­A Skeptic Over Coffee – Young Blood

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A tragic tale of a star-crossed pair,
science vs. a journalist’s flare

When reporting on scientific topics, particularly when describing individual papers, how important is it for the popular coverage to have anything to do with the source material? Let’s take a look at a recent science paper from Justin Rebo and others in Nature Communications and the accompanying coverage by Claire Maldarelli at Popular Science

Interest in parabiosis has increased recently due to coverage of scientific papers describing promising results in mice and the high-profile of some parabiosis enthusiasts. Parabiosis, from the Latin for “living beside”, typically has involved stitching two mice together. After a few days the fused tissue provides blood exchange through a network of newly formed capillaries.

The most recent investigation into the healing effects of youthful blood exchange from Rebo et al. expands the equipment list used for blood exchange beyond the old technique of duct-taping two animals together surgically joining two animals. Instead of relying on the animals to grow new capillary beds for blood exchange to occur, the authors of the new paper used a small pump to exchange a few drops of blood at a time until both mice had approximately the same proportion of their own blood and that of a donor and vice-versa.

According to the coverage from Popular Science:

While infusing blood from a younger mouse into an older mouse had no effect on the elderly mouse in the latest study, infusing blood from an older mouse into a younger one caused a host of problems in organs and other tissues.

Just a few paragraphs further Maldarelli quotes Conboy (last author on the paper) as saying “‘This study tells us that young blood, by itself, cannot work as medicine’.” In contrast, in the paper the authors state that “Importantly, our work on rodent blood exchange establishes that blood age has virtually immediate effects on regeneration of all three germ layer derivatives.” and later that “. . . extracorporeal blood manipulation provides a modality of rapid translation to human clinical intervention.”[1] There seems to be a bit of disagreement between the version of Conboy on the author list of the scientific article and the version of Conboy quoted in the PopSci coverage of the same article.

We also learned from Maldarelli that the tests reported in the paper were performed a month after completing the blood exchange procedure, but the longest duration from blood exchange to the experiment’s end (sacrifice for post-mortem tissue analysis) was 6 days after blood exchange.

I came across the PopSci coverage when it appeared on a meta-news site that highlights popular web articles, so it’s safe to assume I wasn’t the first to read it. Shouldn’t the coverage of scientific articles reported in the lay press have more in common with the source material than just buzzwords? The science wasn’t strictly cut and dried: not every marker or metric responded in the same way to the old/young blood exchange, and while I agree that we shouldn’t be encouraging anyone to build a blood-exchange rejuvenation pod in their garage, the findings of the article fell a long way from the conclusions reported in the lay-article: that young blood had no effect on the physiology of old mice. This is to say nothing about the quality of the paper itself and the confidence we should assign to the experimental results in the first place: with 12 mice total* and a p-value cutoff of 0.05 (1 out of every 20 experiments will appear significant at random), I’d take the original results with a grain of salt as well.

This is the face of science we show the public, and it’s unreliable. It is no easy task for journalists to accurately report and interpret scientific research. Deadlines are tight, and writers face competition and pressure from cheap amateur blogs and regurgitation feeds. “What can I do to help?” you ask. As a consumer of information you can demand scientific literacy in the science news you consume. Ask for writers to convey confidence and probability in a consisent way that can be understood and compared to other results by non-specialists. As a bare minimum, science and the press that covers it should at least have more in common than the latest brand of esoteric jargon.

If we only pay attention to the most outlandish scientific results, then most scientific results will be outlandish.

*The methods describe a purchase of 6 old and 6 young mice. However, elsewhere in the paper the groups are said to contain 8 mice each. Thus it is not clear how many mice in total were used in these experiments, and how they managed to create 12 blood exchange pairings for both control and experimental groups without re-using the same mice.

[1] Rebo, J. et al. A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nat. Commun. 7, 13363 doi: 10.1038/ncomms13363 (2016).

Come on you monkeys, do you want to live forever?

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Members of the control group for the Wisconsin National Primate Research Center caloric restriction study were fed an ad libitum diet of processed food.

The infinite monkey theorem, perhaps first invoked by French mathematician Émile Borel, posits that a monkey condemned to randomly punch keys on a typewriter for an infinite period of time would eventually produce the complete works of Shakespeare. The thought experiment may also be a good metaphor for encapsulating the experience of writing amateur science journalism.

Now consider the same experiment, replacing the generic monkey with members of the species Macaca mulatta, rhesus macaques, and the typewriter with as much processed food as the macaques can stuff into their furry little faces. Modestly pare down the timescale of the experiment from infinite time to about 25 years, increase the number of macaques from one lonely typist to about 38 individuals, and you have a pretty good first approximation of the control group for the University of Wisconsin-Madison Energy Metabolism and Chronic Disease study. You’ll be more familiar with the name used in the popular press, something including the words “caloric restriction,” “longevity” or “lifespan,” and “monkey.”

Caloric restriction (CR) has a long history of increasing longevity in yeast, nematodes, and mice. Youtube is full of mini-documentaries detailing the lives of the voluntarily emaciated, and many a blogger describes their day to day struggle to minimize caloric intake. The human caloric restriction community may have breathed a combined sigh of frustration and relief in 2012 when de facto rivals at the National Institutes of Aging (NIA), led by Dr. Rafa da Cabo, published an article contradicting the 2009 claim that it works in monkeys, too.

The most recent foray in the field of macaque CR published in Nature Communications by Dr. Ricki Colman et al. from Wisconsin, claims the NIA study control monkeys were actually on a CR diet as well, albeit less extreme than the 30% reduction of the experimental diet. They compared the mean weight of control monkeys in both studies to a national database of research macaque mass, the internet Primate Ageing Database or iPAD. The NIA controls were indeed as much as 15% lighter than the averages in the database, as would be expected if the animals were on a restricted diet. However, the UW controls were 5-10% heavier than average, blurring the line between normal feeding and overeating. iPAD does not distinguish between solitary or group housing in macaques, while both the NIA and the Wisconsin study house each individual separately.

The difference ultimately comes down to a discrepancy in what is considered a normal diet. Colman et al fed controls as much of a fortified, low-fat diet, relatively rich in sugar content, as they wanted. This ad libitum feeding was meant to mirror the eating habits of humans. At the NIA, controls wer given a diet based on estimated nutritional need, rather than appetite, and the food was less processed.

Since the goal of using primates in this research is to translate the results to humans, the differing diet choices for controls represent a meaningful philosophical difference: should we compare experiments to how we are or how we should be? Granted the industrialized world is now more overweight than not, and the control group studied by UW researchers may be a more realistic mirror of the human condition. But the survival benefits seen in the CR group may boil down to the benefits of eating a reasonable diet, avoiding excessive sugar and getting out of the cage once in a while. In short the UW study was designed in a way that would err on the side of confirming their hypothesis, while the NIA study was much more conducive to leaving room for the null alternative.

The controversy underlines the difficulty of taking promising results in “lower” animals and common model organisms and applying them to humans. The idea of putting 76 humans into controlled conditions for 25 years to test a radical diet or any other intervention is limited to the realm of the horror subtype of science fiction. This is why much of the health reports that trickle down into the popular press are based on “survey science,” in which respondents answer questionnaires regarding their diet and lifestyle, with varying degrees of quantitative oversight. This is in large part what leads to the impression that every other week the things that kill you are healthy again and vice-versa. It pays in terms of publicity for a university press office to encourage journalists to parrot a warning that eating meat is as deadly as smoking, even if human self-reporting is notoriously bad, and the underlying data may be a bit more subtle.

The climate for ethical considerations in even non-human primate research is evolving. In early 2013, the National Institutes of Health announced that they would begin retiring active chimpanzees from research with no intent to replace them. It is unlikely that either the experimental conditions for the NIA or the Wisconsin study will be reproduced in the near-future, so there won’t be any mulligans for CR in monkeys. This increases the scrutiny and standard of evidence for the results from these experiments, and makes it all the more important for the scientific community and popular press to come to cohesive conclusions.

The “need for consensus” may be overstated, as the studies are very different experiments. It is likely that those both scientifically literate and with the time and inclination to read the literature wouldn’t be misled in their conclusions, but this group will not include most people who may be affected by the outcome. After all, everyone gets old eventually, if they are lucky enough. The responsibility to avoid painting the situation as a sensational controversy and accurately convey the results of these experiments belongs to science journalists and academics in combination.

Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys

Relevant articles (appended 2016/01/06):
Ricki J. Colman, T. Mark Beasley, Joseph W. Kemnitz, Sterling C. Johnson, Richard Weindruch & Rozalyn M. Anderson. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nature Communications 5, Article number: 3557 doi:10.1038/ncomms4557
Received 12 October 2013 Accepted 05 March 2014 Published 01 April 2014

Evi M. Mercken, Bethany A. Carboneau, Susan M. Krzysik-Walker, and Rafael de Cabo.Of Mice and Men: The Benefits of Caloric Restriction, Exercise, and Mimetics Ageing Res Rev. 2012 Jul; 11(3): 390–398. Published online 2011 Dec 20. doi: 10.1016/j.arr.2011.11.005