed intervention of Akshay Sanghvi who too saw there was another way and provided the structural, monetary, and emotional support (and some good ideas) that had me start a new career at age 72 in Mumbai, India.  I feel twenty years younger than I did three years ago, I guess that’s another hint about aging. Now the ‘mystical’ dream?  It wouldn’t be the first time in history that that happened – take that as a datum.

Where did COVID-19 come from? Part 2

Last week, I outlined genetic evidence that the present pandemic had its origin in a laboratory. In the segment below, I tell two stories of how this might have occurred, one as leak from an American lab and one from a Chinese lab. I was surprised to find that there is a history of collaborative work between American and Chinese bioweapons labs on exactly the kind of Coronavirus responsible for the current epidemic, in which a protein that binds with ACE2 was artificially spliced onto the genome of the bat virus ancestor.


After I posted this, Yuri Deigin, who is a frequent commenter on this page, posted this article on Medium. It is great background reading for anyone who wants to understand more deeply how viruses get inside cells, how they manipulate the cell chemistry, and how SARS-CoV2 is related to its ancestors. Spoiler: The virus seems to combine the backbone from a known bat virus genome with a spike protein (the part that binds to a target cell) from a pangolin virus. These two animals share no common habitat, so it is possible but unlikely that they could have combined in nature. Newly added to the SARS-CoV2 binding protein is a precisely placed insert that acts as an instruction to the cell, “cut here” making the virus a great deal more infective.


Here’s a puzzle worthy of Sherlock Holmes’s story of the dog who didn’t bark. The Chinese are eagerly promoting narratives about the SARS-CoV2 virus originating in America, while the Americans assume that, of course, the virus evolved where the first cases were identified, in Wuhan, China. But both sides agree, SARS-CoV2 had a natural origin, and had nothing to do with genetic engineering or breeding in a laboratory.  As we shall see below there are credible links to both the Wuhan Institute of Virology and to the US bioweapons HQ at Fort Detrick, MD and a university lab at Chapel Hill.

Why wouldn’t these two propaganda machines be eager to demonize one another by promoting stories about leaks from the other’s weapons lab? If one but not the other of these spin-control states were too eagerly dismissing the bioweapons meme, I know what I would suspect. But what does it mean that both these rivals are suppressing all discussion of the issue?

Two stories—they can’t both be true

There is a plausible story about a Chinese origin for COVID. There is another story, in my view equally plausible, about an American origin. The two stories are not easily reconciled, and that suggests to me that I have been suckered by disinformation, one way or the other. Some part of what I am about to report is not true. More confusion: there are hints that fall short of being a “story” about coordinated bioweapons development between China and the US. I like to think of it as a real-life mystery novel. I ask you, dear readers, to help figure out who is telling the truth, who is lying, and whodunnit. America? China? A cooperation between the two?

Or maybe it was Professor Pangolin*.

Outline of the Chinese story:

  • China’s main bioweapons research facility is right there in Wuhan, where the first patients were identified.
  • The laboratory has published papers in which they were doing closely-related research. [2009, 2013, 2015]
  • In fact, we know that they were harvesting bats from SW China, extracting SARS virus from them, genetically modifying the virus to enable “gain-of-fuinction” to infect human cells in vitro. (see 2015 link above)
  • Even the human ACE2 receptor used by SARS-CoV2 is mentioned in published articles from the Wuhan research facility.  (see 2015 link above)
  • Security at Chinese facilities is reported to be more lax than at comparable American facilities.
  • The Chinese government has reportedly silenced discussion of bioweapons research at the Wuhan facility, and of a possible leak. (Here’s an early complaint about lack of transparency. I offer this video as a source because it documents well the Chinese suppression of discussion of the bioweapon question. In other respects, the video is misleading, blaming the Chinese government as if the American government were not equally culpable.)

Outline of the American story:

  • The world’s most extensive bioweapons facility is at Fort Detrick, MD.
  • The Fort Detrick lab was closed by CDC for undisclosed security leaks last August.
  • I personally had a persistent cough for more than 2 months beginning in November. Other (American) friends have told me of similar unusual respiratory infections last fall and early in the winter. CDC reported in early December that “The U.S. winter flu season is off to its earliest start in more than 15 years.” [NBC news] Could this have been early cases of COVID-19, undetected as such?
  • The SF Chronicle reports today that an American who had not traveled recently died of COVID Feb 6, so he must have contracted the disease early January, a month earlier than the previous “first” American case which arrived in Seattle from Wuhan in February. It may be that we have not found even earlier examples because we have not been looking.
  • Late last October, there were military games, a kind of Olympic competition for the world’s armies, held in Wuhan. This was 6 weeks before the first COVID-19 cases were recognized by the Chinese, but only 3 weeks before the first Chinese case identified with hindsight.
  • Some of the American military personnel attending the Games in Wuhan were stationed in Maryland and had recently frequented Fort Detrick.
  • The entire American team, 300 strong, stayed at the Oriental Hotel, just a half mile from the infamous open-air market which has been blamed for the outbreak.
  • According to one report, the entire first cluster of 42 COVID patients were employees and their families of the Oriental Hotel.
  • Genetic diversity analysis can be used to estimate how long a virus has been mutating away from Patient Zero. One such analysis is consistent with an origin last fall.
  • Maximum Likelihood Analysis for the evolutionary tree of the SARS-CoV2 virus worldwide indicates that the “A” strain from which all other strains were derived is present only in America and Australia. The predominant strain in China is “B”. [ScienceDaily]
  • According to ABC News, “As far back as late November, U.S. intelligence officials were warning that a contagion was sweeping through China’s Wuhan region, changing the patterns of life and business and posing a threat to the population, according to four sources briefed on the secret reporting.” The Defense Intelligence Agency had already identified it as a coronavirus in November. But the “first 41 patients” in the Lancet article were admitted to Wuhan hospitals in December. Please stop and consider the implications of the fact that the US Dept of Defense knew that there was a dangerous coronavirus and knew it was in Wuhan before the first reported COVID patients. Pepe Escobar conjectures.
  • The only countries in the world where all known strains of COVID have been identified are China and USA.

Reports of bioweapon collaboration between USA and China

Exhibit A for this hypothesis is this Nature Medicine article from 2015. It describes a collaboration between University of North Carolina scientists and the Wuhan Virology Laboratory, funded jointly by American agencies, including Fauci’s NIAID, and the Chinese National Science Foundation. They describe modifying the bat coronavirus, the very one that is most closely related to the SARS-CoV2 pandemic. They use genetic engineering to add an ability to bind to the human (and mouse) ACE2 receptor, the very same modification that makes SARS-CoV2 so contagious.

The nominal justification for such research is to understand how such recombinations might occur in nature, so that we might be better prepared to defend against them if such a recombination should happen to take place. The number of such recombinations that could conceivably take place is enormous. But this group was lucky to anticipate the exact virus and the exact modifications that would make it a problem five years later. They had a jump on the competition. “Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.” Prophetic. And the research took place in the Chinese city where the current pandemic was first recognized. Coincidental.

It is morally outrageous that such research should be proceeding. It has been against International Law since 1975 (based on a 1969 treaty), and explicitly outlawed in the US since 1989. “Whoever knowingly develops, produces, stockpiles, transfers, acquires, retains, or possesses any biological agent, toxin, or delivery  system for use as a weapon, or knowingly assists a foreign state or any organization to do so, shall be fined under this title or imprisoned for  life or any term of years, or both.” The law singles out research in gain-of-function engineering, as described in the Nature Medicine article.

Layered on my moral outrage is a head scratch: Why would a government agency steeped in secrecy publish such research? Even if we grant that their intent was not to produce a bioweapon but to learn about what might, at some future date, happen in nature, the fact remains that the paper contains explicit instructions that anyone with hostile intent might use to create a bioweapon.

Earlier in my career, I had security clearance as part of my research at Physical Sciences, Inc in the 1970s. I saw just enough of the Defense Department’s security system to extrapolate that the CLASSIFIED stamp was used liberally on any finding that might conceivably be used as part of a weapon system, even if the work described basic physics that had been well known for a century or more. Contrast this institutional paranoia with treatment of the Nature Medicine article, which is published freely, though it includes explicit instructions with which a competent but malevolent biochemist might produce an artificial pandemic.

What were the authors thinking when put such research out for the world to read? I have written to two of the authors to ask them.

  • Luc Montagner, French national hero and Nobel laureate in medicine, worked in China for several years. He claims there is a cooperative bioweapons program between China and the West.
  • Francis Boyle, professor of international law and world expert on bioweapons law, claims to have first-hand knowledge of cooperation in developing weapons between China and USA. He also says that the original SARS virus from 2003 was an American bioweapon, and that the high-security facility within Wuhan Virology Lab was set up to study it [interview transcript]
  • Three Published papers on SARS-derived viruses that were authored by scientists at the Wuhan Institute of Virology list sponsorship by American funding agencies, including NIAID, which has been directed by Anthony Fauci for 35 years. [20092013, 2015]
  • Last summer, the National Microbiology Laboratory in Winnipeg abruptly cut off a Chinese-Canadian researcher’s access to her own laboratory. Details of the reasons were not disclosed. “A number of observers have speculated that case involves concerns about the improper transfer of intellectual property to China,” according to Science Magazine. What the Science article omits to say is that NML Winnipeg is Canada’s primary bioweapons laboratory.
  • The chair of Harvard’s Chemistry Department is a specialist in the technology of microparticles. He has had long-standing contracts with the Wuhan University of Technology (not to be confused with the Virology Institute), and was recently dismissed by Harvard, where the Administration claimed to be ignorant until recently of his work with the Chinese university. [February news article from Nature] [EuroWeekly article] [Wall St Journal]

American work on bioweapons can be traced to Nazi scientists who had been experimenting with non-consenting human subjects, exempted from being charged as war criminals and imported to the US to continue their work under Operation Paperclip. The current wave of research sponsored not by the Defense Department but by civilian NIAID was begun in 2003, and protested widely in 2005.

More than 700 scientists sent a petition on Monday to the director of the National Institutes of Health protesting what they said was the shift of tens of millions of dollars in federal research money since 2001 away from pathogens that cause major public health problems to obscure germs the government fears might be used in a bioterrorist attack. [NYTimes]

Regardless of whether COVID-19 derived from a laboratory, let’s put an end to state-sponsored bioweapons research. It’s already illegal.


The case for the Wet Market origin has gained popular acceptance despite evidence that is thin to nonexistent. Pictures like this one are used to appeal to our lizard brains. Of course something so disgusting must be a breeding ground for germs.

Here’s how we do it in America. Is it any less distasteful?

Yes, the way in which animals are killed for food is disgusting, and we don’t like to look at it. But does it have anything to do with the way viruses mutate and acquire new functions?

Standard evolutionary theory tells us that mutations are random. (I’ve been a critic of standard evolutionary theory, but for reasons that I think are not relevant to the present discussion.) Occasionally, a random mutation makes it possible for a virus to jump from one species to another. But these mutations are rare enough that we don’t expect them to occur simultaneously with three other gain-of-function mutations that make a virus both more lethal and more contagious. Computer models based on the full SARS-CoV2 genome have trouble accounting for all the differences from the bat genome in a sufficiently short time frame. The wet market hypothesis is a politically convenient fallback, without a proposed mechanism. The bats that harbor SARS viruses live 1,000 miles from Wuhan and are not sold in the local meat market at Wuhan.


* The pangolin that has been proposed as an intermediate host is an endangered species. It cannot be sold legally in China, and the idea that there were underground pangolin vendors in the Wuhan wet market has not even been alleged, let alone researched. This Guardian article is appropriately skeptical. The Nature article which is the original source of the pangolin theory does not claim there were pangolins at the Wuhan market. A follow-up Nature article points to further weaknesses in the pangolin hypothesis, and clarifies that the pangolin virus genome is not closer than the bat virus to SARS-CoV2.

Where did COVID-19 come from?

There is genetic evidence suggestive of human tinkering in the genome, and there are news stories suggesting the virus might have been developed either at the Wuhan Institute of Virology or at the American virology lab at Fort Detrick. There are even some suggestions that the American and Chinese bioweapons labs may be working together, sharing samples and exchanging funding.


Part 1: The Genetic Evidence

Preface

We rely on the scientific community as a context for almost every public policy decision. People who want to influence policy know this, and they don’t just lobby Congress, they also buy scientists, scientific reporting, and placement in prominent journals. Most scientists are honest, but they have to survive in a world where funding is tighter than it should be. It’s not surprising that some of them succumb and publish what powerful and corrupt institutions want them to.

The question of a laboratory origin for COVID is politically explosive, so we expect a heavy hand restraining the science establishment. Those of us seeking an honest answer, who have a little expertise, a little horse sense, and a lot of patience, are left to sift through information, misinformation, and disinformation in a politicized environment.

My personal opinion is that I don’t like having to wonder if global pandemics have been created, accidentally or otherwise, by my own government. Bioweapon research is extensive in several countries, but dominated by the US. The disclosed US budget is over $10 billion per year, and who knows what the black budget is. There is no legitimate purpose for this “research,” and it is illegal. No bioweapon can ever attack “enemies” without unacceptable risk of infecting “friends”. Over time, it is virtually certain that there will be leaks with horrific consequence. Lyme disease is a case in point.

Regardless of whether COVID19 came from a lab, we the people must demand disclosure of this secret “research”, and demand an end to the American bioweapons program in its entirety.

I know of no coalition organized to this end. We’ll have to start one.

Three useful books to get into this subject:

Bitten: The secret history of Lyme disease and biological weapons
Poisoner in Chief: Sidney Gottlieb and the CIA Search for Mind Control
Lab 257: The disturbing story of the government’s secret germ laboratory

Expert opinion

Here’s an interview by Dr Francis Boyle describing the big picture. Boyle is a professor of international law at University of Illinois with a history in both government and academia working on the limitation of biological weapons. In this interview he alleges:

  • The US program in biological weapons was jump started after WWII by giving a new home to Japanese and German scientists who had been doing horrific human experimentation.
  • These programs continue to this day, at Merck, U of NC, U of Texas, Harvard, NIH and elsewhere.
  • Anthony Fauci and NIAID have also been tied to sponsors of bioweapons research, specifically relating to making coronaviruses more lethal. Boyle sites this NYTimes article about the shift of NIAID money in 2001 to bioweapons applications.

    Wikipedia states: “Since the 2001 anthrax attacks, and the consequent expansion of federal bio-defense expenditures, USAMRIID has been joined at Fort Detrick by sister bio-defense agencies of the U.S. Department of Health and Human Services (NIAID‘s Integrated Research Facility) and the U.S. Department of Homeland Security…”
  • American bioweapons labs are sharing knowledge and specimens with foreign labs, including the high-security (BSL-4) Chinese installation at Wuhan.
  • Boyle believes that the origin of COVID was a Chinese-American research project, and that the proximate cause was an accidental release from the Wuhan facility.

Whoever knowingly develops, produces, stockpiles, transfers, acquires, retains, or possesses any biological agent, toxin, or delivery system for use as a weapon, or knowingly assists a foreign state or any organization to do so, shall be fined under this title or imprisoned for life or any term of years, or both. 
The Bioweapons Anti-Terrorism Act of 1989, authored and promoted by Prof Francis Boyle 

Since passage of this Act in 1989, offensive bioweapons research has been illegal in America. But Boyle claims that the research has continued under the guise of bioweapons defense or pandemic control. It is explicitly forbidden to genetically engineer pathogens for gain-of-function. That would mean deliberately making them more lethal or more contagious, or modifying an animal pathogen so that it is able to infect humans. Boyle charges that the most explicit violations have been outsourced to avoid technical violation of the Act, and some contracts have been with China.

This british news article claims NIAID gave a $3.7 million grant to the Wuhan Institute of Virology. The Virology Institute is in the same city where COVID-19 was first reported and is reputed to be the largest center for bioweapons research in China.  Here is a 2017 article from PLOS that comes from the Wuhan Institute, describing genetic experiments with SARS virus extracted from bats. In acknowledgments of support, the authors list NIAID as a funder.

And here is an  article that appeared on the Web yesterday, titled Evidence SARS-CoV-2 Emerged From a Biological Laboratory in Wuhan, China. The article is unsigned, but contains only verifiable information in the public domain. It cites this article from 2007, in which Chinese researchers in collaboration with Australian researchers modify a bat coronavirus to enable it to infect humans. “A second paper, from 2015, not only reiterates the first paper’s findings, but outright claims they ‘synthetically re-derived an infectious full-length SHC014 recombinant virus and demonstrate robust viral replication both in vitro [human cell cultures] and in vivo [mouse models].”” Also in the anonymous article are recent job postings from the Wuhan lab, seeking researchers expert in bat virus and cross-species transmissions.

Not in this article, but also of interest, were a FEMA report from last summer that was eerily prescient. A job listing at CDC last November seemed to anticipate a coming need for emergency management. And a conference sponsored by Johns Hopkins University and the Gates foundation last October simulated a coronavirus outbreak that started in China and spread worldwide.

Where did COVID come from?

I don’t pretend to know the answer, and based on publicly-available information, I don’t think it is knowable. But there is genetic evidence suggestive of human tinkering in the genome, and there are news stories suggesting the virus might have been developed either at the Wuhan Institute of Virology or at the American virology lab at Fort Detrick. There are even some suggestions that the American and Chinese bioweapons labs may be working together, sharing samples and exchanging funding. I will defer these stories for Part 2 of this report.

The official story is that the origin of the epidemic was the “wet market” where meat and some wild livestock is sold to consumers in Wuhan. This hypothesis was challenged by an article in Lancet, summarized here in Science Magazine. The authors interviewed the first 41 known patients in Wuhan, who were assumed to have contracted COVID concurrently from “patient zero”. For 28 of them, there were links to the Market, either personal or through a family member, but for 13 of them, no links to the Market could be identified. In this neighborhood of Wuhan, most people did shop at the Market, so the authors were more impressed with the 13 who had no link, and suggested that 28 out of 41 could have been consistent with a random sample of people from that neighborhood.

Other sources claim that all 41 had links to the nearby Oriental Hotel, a short walk from the Market, and that Patient Zero was an American soldier/cyclist. I will have more to say in Part 2.

Is it plausible that the SARS-CoV2 mutated directly from a virus that infected local bats? For this question, I am dependent on evolutionary geneticists for an opinion, and there is a divergence of opinion on the scientific literature. Geneticists who say evidence points to a laboratory origin are typically cautious, but they make these points:

  • Wuhan is in central-eastern China. The bats that carry SARS come from Yunnan province in the southwest, about 1,000 miles away. It is known that the bats were collected for research on the SARS virus conducted at the Wuhan laboratory.
  • The genome has at least 4 gain-of-function mutations (if they are mutations) compared to the ancestor bat virus. Gain-of-function mutations are rare compared to loss-of-function, and usually the virus makes its leap when there is one gain-of-function. 
  • About a fourth of the genome looks nothing like a coronavirus, and must have arrived via genetic recombination. The recombined part bears a resemblance to HIV. Viral genome recombinations do occur in nature, but this one is particularly hard to explain, since HIV is a fragile virus that can’t survive outside human blood. How would it get into a bat virus? 

  • COVID has some pathological effects never before seen in a coronavirus, including attack on the GI tract and on artery walls. There are some reports that the virus’s lethality comes from its attack on hemoglobin, the red blood molecule that carries oxygen around the body. 

The claim that the four insertions look suspiciously like HIV was considered shaky, but it is supported just today by a testimonial from a French Nobel laureate. In 2008, Dr Luc Montagnier was awarded the Nobel Prize in medicine for having discovered (much earlier) the HIV virus that causes AIDS. In this radio interview (in French) with Dr Jean-François Lemoine, Montagnier expresses his conviction that the SARS-CoV2 genome points to a laboratory origin. 

“Indian researchers have already tried to publish the results of the analyses that showed that this coronavirus genome contained sequences of another virus, … the HIV virus, but they were forced to withdraw their findings as the pressure from the mainstream was too great.”

Against these analyses, there is one prominent article in Nature Medicine that claims to “irrefutably” rule out a laboratory origin. Their basis for saying this is

  1. That computations suggest that the virus’s surface proteins are not ideal for binding to a human enzyme called ACE2, and that if the virus were designed in a lab, the designers would certainly have found the ideal solution, and used that instead.
  2. That the backbone of the virus contains a piece that looks like a pangolin virus, and the pangolin virus genome wasn’t published until very recently, so lab scientists could not have used it. 

(The pangolin is a rare, endangered species of armored anteater. It looks a bit like an armadillo.)

I’m always suspicious when scientists use words like “irrefutably” and “definitive”. But, more objectively, I would point out that none of the four bullet points above were refuted or even considered in the Nature Medicine paper.

There is also a statement in Lancet signed by 27 researchers which was prominently echoed in Science Magazine that “strongly condemns rumors and conspiracy theories”, without refuting any of the geneticists’ claims. They cite dozens of papers that they say support a natural origin, but, reviewing these papers, I find that they rather assume a natural origin. In fact several of the papers note difficulties with this hypothesis. One of the papers concludes on the basis of evolutionary models that, if SARS-CoV2 evolved naturally from a bat ancestor, it must have diverged at least 40 years ago. This is difficult to reconcile with the story that SARS-CoV2 jumped from bats to humans just last year.

My personal perspective inclines me to think the Lancet statement is politically motivated. I find it suspicious that prominent scientific publications have seen fit to deny claims that COVID had a laboratory origin, but none have refuted the considered details of those claims.

The US Military has been studying Coronaviruses as bioweapons 

It is undisputed that the US has an extensive bioweapons “research” program, and that modifying Coronaviruses to make them more dangerous is part of their program of work.

Here is the first person account of Judy Mikovits, who claims she worked in the 1990s at Fort Detrick, an Army biology lab in Maryland. Part of her job was to weaponize coronaviruses. This work was ongoing and controversial as late as 2015. President Obama approved and extended the programs. Three years ago, Nature reported that “the SARS virus has escaped from high level containment facilities in Beijing multiple times”. Only in China? Also in 2017, the House Committee on Energy and Commerce requested from CDC information about leaks from similar research facilities in the US, and they got back a 503-page document with all specifics redacted.

Conclusions

I find it suspicious that the debate over whether COVID came from a laboratory is being avoided with ad hominem attacks, blanket denials, and straw man arguments. I’m impressed that the people who are supporting a laboratory origin have promptly corrected their misstatements, while I see no such willingness on the other side.

The totality of evidence for the hypothesis is not conclusive. The most compelling evidence I see is 

    • Bats that are reputed to be source of the virus are found naturally more than 1,000 miles from Wuhan, but we know that the Wuhan Laboratory was studying just these bats and just this virus, and further that they were experimenting with modifying the spike protein that the virus uses for entry, to make it compatible with human ACE2. 
    • The virus gained several new abilities on emerging from bats. Usually, we would expect just one.
    • Closely related to this, the genome shows four RNA segments that differ substantially from the bat ancestor where, again, we would expect just one.
    • Genetic analysis indicates that the divergence from bats happened decades ago, and yet the disease only appeared in humans recently.

I take Francis Boyle’s testimony quite seriously. He’s a career expert in biological warfare. Luc Montagnier is as credible a source as they come, but I don’t know what to make of how certain he seems about genetic evidence that others have said is inconclusive.

In Part 2, I hope to tie in American bioweapons research. Linking the American and Chinese bioweapons programs seems stranger than science. Teaser: Evidence suggests that SARS-CoV2 has been in America longer than it has been in China.

Overreaction

I have become concerned that dangers of the COVID pandemic have been overstated, perhaps deliberately. The containment measures adopted in most Western countries have had little effect on the spread of the virus, but they have been maximally disruptive of our economic and cultural lives, and have produced loneliness and isolation, while throwing millions of people living on the edge of their means into desperate poverty.

(graphic is my own, based on data from http://OurWorldInData.org/coronavirus )

Here is Dr John Ioannidis, professor of epidemiology at Stanford Medical School, speaking to this point.

The good news is that daily deaths from the virus have peaked worldwide, and begun their decline. Since death rates trail the rate of new infections by 2-3 weeks, we expect that spread of the virus peaked worldwide in mid-March and in the US 10-12 days ago.

Does it make sense to continue with policies of economic shutdown and social isolation now that COVID is declining? The answer depends on whether these policies have been responsible for the decline, or whether COVID is declining for other reasons. I tend to think “other reasons”, but I’ll try to present both sides. I recognize that there is no definitive proof, but only judgment in the face of diverse evidence. My bias is that in such situations I lean toward a contrarian view. 

There are three factors which I consider to be plausible reasons for the decline of COVID:

  1. Warmer weather is arriving
  2. Doctors are learning how to treat COVID from others’ experience
  3. Saturation / herd immunitymost people have already been exposed and have built up immunity

1. Respiratory illnesses tend to be seasonal. Reasons for this are not fully understood, and there may be several factors [ref, ref, ref]. Every year, there is a flu season, and deaths from flu are down almost 100-fold from winter to summer.

Is COVID19 likely to be an exception to this rule? We already see that cold countries have much higher incidence and much higher death rates from COVID than warm countries.

India may be the most striking example, a very hot country with weak central controls and a large population that is unreached by medical services. There has been no effective lockdown in India, yet COVID deaths per million population are comparable to the US.

The above leaves me very hopeful that, like SARS and MERS and countless strains of cold and flu that went before it, COVID is dying out as spring weather sets in.

In this week’s Science magazine, an article (summarized on ScienceBlog) argues that unlike these predecessors, COVID may not slow down with warm weather. As I read it, their basis for this claim is that these other seasonal illnesses spread sufficiently to engender herd immunity in the spring, but because of lockdown COVID has not crossed that threshold. Both these assumptions, in my view, are suspect. There is no scientific agreement why respiratory infections are so deeply seasonal, but it’s an empirical fact. If it were just about herd immunity, then we would see some waves of cold and flu that start in the spring or summer and die out by fall; but we rarely see this. And below I argue that if COVID is as contagious and as persistent as is claimed, then we (America and the world) may be acquiring herd immunity already.

2.  In just a few months, doctors have shared their successes, and there are now several promising treatments (though there has not been time for blinded, controlled clinical trials).

3.  It’s more difficult to know whether herd immunity is already being established around the world. We depend here on experts and on computer models. Here’s an expert (Professor Knut Wittkowski, head of Rockefeller University’s Department of Biostatics):

COVID is reputed to be extraordinarily contagious, and if that is so, I would argue that the kinds of half-measures used in the US and other Western countries are slowing but not preventing spread of the virus. People are still shopping in supermarkets and drug stores. Labs are claiming the virus remains active on surfaces we touch for 24 hours, but we are still freely sending and receiving mail and packages. 

If claims that non-symptomatic carriers can be contagious are credible, then surely a majority of people have been exposed by now, enough that our immune systems have generated the first few antibody-producing B cells, which can multiply rapidly (exponentially) when we are exposed to more virus.

If claims that non-symptomatic carriers can be contagious are not credible, then why are we locking ourselves away from people who look and feel perfectly healthy?

Herd immunity is the population’s usual way to stop an epidemic, and social distancing may have slowed the acquisition of herd immunity, but by now we have all touched someone who has touched someone who has touched someone who has been exposed.

Possibility number 4: Can we credit the lockdown for present decline of COVID?

There are many politicians and policymakers who will line up to take the credit for COVID’s decline. We would all like to think that the individual sacrifices we are making these months have achieved a collective purpose.

Empirically, we can never resolve the counter-factual, “what if we had not locked down?” The best we can do is to compare regions that have locked down to regions that have remained open. If we do this, then, subject to the caveat that all these numbers have been gamed in the reporting, we have to conclude that the evidence for effectiveness of lockdown is not strong.

The scale on the left is in deaths per million population. For comparison, the ten most recent flu seasons in the US have caused death rates ranging from 34 to 175 (according to CDC).

Rates of COVID deaths vary widely. But countries that have locked down do not appear to have an advantage over countries that have not.

As of this writing, there are 8 US states that have not locked down by executive order: Arkansas, Iowa, North and South Dakota, Oklahoma, Nebraska, Utah and Wyoming. Their death rates per million are, respectively, 11, 15, 7, 12, 27, 9, 6, and 3, all well below the national average of 77.

Looking at the state and country data, it appears to me that lockdown has been a response to high COVID mortality, rather than a preventer in advance of mortality. Perhaps this is the nature of political humans, to respond only after a threat becomes serious. But as policy, it is (to use the technical term) bass ackwards. Quarantine measures are very effective in early stages of an epidemic, but of limited usefulness once the epidemic has gotten its toehold in the population. 

China locked up quickly, cutting off all travel out of Wuhan in late January. Rules were liberalized and commerce resumed 2 months later. This makes sense. The US waited too long to lock down, and now, at a time when isolation measures are least useful, they are being intensified. I fear that the economic, psychological, and cultural consequences of this new wave of restrictions will be severe, while the epidemiological benefit will be marginal.

Greece locked down promptly and probably saved the whole country an ordeal. (I’m grateful to Zisos in the comment below.)

Theoretically, is there reason to believe that limited social contact and economic activity slows the spread of the disease. Yes, without a doubt. But is there reason to believe that it can affect the number of people who will eventually be exposed? Much less clear. I would say, only if the disease is truly wiped out in its early stage, before it becomes widespread and engenders herd immunity.

Costs

Heaven knows we all could use a few weeks of vacation. But we wouldn’t choose to spend it indoors, apart from our friends, deprived of cultural events and social supports, church, Kiwanis and AA meetings and yoga classes and folk dancing and community theater. 

Congress has appropriated $2.3 trillion for the Covid Relief Act (CARES), but some claim the true cost is $6 trillion. On Wall St, the S&P lost $10 trillion in March. If we were willing to spend any tiny fraction of this money on a rationally-designed program of public health, the number of lives saved would be far greater than the highest estimate of COVID’s potential toll. Diabetes is an eminently preventable disease that causes more deaths every year than COVID will cause over its entire lifetime, and NIH spends $0.0002 trillion to prevent it. 

Millions of small businesses are bankrupt. Tens of millions of people are unemployed. Depression and isolation have major impacts on health, much more so if they are prolonged as some are proposing.

Politics

I am all too aware of the potential for scientific opinion to be swayed by money and political influence. In the shadow of these unimaginable economic costs, there are a few who are profiting handsomely. Why did so much of the CARES money go to banks? Why is so much of the reporting promoting a vaccine to rescue us from COVID, when many past attempts to develop a coronavirus vaccine have been halted because test animals died. Vaccines are the most profitable segment of the pharmaceutical market, and drug companies are spared by law the costs of safety tests and are indemnified from legal liability.

The thing that keeps me up at night is not fear that I might catch the disease, but fear that Constitutional liberties in America are being systematically erased. “Hate speech” laws are being used to censor inconvenient political truths. The US government is barred by the First Amendment from direct censorship, but Google and Facebook and Twitter are immune because they are private companies, and they collectively have enormous influence on what we can find out and what we can discuss. They are doing the government’s bidding, suppressing dissent.

Dear readers, this is how fascists take power. They don’t say “Ha ha ha HA…now I’ve got you where I want you.” Rather, they get everyone scared, declare an emergency, and they offer to save us all from danger.

Read Naomi and Naomi. Remember the Reichstag fire. Discover, if you have not already, the shocking history of Operation Northwoods. Read Sinclair Lewis, It Can’t Happen Here (1936). 

Eternal vigilance is the price of liberty has been attributed to Thomas Jefferson so often that he might as well have said it.

The “Scientific World-view” Needs an Update

At the end of each year, I take the liberty of speculating on a scientific subject beyond the usual scope of this blog. This one is the broadest yet.


We live on an island surrounded by a sea of ignorance. As our island of knowledge grows, so does the shore of our ignorance.
— John Archibald Wheeler

The more you know, the more you know you don’t know.
— Mrs Haine, my 6th Grade teacher (1961)

It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so.
erroneously attributed to Mark Twain

The community of scientists has bequeathed to us a picture of the world that is fundamentally wrong. The picture so many of us carry in our minds is derived from 19th Century science. It is utterly inconsistent with quantum physics, and has been contradicted directly by a body of research on powers of the mind that has been marginalized by the mainstream. Somehow, the picture has survived and become ossified in some of the smartest minds on the planet.

The big-picture stories that our culture carries have consequences for the way we live our lives and the way we organize our communities. The ”scientific world-view“ is not only deeply at odds with science, it is also related to the ways our world is falling apart—the sense of powerlessness and hopelessness that we carry, and especially the sense of isolation and existential loneliness.


What is the scientific world-view?

How do we know it is wrong? Six stories

  1. The Anthropic Principle
  2. Memory is not only in synapses. Thought is not confined to brains.
  3. PSI research, especially the REG experiments of Jahn and Dunne
  4. Bell’s Theorem is a proof that the observer participates in the creation of reality.
  5. QM of many-particle systems
  6. Quantum Zeno Effect

What will our world look like after the coming paradigm shift?


What is the scientific world-view?

Physical reality is the only reality. Particles and fields are real. Thoughts, emotions, desires are abstract concepts useful to us, but not fundamental constituents of reality. Elementary particles can be visualized well enough as miniature billiard balls. They interact with their near neighbors, following fixed laws. The laws of physics explain properties of the chemical elements, and the known laws of chemistry and physics are sufficient to understand biology, ecology, sociology, and on up.

Life is subject to the same physical laws as non-living matter. Life has no fundamental relationship to the physical universe. It’s just something that happened, going along for the ride.

There is no room for free will. Our feeling of making choices must be an illusion. The future is determined by the past plus pure chance. “Quantum random” is the gold standard for random events absolutely unpredictable and unrelated to anything else in the world.

This view is sometimes called “physicalism”—the physical world is the only thing that is real; and it is sometimes called “reductionism”—everything on large scales can be explained in terms of emergent, aggregate properties of smaller systems, coming down ultimately to the level of particles.

The perspective of the mechanical universe was inherited by Nietzsche, who declared that “God is dead”. There followed the nihilistic movements of the 20th Century: Dadaism, Existentialism, atonal music and punk rock, Post-modernism. If, as Yeats says, “the best lack all conviction…”, perhaps part of the reason lies in the fact that our best and brightest have been drawn to the Scientific World-view, with its subtext that all is mechanical, random, and ultimately meaningless… Am I being unfair, linking all this to a belief that the only things that exist are particles and fields?

How do we know it is wrong?

1. The Anthropic Principle

All physical theories rely on fundamental constants, numbers that are arbitrary inputs that just happen to be what they are. Examples are the speed of light, the mass of the electron, the size of Planck’s constant (which scales quantum effects), and the strength of gravity. After accounting for the arbitrariness of scales in mass, length, and time, there are about 20 such arbitrary constants. Beginning in the 1970s, it has been noticed that the kind of universe we live in depends sensitively on these numbers. In fact, many of them seem to be very finely tuned in the sense that if they were a little bit different from what they are, our universe would be vastly simpler and less interesting than it is. For example, if the gravitational constant were smaller, then there would be no galaxies or stars, just hydrogen and helium forever spread through space. If the strong force were a little less strong, there would be no chemical elements except hydrogen; and an extremely precise coincidence accounts for the abundance of carbon, which otherwise would be a trace element, far too rare to support life. Here are three books on the Anthropic Principle (Barrow & Tipler 1988, Davies, 2007, Rees, 1999).

How do scientists interpret this fact? The majority eschew any implication of design by positing that our universe, infinite though it may be in space and time, is but one among a truly stupendous number of universes that exist. The vast majority of such universes are incapable of supporting life. The very fact that we’re here to ask the question explains the special combination of constants that characterizes our particular universe.

But to me, all those extra universes are a gross violation of Occam’s Razor. The “Anthropic Coincidences” say to me that life is a fundamental reason why our universe is the way it is. I connect this idea to experiments of Robert Jahn cited below.

2. Memory is not only in synapses. Thought is not confined to brains.

Every October, Monarch butterflies across ⅔ of North America turn around and fly home, up to 2,000 miles, to find the exact tree (in California or Mexico) where their great, great, great, great grandparents overwintered the previous year. How is the road map transmitted from generation to generation? Plants don’t have anything that corresponds to nerves or brains, but Monica Gagliano has demonstrated that plants can learn, can store memories, can sense their environment and make decisions that have all the appearance of signal processing. Even single-celled ciliates can learn and remember. Caterpillars’ nervous systems are dismantled completely in the chrysalis, yet memories of the caterpillar survive in the butterfly. Humans who receive a heart transplant can take on some of the tastes, interests, and personality traits of the heart donor. There are too many stories of young children remembering verifiable details of a past life to dismiss the possibility of reincarnation.

Memory plays such a key role in defining our identities and personalities. These examples indicate that memory is not just in our brains, but at least sometimes can be in tissues other than nerves, or even outside the body altogether.

3. PSI research, especially the REG experiments of Jahn and Dunne

Almost everyone will acknowledge precognitive dreams or uncanny premonitions. We have learned to dismiss these as chance occurrences, coincidences without significance. We may be unaware there are surveys and statistical studies of such stories, arguing that explanations from selective memory or embellished storytelling are absurdly inadequate to account for their frequency and specificity. Studies of telepathy and precognition under laboratory conditions complement this anecdotal evidence and lend it credence. A robust, incontrovertible body of research on the paranormal demonstrates the reality of telepathic communication with an aggregate p value that is astronomically small. (If this assertion is new to you, I recommend Etzel Cardeña for a scientific review, or Dean Radin for an entertaining overview backed by rigorous science. A protocol called Ganzfeld produces consistent effects of size 14%, averaged over thousands of experimental trials in the last 30 years.)

I find special significance in a series of experiments done by Brenda Dunne and Robert Jahn, Dean of the Princeton University School of Engineering, over a 35-year period, using Random Event Generators (REG). They showed that the conscious intent of a human can bias the results of a quantum random process. This is of special significance because it cries out to us to consider that consciousness may play a role in fundamental physics. Standard quantum physics tells us that exactly half the information necessary to predict the result of any experiment is coded in the wave function. The other half does not exist. An element of pure randomness enters into every observation of reality. Jahn and Dunne’s results have been corroborated with completely different equipment, using optical interference fringes instead of REGs. They offer us a radical idea: that “quantum random” may not be random at all, but the gateway by which conscious intent creates physical effect. I’ll have more to say below.

James Carpenter cites evidence that psychic abilities inform our subconscious minds just as commonly as other, well-acknowledged subliminal input, but most of this information is never delivered up to the conscious mind that sits atop a far more extensive cognitive process. We who have been raised to trust our senses and our reason suppress these ubiquitous psychic messages far more thoroughly than indigenous peoples, who routinely regard extra sensory perception as part of their everyday reality.

4. Bell’s Theorem is a proof that the observer participates in the creation of reality.

Irish/Swiss physicist John Bell proved (1964 original) that the known and accepted principles of quantum mechanics imply that every observer affects what is being observed, and furthermore that that effect transcends space and time. The observer affects anything that has ever interacted with what he observes, and the effect can act on the past as easily as the future. (Subsequently, it has been verified in lab experiments that real physical systems do behave in this way, so you don’t even have to accept quantum mechanics to know that observers affect what they observe.

The implications of this force us to rethink the idea (fundamental to the scientific method) that there is an objective physical world, independent of the scientists who study it. Do we find a clue to the physical basis of the intention effect that Jahn and Dunne observed? Might we imagine that the Big Bang event (when, for a tiny fraction of a second, all matter was packed so tight that every particle interacted with every other) was caused in some sense by our looking out at the universe 14 billion years later?

John Wheeler describes the observer’s participation in creating reality by analogy with a game of 20 Questions, in which the observer asks the question and Nature makes up her answers ad libitem.

We think of observers as independent humans with free will, but the model of participatory co-creation raises the question, how does it come about that there is so much we can agree on in the one universe co-created by you and me and at least 7 billion other observers? Considering this question has led me to the conclusion that our consciousnesses are not really so independent as we experience them to be. This idea seems puzzling and wildly counter-intuitive, but it aligns well with the wisdom of mystics throughout the ages.)

5. QM of many-particle systems

Quantum mechanics is essentially about situations, not particles. We associate quantum physics with experiments and high-energy particles and with physics of the atom. The reality (rarely acknowledged) is that we do quantum experiments with single particles because that’s all we know how to calculate. Quantum mechanics provides a prescription for calculating future probabilities based on present measurements, but that calculation is utterly intractable except in the very simplest cases. Yes, the simple Schrödinger equation (not even relativistic QM or second-quantization quantum field theory) becomes completely intractable for any system more complicated than two particles. This is different from classical mechanics. You can solve the equations of motion for 2 particles in classical mechanics with twice as much computational effort as 1 particle, and 3 particles require 3 times as much computation. But in QM, a 2 particle system is represented by a wave function in a 6-dimensional configuration space, and a 3-particle system requires 9 dimensions, etc. This is sooo different from tracking one more particle in the same 3-dimensional space. In practice, a 2-electron computation requires a billion times more computing power than a single electron, and a 3-electron computation is beyond the conceivable ability of any transistor-based computer that will ever be built. A garden variety biomolecule typically contains a few thousand electrons.

(In practice, physical chemists do computations of large atoms and complex molecules all the time, but to do so they start with the fiction that electrons don’t interact with one another (except through the Pauli exclusion principle) and then correct their calculation based on experimental measurements of chemical properties.)

We do experiments to test quantum mechanics on systems with a single particle, isolated through careful laboratory conditions, because that’s all we know how to calculate. But quantum mechanics is fundamentally a theory of systems. It applies naturally to many-particle systems, and to single particles in idealized circumstances that only obtain in specialized laboratories. The observations that we make in everyday life measure macroscopic properties of Avogadro’s numbers of particles. We cannot in practice perform quantum calculations for such systems, so we do non-quantum calculations that work well in most circumstances.

But we know there are exceptions. There are bulk quantum properties that occasionally surface, and we understand them only dimly. Superconductivity was observed for 50 years before there was a theory of it. Lasers are another bulk quantum phenomenon. Low energy nuclear reactions have been reported in dozens of laboratories around the world, but there is no accepted theory for them. They are a complete surprise to physicists who work with the standard approximations [New Scientist article]. Evidence from a handful of experiments suggests that plants and even bacteria are able to harness nuclear physics to transmute one element into another [reviewed by C. L. Kervran]. Biological nuclear transmutation is an observed phenomenon that defies explanation in terms of the usual approximations made by physicists when they apply quantum mechanics to macroscopic objects.

There is a small, pregnant field called quantum biology which has carefully documented a few examples of biological effects. I hold with those who speculate that life is an essentially quantum phenomenon, and that the observer effect is being harnessed continually to maintain the living state. A suggested approach to this topic derives from the

6. Quantum Zeno Effect

If you don’t watch an atom of Carbon 11, it will emit an electron and transform itself into Boron in about 20 minutes. But if you observe it after 1 minute, chances are 95% that it hasn’t decayed yet, and the 20 minutes starts all over again. You can observe it much more often, say every second, and then the probability that it has decayed in that time can be infinitesimally small. Curiously—this is a purely quantum effect—frequent observation helps to keep the atom in its metastable C11 state, and can greatly delay the average half-life. This is called the Quantum Zeno Effect (named for the Zeno paradox from the ancient Greek philosopher).

It is only slightly more complicated to use the same principle to guide one quantum state into another. You can demonstrate this easily in asimple home laboratory setup. If you polarize light with a horizontal polarizing filter, then none of it will get through a second filter that is rotated to be vertical. But if you insert a third filter halfway between the two, and you rotate that filter 45 degrees, then half the originally polarized light gets through the 45 degree filter, and half of that gets through the final vertical filter. The result looks like magic. You have complete dark at the back end, then you insert another dark filter into the system, and the light coming out the back becomes visibly brighter. You can extend the idea by using a dozen or a hundred different filters between the front (horizontal) and back (vertical) polarizers, with each one rotated just a smidgen compared to the previous one. The result is that you gradually rotate the polarization in many steps, and almost all the light that was horizontally polarized emerges as vertically polarized.

This is called the Inverse Quantum Zeno effect, and it could be used (in principle) to guide complex quantum systems along any desired path. In a brilliant book published 20 years ago, Johnjoe McFadden outlines a way in which the Quantum Zeno effect might be a breakthrough concept in explaining the origin of life and the efficiency of the evolutionary process in general.

Combining the Jahn experiment with the Quantum Zeno Effect, we can imagine how consciousness (or subconscious intent) might guide chemical processes inside a living cell, such that living cells really are subject to different laws than non-living matter. This is a return to vitalism, that was discredited by 19th Century science.

What will our world look like after the coming paradigm shift?

Life is not an opportunistic happenstance that took advantage of a set of arbitrary rules of physics to construct a self-reproducing hypercycle of chemical catalysts, primed to transform itself by the laws of chance and competition for resources into a diverse community of “forms most beautiful and wonderful”.

Conscious awareness is not an illusion, nor an epiphenomenon that arises whenever a sufficiently sophisticated computational algorithm achieves a threshold of self-reference.

While quantum mechanical equations are well-established, there are conflicting interpretations of what they mean . What is a measurement? And what happens when the wave function collapses. When we take Jahn and Dunne into account, there is a strong preference for the view that consciousness has an independent existence, outside the equations of QM, and that it is conscious observation that collapses the wave function. (This perspective was championed by von Neumann, Wigner, and others, but is currently out of fashion.)

Beyond this, anything I say about the coming paradigm will be hubris and foolish speculation. I’m not going to let that stop me.

There is a new science waiting to be formulated that will fundamentally redefine the way we think of our relationship to the universe and to the biosphere. It can only be called “biophysics”, though it will have nothing in common with what today is called “biophysics” (=application of known principles of physical chemistry and of fluids to cell structures.) My guess is that the new theory will embrace Cartesian dualism, and bring consciousness into the fold of physics, as a third realm of existence distinct from particles and fields.

Quantum biology is going to grow and morph from a quirky intersection of two largely-independent fields of science, and become our fundamental understanding of what life is. The non-living world is steered and guided loosely by a global Conscious observer or by many competing or reinforcing consciousnesses (small “c”). But a living being has an observer inside who is constantly asking the question of Schrödinger’s cat, “Am I alive or dead?”. The Quantum Zeno effect sustains life.

Medical research is going to realize that what we have swept aside as the “placebo effect” is a window into a much richer realm in which the mind influences the body via attention, expectation, and intention. Western medicine based on chemistry will be seen as tapping only half the potential ways in which we can create health and wellness.

The tension will be resolved between Christians who insist that all life is the handiwork of an old man who lives in the sky, and the Darwinian fundamentalists who insist that all evolution from a dilute pool of simple molecules to the diverse biosphere has been the result of chance mutations and a race for the fastest reproducer. Evolution is directed by consciousness through the Quantum Zeno Effect, as Johnjoe McFadden described 20 years ago .

The Life Extension movement and the transhumanist movement will embrace the solid evidence for reincarnation , and for the reality that consciousness is flavored by but not dependent upon a physical brain . Freed from the desperate urgency that derives from belief that death is the end of all, we will continue to pursue life extension, but moved by love of life, rather than fear of death; and we will supplement the tools of biochemistry and regenerative medicine with technologies of the traditional shamans and spiritual masters.

There is a biological destiny in which we all participate, a guiding hand pulling us toward an ever richer and more diverse biology. Planet Earth is probably just one among trillions of ecosystems that are destined to merge and co-evolve as humans learn the technology of space travel from alien visitors who are, in fact, far less alien than we imagine.

New Aging Clock based on Proteins in the Blood

Methylation clocks are far and away the most accurate markers of a person’s age, and so are a promising tool for evaluating anti-aging interventions, but they are a bit of a black box. We know from statistics that certain places on chromosomes become steadily methylated (or demethylated) with age, but we often don’t know what effect that has on expression of particular genes. 

For the first time, a clock has been devised based on proteins in the blood that is comparable in accuracy to the best methylation clocks. This has the advantage of being downstream of epigenetics, so it is less of a black box. What can we learn from the proteins that are increased (and decreased) with age?


I’ve written often and enthusiastically about the utility of methylation clocks for evaluation of anti-aging interventions [blog, blog, blog, journal article]. This technology offers a way to promptly identify small age-reversal successes (perhaps not in individuals, but averaged over a cohort of ~50 to 100 subjects). Before these tests were available, we had no choice but to wait — usually 10 years or more — for enough experimental subjects to die that we could be sure the intervention we were evaluating affected life expectancy. (This is the plan of the worthy but ridiculously expensive TAME trial promoted by Nir Barzilai.)

Can we rely on methylation clocks to evaluate anti-aging interventions? If we succeed in setting back the methylation clocks, are we actually making the body younger? The answer depends critically on the relationship of methylation to aging. 

The majority view derives from the belief that aging is a passive process, while methylation (epigenetics) is a process under tight evolutionary control. The majority holds that methylation changes with age are a response to the damage that accrues unavoidably, and the changes in gene expression that result are actually the body’s best effort to fight back against this damage.

My view is with the minority. Aging is a programmed process (evolved, I believe, for the purpose of demographic stability). Changes in methylation and epigenetic changes generally are the primary cause of aging. Far from being a response to damage, epigenetic changes with age invoke the very signals that cause damage (e.g. inflammation) and simultaneously cut back our repair processes (e.g., detoxification and autophagy). 

If you hold with the majority, then setting back the methylation clock (with drugs or gene therapies or …) could actually shorten our lifespans. Setting back the methylation clock means thwarting the body’s efforts to rescue itself. We should not use methylation clocks as a measure of whether a particular technology has achieved rejuvenation. 

If you hold with the minority, then setting back the methylation clock is an indication that whatever we have done has struck at the root cause of aging, reversing the epigenetic changes that are the primary driver of senescence.

(In the scientific community of aging, there are a few of us speaking directly about the primary importance of epigenetics [Horvath, Barja, Johnson, Rando, Mitteldorf ], and many more who are tacitly accepting the idea that setting back the methylation clock is a good thing. Most scientists remain skeptical and are not embracing the methylation clocks as a reliable gauge for anti-aging technologies [Han, West].)

The battle lines are not clearly drawn, and the basic conflict in beliefs is not yet out in the open. But resolution of this issue is a major next step for geriatric research. I say this because it is likely there is some truth on each side. Most of the epigenetic changes with age are drivers of senescence (Type 1), but some are the body’s attempts to rescue itself from damage (Type 2). Each of the methylation clocks that are now available averages hundreds of methylation sites, and it is likely that they are a mixture of sites that play these two opposing roles. [background in my October blog]

So the urgent need is for a clock that is constructed exclusively of drivers of aging (Type 1), so that we can use it with confidence as a measure of whether an intervention that we are testing will extend lifespan.

Can we design experiments with the methylation clock that would tell us which of the age-related methylation sites are Type 1 and which are Type 2? It’s hard to know how to begin, because we don’t yet have a way to do controlled experiments. What we want is a molecular tool that will methylate a selected target CpG site while leaving everything else untouched, and we don’t have that yet. (It may become feasible as CRISPR technology improves.) Based on present technology, the only way to tell for sure is to compare how different interventions affect the methylation clocks in thousands of experimental subjects, and then wait and wait and wait and see how long these subjects live. LEF is undertaking this ambitious plan, but it will be decades before it bears fruit.

Clocks based on the proteome

This month, a new clock came out of the Stanford lab of Tony Wyss-Coray that is based on measuring levels of proteins in blood plasma, rather than patterns of methylation on chromosomes. It is not the first proteomic clock, but it is the most accurate. For some of the proteins that feature prominently in the clock, we have a good understanding of their metabolic function, and for the most part they vindicate my belief that epigenetic changes are predominantly drivers of senescence rather than protective responses to damage

Wyss-Coray was one of the people at Stanford responsible for the modern wave of research in hetrochronic parabiosis. In a series of experiments, they surgically joined a young mouse to an old mouse, such that they shared a blood supply. The old mouse got younger and the young mouse got older, though both suffered early death from their cruel and macabre condition (excuse my editorial license). Later, it was found that chemical constituents of the blood plasma (proteins and RNAs but not whole cells) were responsible for moderating the effective ages of the animals. As part of the current study, Wyss-Coray compared the proteins in the new (human) proteome clock with the proteins that were altered in the (mouse) parabiosis experiments, and found a large overlap. This may be the best evidence we have that the proteome changes are predominantly Type 1, causal factors of senescence. (Here is a very recent BioRxiv preprint of a UCSD study relating epigenetic clocks in people to mice and dogs.)

 

Different proteins change at different ages

The Stanford group notes that some of the proteins in their clock increase in the blood with age and some decrease. Typically, the changes do not occur uniformly over the lifespan. Though none of the curves is U-shaped (on-off-on, or off-on-off), some proteins do most of their changing early in life, and some later. 

The group identifies three life periods and three groups of proteins: mid-30s, ~60yo, and late 70s. 

At young age (34 years), we observed a downregulation of proteins involved in structural pathways, such as the extracellular matrix. These changes were reversed in middle and old age (60 and 78 years, respectively). At age 60 years, we found a prominent role of hormonal activity, binding functions and blood pathways. At age 78 years, key processes still included blood pathways but also bone morphogenetic protein signaling, which is involved in numerous cellular functions. Pathways changing with age by linear modeling overlapped most strongly with the crests at age 34 and 60 years (Fig below), indicating that dramatic changes occurring in the elderly might be masked in linear modeling by more subtle changes at earlier ages. Altogether, these results showed that aging is a dynamic, non-linear process characterized by waves of changes in plasma proteins that reflect complex shifts in biological processes.

This paragraph doesn’t tell all we need to know to decide which changes are Type 1 and which Type 2. There is more information in their Supplementary Tables 5 and 14. I don’t have the expertise in biochemistry or metabolics to extract the information, but if you do and you are reading this, I hope you will contact me.

 

“Intriguingly, the three age-related crests were largely composed of different proteins”

For example, the top four proteins changing at age 78 are

  • PTN.3045.72.2
  • CHRDL1.3362.61.2
  • SMOC1.13118.5.3
  • CCDC80.3234.23.2

With Google searches, what I could find about all of these was that they have been previously identified as CV risk factors, and they all are increasing rapidly at age 78. The third one (SMOC) is described as binding calcium, which presumably affects blood clotting. All are clearly Type 1 — an important bottom line — but it would be nice to know more about their metabolic roles. Caveat: the technology used to measure these proteins comes from SomaLogic, and their mission was to look for proteins that could signal CV risk.

I could find nothing about numbers 5 through 8

  • WFDC2.11388.75.3
  • PTGDS.10514.5.3
  • SCARF2.8956.96.3
  • SVEP1.11178.21.3

It is interesting to me that almost all the proteins identified as changing rapidly at age 78 are increasing. The few I have identified seem to be increasing in a way that makes us more vulnerable to CV disease. It is natural to interpret this phenomenon as programmed aging.

In contrast, a few of the fastest-changing proteins at age 60 are decreasing (though most are increasing). The one decreasing most significantly is identified as SERP a2-Antiplasmin, which seems to me to be involved in autophagy, but I’m out of my depth here. At age 60, the proteins increasing most rapidly is PTN.3045.72.2, another CV risk factor, and GDF15.

GDF15 deserves a story of its own. The authors identify it as the single most useful protein for their clock, increasing monotonically across the age span. It is described sketchily in Wikipedia as having a role in both inflammation and apoptosis, and it has been identified as a powerful indicator of heart disease. My guess is that it is mostly Type 1, but that it also plays a role in repair. GDF15 is too central a player to be purely an agent of self-destruction. 

 

Why not make use of different proteins at different ages in constructing the clock?

The implication is that a more accurate clock can be constructed if it incorporates different information at different life stages. Age calculation should be based on different sets of proteins, depending on how old the subject is. (You might object that you have to know how old the subject is in order to know which proteins to emphasize, but this problem is easy to overcome in practice, by calculating age in two stages, a rough cut using all proteins, and then a fine tuning based on proteins that change most rapidly around that age.) In my reading of the paper, the Stanford team prominently notes that patterns of change roll along in waves through the lifetime, but then they fail to incorporate this information into their clock algorithm, which is independent of age. This seems to be a lost opportunity. The methylation clocks, too, might gain accuracy by this approach. (All the Horvath clocks use the same collection of CpG sites for young and old alike.)

Maybe I am misreading the text about how the clock was constructed, and maybe the authors have already optimized their algorithm with different proteins at different ages. The text in question is

To determine whether the plasma proteome could predict biological age, we used glmnet and fitted a LASSO model (alpha= 1; 100 lambda tested; ‘lamda.min’ as the shrinkage variable was estimated after tenfold cross-validation). Input variables consisted of z-scaled log–transformed RFUs and sex information. [ref]

In any case, I know that none of the Horvath clocks have been derived based on different CpG sites at different ages, and this suggests an opportunity for a potential improvement in accuracy.

Comparison to Predecessor

Last year, this paper was published by a group at NIH, describing their own study of how the human proteome changes with age. Their sample was smaller, but they also found that aging is characterized more by increasing plasma proteins than by proteins lost with age. They also singled out GDF15 as their most prominent finding. They didn’t look for different proteins at different ages, as the Stanford group did. “The functional pathways enriched in the 217 age‐associated proteins included blood coagulation, chemokine and inflammatory pathways, axon guidance, peptidase activity, and apoptosis.” The clock they constructed showed correlation with age r=0.94, compared to r=0.97 for the new Stanford clock. (The difference between 0.94 and 0.97 implies that the Stanford clock is twice as accurate (half the uncertainty)).

 

The bottom line

If proteome clocks eventually replace methylome clocks, the process will take several years. Proteome lab procedures are more complicated and more expensive than technology for measuring methylation. More to the point, the Stanford results must be replicated by independent labs, and must be stress-tested and cross-checked against other markers of aging. For the next few years, we have more confidence in the methylation clocks, which have been through this process and found to be solid.

But starting immediately, we can use the specifics of the proteome clock to engineer anti-aging remedies. The plasma proteome is directly related to the metabolism, and it can be altered with intravenous transfusions. (We cannot yet directly directly modify the methylome.) So let’s apply the results of the proteome clock. Most of the significant changes with age involve increases in certain proteins, so we will have to either remove these from the blood or infuse antibodies designed to bind to them and neutralize them. The infusions will probably have to be carefully titrated so as not to overdo it.

The large and crucial question hanging over the clock technologies (methylome and proteome) is which of these changes are drivers of senescence and which are protective responses to damage.  The new proteome data provides reassurance that the predominance are of Type 1 (drivers of aging), and we can safely use them to gauge the effectiveness of our anti-aging interventions. But this issue is central, and deserves explicit attention. Every methylation site and every plasma protein that we use to evaluate new technologies should be individually validated as Type 1.