Cars Parts Show Us How Some Genetic Stats Mislead
We can “read” genes with ease now, but still can’t say what most of them “mean.” To show why we need clearer “causology” and fitter metaphors, let's scrutinize cars and their parts like we do bodies and genes.
1. We can “read” genes with ease now, but still can’t say what most of them “mean.” Mastering precisely how they “cause” higher-level traits will require clearer “causology” and fitter metaphors.
2. Genes (more precisely, gene products) contribute to fiendishly complex processes that confound the standard stats grinder. To illustrate, imagine scrutinizing cars and their parts like we do bodies and genes in “genome-wide association studies” (GWAS). The details don’t matter here, beyond that a car-GWAS would analyze a car-level trait like fuel efficiency by variations in the properties of all the car’s parts.
3. Consider a car having standard and sporty models. The latter have larger gas-guzzling engines and available pimped-up painted brake calipers. And let’s say sporty buyers more often pick red brakes, then statistically speaking red brakes bring greater gas guzzling “risk.”
4. If I’m not mistaken (please correct me stats geeks), no stats-only data wizardry can distinguish such non-causal entanglements (p-values can’t discern “phantom patterns”).
5. Generally, part-level properties can have non-causal and non-random “links” to higher-level traits. And including non-causal factors distorts the statistics (misallocating the variation that seems “explained by,” “accounted for,” or “linked to”). Lacking causal insights, you always run the “red-brake” risk.
6. Regarding metaphors, gene products work more like words than car parts (genes aren’t static “blueprints”). They act via sentence-like structures with collective effects and multiple “meanings.” But we lack the rules (~cellular syntax, gene grammar) for how parts of biology compose life’s activity-sentences.
7. Genes also sort of work like music: Typically “played” in precise synchrony to orchestrate many molecular melodies (simultaneous biochemical sentences) enabling enormous ensemble effects.
8. And life typically has way more moving parts than cars, and more complex transient casual structures. It’s traits often have multiple hetero-causal etiologies (roadmaps exhibiting sufficient but not necessary logic). Current stats can’t disentangle hetero-causal effects (larger type-mixed samples often won’t help).
10. Thankfully, fitter thinking is afoot—for instance, geno-pheno mapping (Massimo Pigliucci), better “Laws of Biology” (Kevin Mitchell), Reductionist Bias Corrections (Krakauer), and Causal Structure Modeling (Judea Pearl).
11. Biology and social science need less primarily parts-focused thinking (you can't grasp chess by studying the properties of its pieces alone), and ways to handle different kinds of causes and roles—see Krakauer’s Figure 4, Aristotle’s four causes, Tinbergen's four questions, Marr’s three levels. Much in these fields is more process-or-algorithm shaped (often resisting Occam’s Razor).
12. Related iffy thinking exists far beyond genomics. As mostly practiced, stats presume a flat or “heap” causal structure that’s often ill-suited for process-oriented life, or car making, or even cooking (cooks need step-by-step recipes to turn parts into wholes).
13. Statistical analysis without causal insights often runs the red-brake risk. The habit of adding variables to “control for” factors can misallocate variation (itself often a nonsensical or low quality quantification).
14. Similar structureless-sausage data risks pervade black box approaches to Big Data and AI.
15. You know that correlation doesn’t imply causation, but AI doesn’t “know” that.
Illustration by Julia Suits, The New Yorker cartoonist & author of The Extraordinary Catalog of Peculiar Inventions
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Technique may enable speedy, on-demand design of softer, safer neural devices.
The brain is one of our most vulnerable organs, as soft as the softest tofu. Brain implants, on the other hand, are typically made from metal and other rigid materials that over time can cause inflammation and the buildup of scar tissue.
New research establishes an unexpected connection.
- A study provides further confirmation that a prolonged lack of sleep can result in early mortality.
- Surprisingly, the direct cause seems to be a buildup of Reactive Oxygen Species in the gut produced by sleeplessness.
- When the buildup is neutralized, a normal lifespan is restored.
We don't have to tell you what it feels like when you don't get enough sleep. A night or two of that can be miserable; long-term sleeplessness is out-and-out debilitating. Though we know from personal experience that we need sleep — our cognitive, metabolic, cardiovascular, and immune functioning depend on it — a lack of it does more than just make you feel like you want to die. It can actually kill you, according to study of rats published in 1989. But why?
A new study answers that question, and in an unexpected way. It appears that the sleeplessness/death connection has nothing to do with the brain or nervous system as many have assumed — it happens in your gut. Equally amazing, the study's authors were able to reverse the ill effects with antioxidants.
The study, from researchers at Harvard Medical School (HMS), is published in the journal Cell.
An unexpected culprit
The new research examines the mechanisms at play in sleep-deprived fruit flies and in mice — long-term sleep-deprivation experiments with humans are considered ethically iffy.
What the scientists found is that death from sleep deprivation is always preceded by a buildup of Reactive Oxygen Species (ROS) in the gut. These are not, as their name implies, living organisms. ROS are reactive molecules that are part of the immune system's response to invading microbes, and recent research suggests they're paradoxically key players in normal cell signal transduction and cell cycling as well. However, having an excess of ROS leads to oxidative stress, which is linked to "macromolecular damage and is implicated in various disease states such as atherosclerosis, diabetes, cancer, neurodegeneration, and aging." To prevent this, cellular defenses typically maintain a balance between ROS production and removal.
"We took an unbiased approach and searched throughout the body for indicators of damage from sleep deprivation," says senior study author Dragana Rogulja, admitting, "We were surprised to find it was the gut that plays a key role in causing death." The accumulation occurred in both sleep-deprived fruit flies and mice.
"Even more surprising," Rogulja recalls, "we found that premature death could be prevented. Each morning, we would all gather around to look at the flies, with disbelief to be honest. What we saw is that every time we could neutralize ROS in the gut, we could rescue the flies." Fruit flies given any of 11 antioxidant compounds — including melatonin, lipoic acid and NAD — that neutralize ROS buildups remained active and lived a normal length of time in spite of sleep deprivation. (The researchers note that these antioxidants did not extend the lifespans of non-sleep deprived control subjects.)
Image source: Tomasz Klejdysz/Shutterstock/Big Think
The study's tests were managed by co-first authors Alexandra Vaccaro and Yosef Kaplan Dor, both research fellows at HMS.
You may wonder how you compel a fruit fly to sleep, or for that matter, how you keep one awake. The researchers ascertained that fruit flies doze off in response to being shaken, and thus were the control subjects induced to snooze in their individual, warmed tubes. Each subject occupied its own 29 °C (84F) tube.
For their sleepless cohort, fruit flies were genetically manipulated to express a heat-sensitive protein in specific neurons. These neurons are known to suppress sleep, and did so — the fruit flies' activity levels, or lack thereof, were tracked using infrared beams.
Starting at Day 10 of sleep deprivation, fruit flies began dying, with all of them dead by Day 20. Control flies lived up to 40 days.
The scientists sought out markers that would indicate cell damage in their sleepless subjects. They saw no difference in brain tissue and elsewhere between the well-rested and sleep-deprived fruit flies, with the exception of one fruit fly.
However, in the guts of sleep-deprived fruit flies was a massive accumulation of ROS, which peaked around Day 10. Says Vaccaro, "We found that sleep-deprived flies were dying at the same pace, every time, and when we looked at markers of cell damage and death, the one tissue that really stood out was the gut." She adds, "I remember when we did the first experiment, you could immediately tell under the microscope that there was a striking difference. That almost never happens in lab research."
The experiments were repeated with mice who were gently kept awake for five days. Again, ROS built up over time in their small and large intestines but nowhere else.
As noted above, the administering of antioxidants alleviated the effect of the ROS buildup. In addition, flies that were modified to overproduce gut antioxidant enzymes were found to be immune to the damaging effects of sleep deprivation.
The research leaves some important questions unanswered. Says Kaplan Dor, "We still don't know why sleep loss causes ROS accumulation in the gut, and why this is lethal." He hypothesizes, "Sleep deprivation could directly affect the gut, but the trigger may also originate in the brain. Similarly, death could be due to damage in the gut or because high levels of ROS have systemic effects, or some combination of these."
The HMS researchers are now investigating the chemical pathways by which sleep-deprivation triggers the ROS buildup, and the means by which the ROS wreak cell havoc.
"We need to understand the biology of how sleep deprivation damages the body so that we can find ways to prevent this harm," says Rogulja.
Referring to the value of this study to humans, she notes,"So many of us are chronically sleep deprived. Even if we know staying up late every night is bad, we still do it. We believe we've identified a central issue that, when eliminated, allows for survival without sleep, at least in fruit flies."