Category Archives: Genetics/Epigenetics

The Delectable Myths of Healthy and Healthier Obesity.

by Kenneth W. Krause.

Kenneth W. Krause is a contributing editor and “Science Watch” columnist for the Skeptical Inquirer.  Formerly a contributing editor and books columnist for the Humanist, Kenneth contributes frequently to Skeptic as well. He can be contracted at krausekc@msn.com.

obesity-paradox1

Why, sometimes I’ve believed as many as six impossible things before breakfast.–The Queen, to Alice in Through the Looking Glass.

Wouldn’t it be splendid to have our cakes and eat them too? Arguably, both ideology and popular culture allow their followers to do just that.  Until they don’t, of course.  At that point, when facts and logic can no longer be denied, the rudely awakened find themselves confronted with difficult choices.

The concept of healthy obesity, for example, has gained much traction during the last fifteen years. At one end of the continuum, members of the popular but clearly flawed “Healthy at Every Size (HAES)” movement profess the nonexistence of excess adiposity and suggest that even the most obese people can lead perfectly healthy lives (“Every size”—really?).  On the other end, and somewhat more credibly, others allege the existence of an “obesity paradox” and a “metabolically healthy obesity.”  Such are the tantalizing subjects of this column.

Cardiologist and obesity researcher, Carl J. Lavie, has described the paradox as follows: “Overweight and moderately obese patients with certain chronic diseases … often live longer and fare better than normal-weight patients with the same ailments” (Lavie 2014). In addition to his own research, Lavie’s conclusions are based on a revolutionary and, in some circles, much-celebrated JAMA study led by Katherine Flegal at the US Centers for Disease Control and Prevention, who reviewed 97 studies of more than 2.88 million individuals to calculate all-cause mortality hazard ratios for standard body mass index (BMI) classifications (Flegal et al. 2013).

Katherine Flegal

Katherine Flegal

Flegal’s team reported as follows: Relative to normal weight, all combined grades of obesity were associated with an 18 percent higher incidence of all-cause mortality. In cases of more extreme of obesity, the association rose to 29 percent.  By itself, however, the mildest grade of obesity was not correlated with a significantly elevated risk, and the overweight but not obese category was actually associated with a 6 percent lower incidence of all-cause mortality.  Predictably, the popular media quickly seized on the overweight population’s presumed appetite for these tempting results.

bmi

Metabolically healthy, or “benign,” obesity, on the other hand—which Lavie dubs the “ultimate paradox”—appears to have no standard definition or list of qualifying criteria, but is often characterized generally as “obesity without the presence of metabolic diseases such as type 2 diabetes, dyslipidemia or hypertension” (Munoz-Garach et al. 2016). Retained insulin sensitivity, however, is the hallmark trait of this subpopulation.  Researchers have assigned up to 32 percent of the obese population to this phenotype.  It applies more prevalently to women than men, but is thought to decrease with age among both sexes.  Researchers have yet to determine whether these obese are genetically predisposed to decreased risks of disease or mortality.  But their existence, along with that of the metabolically unhealthy normal-weight population, suggests that factors other than excess adiposity are at play.

All of which might sound at least somewhat comforting to the now 600 million obese worldwide (and still growing) who have been told for decades that obesity per se will significantly increase one’s susceptibility to heart disease, stroke, cancer, diabetes, and arthritis, for example. Preferences and popular reports aside, however, it appears we may yet be forced to choose between possessing our cakes and consuming them, because an impressive body of new and well-conceived research has called both the paradox and healthy obesity into serious question.

Consider, for example, a truly enormous international meta-analysis published last July in The Lancet by the Global BMI Mortality Collaboration (GBMC 2016).  Led by Harvard professor of nutrition and epidemiology, Frank Hu, this study poured over data from more than 10.6 million participants who were followed for up to 14 years.  239 large studies conducted in 32 countries were included.  Importantly, the Collaboration attempted to control for a “reverse causation bias,” in which low BMI was the result, rather than the cause, of an underlying or preclinical illness by excluding current or former smokers, those who suffered from chronic disease at the study’s inception, and those who died during the initial five years of follow-up.  In other words, Hu’s team addressed the potential for potent confounders that Flegal’s team, for lack of data, was forced to ignore.

The Collaboration’s results were startling. Interestingly, Hu “was able to reproduce [Flegal’s results] when conducting crude analyses with inadequate control of reverse causality, but not when [he] conducted appropriately strict analyses.”  In the end, then, the Collaboration found that, worldwide, participants with a normal BMI in the 22.5 to 25 range enjoyed the lowest risk of mortality and that such risk increased significantly throughout the overweight and obese ranges.  In fact, every five units of BMI in excess of 25 was associated generally with a 31 percent greater risk of premature death—specifically, 49 percent for cardiovascular-related, 38 percent for respiratory-related, and 19 percent for cancer-related mortality.  According to Hu, his team had succeeded in “challeng[ing] previous suggestions that overweight and grade 1 obesity are not associated with higher mortality, bypassing speculations about hypothetical protective metabolic effects of increased body fat in apparently healthy individuals.”

Frank Hu

Frank Hu

Consider too, a large prospective cohort study published last October in the BMJ in which about 115,000 participants—free of cardiovascular disease and cancer at baseline—were followed for up to 32 years (Veronese et al. 2016).  Evaluating the combined associations of diet, exercise, alcohol consumption, and smoking with BMI on the risk of all-cause and cause-specific mortality, this study was also designed to address Flegal’s peculiar 2013 results.  A lead author here as well, Frank Hu first noted, once again, that previous examinations suggesting an obesity paradox, including Flegal’s, had allowed for potentially confounding bias by failing to distinguish between healthy normal-weight individuals and a “substantial proportion of the US population” in which “leanness is driven by other factors that can increase risk of mortality,” including existing or preclinical chronic diseases and smoking.

Contrary to the alleged paradox, Hu discovered that when lifestyle factors were taken into serious consideration, the lowest risk of all-cause and cardiovascular mortality was enjoyed by participants in the slightly low-to-normal, 18.5 to 22.4 BMI range—that is, when those subjects also displayed at least three out of four healthy lifestyle factors, including healthy eating, adequate exercise, moderate alcohol intake, and no smoking. In the end, according to Hu’s team, “the U-shaped relation between BMI and mortality observed in many epidemiological studies is driven by an over-representation in our societies of individuals who are lean because of chronic metabolic and pathological conditions caused by exposure to smoking, a sedentary lifestyle, and/or unhealthy diets.”  The optimal human condition, in other words, is not overweight of any kind or to any degree, but rather “leanness induced by healthy lifestyles.”

So much for the obesity paradox, at least for now. But what of its somewhat less voracious cousin, the notion of metabolically healthy obesity?

Recognizing prior support for so-called “benign obesity,” a trio of Canadian diabetes researchers led by Caroline Kramer conducted a systematic review and meta-analysis of eight studies evaluating over 61,000 subjects—many of whom were classified as metabolically healthy obese—for all-cause mortality and cardiovascular events (Kramer et al. 2013). When all studies were considered, regardless of follow-up duration, the healthy obese subjects displayed risks similar to those of healthy normal-weight participants.  However, when considering only those studies that followed-up for at least ten years, Kramer and colleagues discovered that the purportedly healthy obese were significantly more likely than their normal counterparts to perish or suffer serious cardiovascular trouble.

Caroline Kramer

Caroline Kramer

Should we infer, then, that the healthy obese are, in fact, healthy until circumstances render them otherwise a decade later? Not according to Kramer.  Regardless of metabolic status, she warned, even in the short term, obesity is associated with subclinical vascular disease, left-ventricular abnormalities, chronic inflammation, and increased carotid artery intima-media thickness and coronary calcification.  In the end, the Canadians found no support for the “benign obesity” phenotype and declared with no uncertainty that “there is no ‘healthy’ pattern of obesity.”

Most recently, however, a diverse and impressively creative group of Swedish scientists used transcriptomic profiling in white adipose tissue to contrast responses to insulin stimulation between never-obese, unhealthy obese, and, again, supposedly healthy obese subjects. (Ryden et al. 2016). Led by Mikael Ryden at the Karolinska Institutet, this group revealed, first, clear distinctions between the never-obese and both groups of obese participants, and, second, nearly identical and abnormal patterns of gene expression among both insulin-resistant and insulin-sensitive obese subjects, independent of other cardiovascular or metabolic risk factors.

Said Ryden during a post-publication interview: “Insulin-sensitive obese individuals may not be as metabolically healthy as previously believed.” (ScienceDaily 2016). His team’s findings, he continued, “suggest that vigorous interventions may be necessary for all obese individuals, even those previously considered … healthy.”

To Lavie’s credit, he generally acknowledges obesity’s proven hazards. He also recognizes serious and consistent exercise as the most reliable strategy for attaining and maintaining good health.  Far less defensible, however, is Lavie’s insistence that exercise can render obesity a benign condition.  First, as much of the research presented here demonstrates, the chronic diseases strongly associated with obesity are, by definition, progressive and apt to cause damage down the road.  Second, in the real world, excess adiposity always leaves meaningful exercise a far more difficult and, thus, far less likely prospect.

obesity-paradox

Obese or not, our health continues to be undermined by the popular, ever-emotion-manipulating media, the misguided and oppressive forces of political correctness, and, most crucially, our own subjective prejudices and appetites. But as their numbers continue to swell, the overweight and obese grow increasingly vulnerable to seductive messages inviting self-deception and failure.  As in all other contexts, their liberation from these influences derives only from an unflinching appreciation for the methods of science—that is, empiricism, rationality, candor, and the assumption of responsibility for individual experimentation.  In a word, skepticism.

References:

Flegal, K.M., B.K. Kit, H. Orpana, et al. 2013. Association of all-cause mortality with overweight and obesity using standard body mass index categories. Journal of the American Medical Association 309(1): 71-82.

Global BMI Mortality Collaboration. 2016. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. The Lancet 388: 776-786.

Kramer, C.K., B. Zinman, and R. Retnakaran. 2013. Are metabolically healthy overweight and obesity benign conditions? Annals of Internal Medicine 159(11): 758-769.

Lavie, Carl J. 2014. The Obesity Paradox: When Thinner Means Sicker and Heavier Means Healthier. NY: Plume.

Munoz-Garach, A., I. Cornejo-Pareja, and F.J. Tinahones. 2016. Does metabolically healthy obesity exist? Nutrients 8: 320.

Ryden, M., O. Hrydziuszko, E. Mileti, et al. 2016. The adipose transcriptional response to insulin is determined by obesity, not insulin sensitivity. Cell Reports 16: 2317-2326.

ScienceDaily. 2016. More evidence that “healthy obesity” may be a myth.” 18 August 2016. https://www.sciencedaily.com/releases/2016/08/160818131127.htm>.

Veronese, N., L. Yanping, J.E. Manson, et al. 2016. Combined associations of body weight and lifestyle factors with all cause and cause specific mortality in men and women: prospective cohort study. BMJ. DOI:10.1136/bmj.i5855.

Obesity: “Fat Chance” or Failure of Sincerity?

by Kenneth W. Krause.

Kenneth W. Krause is a contributing editor and “Science Watch” columnist for the Skeptical Inquirer.  Formerly a contributing editor and books columnist for the Humanist, Kenneth contributes frequently to Skeptic as well. He can be contracted at krausekc@msn.com.

popular culture3

Man is condemned to be free.—Jean-Paul Sartre.

Beginning about five years ago, the chronically overweight and obese were offered a new paradigm, one more consistent with their majority’s shared experiences in the twenty-first century. Emerging science from diverse fields, certain experts argued, complicated—perhaps even contradicted—the established view that weight maintenance was a straightforward, if not simple, matter of volitional control and balancing energy intake against energy expenditure.

As a host of potential complexities materialized, the frustrated members of this still expanding demographic were notified that, contrary to conventional wisdom, they had little or no control over their conditions. The popular literature especially began to hammer two captivating messages deeply into the public consciousness.  First, from within, the overweight and obese have been overwhelmed by their genomes, epigenomes, hormones, brains, and gut microbiomes, to name just a few.  Second, from without, their otherwise well-calculated and ample efforts have been undermined, for example, by the popular media, big food, government subsidies, poverty, and the relentless and unhealthy demands of contemporary life.

In a 2012 Nature opinion piece, Robert Lustig, Laura Schmidt, and Claire Brindis—three public health experts from the University of California, San Francisco, compared the “deadly effect” of added sugars (high-fructose corn syrup and sucrose) to that of alcohol(1).  Far from mere “empty calories,” they added, sugar is potentially “toxic” and addictive.  It alters metabolisms, raises blood pressures, causes hormonal chaos, and damages our livers.  Like both tobacco and alcohol (a distillation of sugar), it affects our brains as well, encouraging us to increase consumption.

Apparently unimpressed with Americans’ abilities to control themselves, Lustig et al. urged us to back restrictions on our own choices in the form of government regulation of sugar. In support of their appeal, the trio relied on four criteria—“now largely accepted by the public health community,”—originally offered by social psychologist Thomas Babor in 2003 to justify the regulation of alcohol: The target substance must be toxic, unavoidable (or pervasive), produce a negative impact on society, and present potential for abuse.  Perhaps unsurprisingly, they discovered that sugar satisfied each criterion with ease.

Robert Lustig.

Lustig, a pediatric endocrinologist and, now, television infomercial star, contends that obesity results primarily from an intractable hormonal predicament. In his wildly popular 2012 book, Fat Chance, Lustig indicted simple, super-sweet sugars as chief culprits, claiming that sucrose and high-fructose corn syrup corrupt our biochemistry to render us hungry and lethargic in ways fat and protein do not(2).  In other words, he insisted that sugar-induced hormonal imbalances cause self-destructive behaviors, not the other way around.

Lustig’s argument proceeds essentially as follows: In the body, insulin causes energy to be stored as fat.  In the hypothalamus, it can cause “brain starvation,” or resistance to leptin, the satiety hormone released from adipose tissue.  Excess insulin, or hyperinsulinemia, thus causes our hypothalami to increase energy storage (gluttony) and decrease energy consumption (sloth).  To complete the process, add an increasingly insulin-resistant liver (which drives blood insulin levels even higher), a little cortisol (the adrenal stress hormone), and of course sugar addiction.  In the end, Lustig concludes, dieters hardly stand a chance.

Journalist Gary Taubes, author of the similarly successful Why We Get Fat, was in full agreement(3).  Picking up the theoretical mantle where Lustig dropped it, Taubes expanded the list of nutritional villains considerably to include all the refined carbohydrates that quickly boost consumers’ glycemic indices. In a second Nature opinion piece, he then blamed the obesity problem on both the research community, for failure to fully comprehend the condition, and the food industry, for exploiting that failure(4).

Gary Taubes with Dr. Oz.

Gary Taubes with Dr. Oz.

To their credit, Lustig and Taubes provided us with some very sound and useful advice.  Credible nutrition researchers agree, for example, that Americans in particular should drastically reduce their intakes of added sugars and refined carbohydrates.  Indeed, most would be well-advised to eliminate them completely.  The authors’ claims denying self-determination might seem reasonable as well, given that, as much research has shown, most obese who have tried to lose weight and to keep it off, have failed.

On the other hand, failure is common in the context of any difficult task, and evidence of “don’t” does not amount to evidence of “can’t.” One might wonder as well whether obesity is a condition easily amenable to controlled scientific study given that every solution—and of course many, in fact, do succeed(5)—is both multifactorial and as unique as every obese person’s biology.  So can we sincerely conclude, as so many commentators apparently have, that the overweight and obese are essentially powerless to help themselves?  Or could it be that the vast majority of popular authors and health officials have largely—perhaps even intentionally—ignored the true root cause of obesity, if for no other reasons, simply because they lack confidence in the obese population’s willingness to confront it?

Though far less popular, a more recently published text appears to suggest just that.  In The Psychology of Overeating, clinical psychologist Kima Cargill attempts to “better contextualize” overeating habits “within the cultural and economic framework of consumerism”(6).  What current research fails to provide, she argues, is a unified construct identifying overeating (and sedentism, one might quickly add) as “not just a dietary [or exercise] issue,” but rather as a problem implicating “the consumption of material goods, luxury experiences, … evolutionary behaviors, and all forms of acquisition.”

Kima Cargill.

Kima Cargill.

To personalize her analysis, Cargill introduces us to a case study named “Allison.”  Once an athlete, Allison gained fifty pounds after marriage.  Now divorced and depressed, she regularly eats fast food or in expensive restaurants and rarely exercises.  Rather than learn about food and physical performance, Allison attempts to solve her weight problem by throwing money at it.  “When she first decided to lose weight,” Cargill recalls, “which fundamentally should involve reducing one’s consumption, Allison went out and purchased thousands of dollars of branded foods, goods, and services.” She hired a nutritionist and a trainer.  She bought a Jack Lalanne juicer, a Vitamix blender, a Nike Feulband, Lululemon workout clothing, an exclusive gym membership, diet and exercise DVDs and iPhone apps, and heaping bags full of special “diet foods.”

None of it worked, according to the author, because Allison’s “underlying belief is that consumption solves rather than creates problems.”  In other words, like so many others, Allison mistook “the disease for its cure.”  The special foods and products she purchased were not only unnecessary, but ultimately harmful.  The advice she received from her nutritionist and trainer was based on fads, ideologies, and alleged “quick-fixes” and “secrets,” but not on actual science.  Yet, despite her failure, Allison refused to “give up or simplify a life based on shopping, luxury, and materialism” because any other existence appeared empty to her.  In fact, she was unable to even imagine a more productive and enjoyable lifestyle “rich with experiences,” rather than goods and services.

Television celebritism: also mistaking the disease for its cure.

Television celebritism: also mistaking the disease for its cure.

Like Lustig, Taubes, and their philosophical progeny, Cargill recognizes the many potential biological factors capable of rendering weight loss and maintenance an especially challenging task.  But what she does not see in Allison, or in so many others like her, is a helpless victim of either her body or her culture.  Judging it unethical for psychologists to help their patients accept overeating behaviors and their inevitably destructive consequences, Cargill appears to favor an approach that treats the chronically overweight and obese like any other presumably capable, and thus responsible, adult population.

Compassion, in other words, must begin with uncommon candor.  As Cargill acknowledges, for example, only a “very scant few” get fat without overeating because of their genes.  After all, recently skyrocketing obesity rates cannot be explained by the evolution of new genes during the last thirty to forty years.  And while the food industry (along with the popular media that promote it) surely employs every deceit at its disposal to encourage overconsumption and the rejection of normal—that is, species appropriate—eating habits, assigning the blame to big food only “obscures our collusion.”  Worse yet, positioning the obese as “hapless victims of industry,” Cargill observes, “is dehumanizing and ultimately undermines [their] sense of agency.”

Education is always an issue, of course. And, generally speaking, higher levels of education are inversely associated with the least healthy eating behaviors.  But the obese are not stupid, and shouldn’t be treated as such.  “None of us is forced to eat junk food,” the author notes, “and it doesn’t take a college degree or even a high school diploma to know that an apple is healthier than a donut.”  Nor is it true, as many have claimed, that the poor live in “food deserts” wholly lacking in cheap, nutritious cuisine(7).  Indeed, low-income citizens tend to reject such food, Cargill suggests, because it “fails to meet cultural requirements,” or because of a perceived “right to eat away from home,” consistent with societal trends.

Certain foods, especially those loaded with ridiculous amounts of added sugars, do in fact trigger both hormonal turmoil and addiction-like symptoms (though one might reasonably question whether any substance we evolved to crave should be characterized as “addictive”).  And as the overweight continue to grow and habituate to reckless consumption behaviors, their tasks only grow more challenging.  I know this from personal experience, in addition to the science.  Nevertheless, Cargill maintains, “we ultimately degrade ourselves by discounting free will.”

popular culture4

Despite the now-fashionable and, for many, lucrative “Fat Chance” paradigm, the chronically overweight and obese are as capable as anyone else of making rational and intelligent decisions at their groceries, restaurants, and dinner tables. And surely overweight children deserve far more inspiring counsel.  But as both Lustig and Taubes, on the one hand, and Cargill, on the other, have demonstrated in different ways, the solution lies not in mere diet and exercise, per se.  The roots of obesity run far deeper.

Changes to basic life priorities are key. To accomplish a more healthful, independent, and balanced existence, the chronically overweight and obese in particular must first scrutinize their cultural environments, and then discriminate between those aspects that truly benefit them and those that were designed primarily to take advantage of their vulnerabilities, both intrinsic and acquired.  Certain cultural elements can stimulate the intellect, inspire remarkable achievement, and improve the body and its systems.  But most if not all of its popular component exists only to manipulate its consumers into further passive, mindless, and frequently destructive consumption.  The power to choose is ours, at least for now.

References:

(1)Lustig, R.H., L.A. Schmidt, and C.D. Brindis. 2012. Public health: the toxic truth about sugar. Nature 482: 27-29.

(2)Lustig, R. 2012. Fat Chance: Beating the Odds Against Sugar, Processed Food, Obesity, and Disease. NY: Hudson Street Press.

(3)Taubes, G. 2012. Treat obesity as physiology, not physics. Nature 492: 155.

(4)Taubes, G. 2011. Why We Get Fat: And What to Do About It. NY: Knopf.

(5)See, e.g., The National Weight Loss Control Registry. http://www.nwcr.ws/Research/default.htm

(6)Cargill, K. 2015. The Psychology of Overeating: Food and the Culture of Consumerism. NY: Bloomsbury Academic.

(7)Maillot, M., N. Darmon, A. Drewnowski. 2010. Are the lowest-cost healthful food plans culturally and socially acceptable? Public Health Nutrition 13(8): 1178-1185.

Dog Behavior: Beneath the Veneer of “Man’s Best Friend.”

by Kenneth W. Krause.

Kenneth W. Krause is a contributing editor and “Science Watch” columnist for the Skeptical Inquirer.  Formerly a contributing editor and books columnist for the Humanist, Kenneth contributes frequently to Skeptic as well. He can be contracted at krausekc@msn.com.

We love our dogs—often more than many fellow humans. In Homer’s 8th century BCE Odyssey, Odysseus referred to the domestic dog as a “noble hound,” and it may have been Frederick II, King of Prussia, who in 1789 first characterized Canis lupus familiaris as “man’s best friend.”  More recently, Emily Dickenson judged that dogs are “better than human beings” because they “know but do not tell.”  Dogs are capable creatures, certainly, but are they as intelligent and considerate as most of humans apparently believe?  Regardless of breed, can their levels of consciousness truly support qualities like nobility, loyalty, and friendship?

Ethologists attempt to assess animal behavior objectively by emphasizing its biological foundations. Classic ethology was founded on the notion that animals are driven by intrinsic motor-patterns, or species-specific, stereotyped products of natural selection (Lorenz 1982).  Modern practitioners, however, often introduce additional factors into the ethological equation.  Many suggest, for example, that intrinsic motor-patterns can be accommodated to developmental and environmental influences.  Some argue as well that complex and otherwise confusing behaviors can emerge from interactions between two or more simpler behavioral rules.

Evolving Motor-Patterns.

Fellow ethologists, biologist Raymond Coppinger and cognitive scientist Mark Feinstein argue that much, if not all, dog behavior can be explained by reference to these three ideas—without resorting to more romantic notions of consciousness or sentience, let alone loyalty and friendship (2015). In the crucial context of foraging, for instance, intrinsic motor-patterns manifest similarly in all canids.

When born, both dogs and wolves spontaneously demonstrate a characteristic mammalian neonatal foraging sequence: ORIENT (toward mom) > LOCOMOTION (to mom) > ATTACHMENT (to her teat) > FOREFOOT-TREAD (stimulating lactation) > SUCK. Here, pups’ mouths and digestive systems are well-adapted to challenges imposed by the foraging environment—that is, mom.  But despite the cozy evolutionary relationship between dogs and wolves, puppyhood is the point after which precise foraging parallels end.

As adults, canid predators display the following generalized foraging sequence: ORIENT > EYE (body still, gaze fixed, head lowered) > STALK (slowly forward, head lowered) > CHASE (full speed) > GRAB-BITE (disabling the prey) > KILL-BITE > DISSECT > CONSUME. But some species, and some individual dogs and wolves, might substitute one motor-pattern for another.  Tending to hunt small prey, coyotes might occasionally swap the FOREFOOT-STAB pattern for the CHASE pattern, and HEADSHAKE for KILL-BITE. Big cats like the puma, by contrast, might substitute FOREFOOT-SLAP for GRAB-BITE to bring larger prey down from behind.

The coyote "forefoot-stab" rule

The coyote forefoot-stab rule

The precise form of GRAB- or KILL-BITE can vary between species as well, often based on the predator’s evolved anatomy. The puma usually kills with a bite to the neck, crushing its prey’s trachea, or to the muzzle, suffocating the victim.  But the wolf often GRAB-BITES the prey’s hind legs, shredding its arteries and slowly bleeding it to death. Puma and wolf anatomies—jaw structure, dentition, and musculature, in particular—apply different mechanical forces, and thus demand the evolution of at least slightly different foraging behaviors.

Domestic dogs, on the other hand, tend to be far less purposeful.   Having long-relied on humans for sustenance, they rarely demonstrate complete predatory foraging patterns.  Instead, different breeds have retained programs for different partial sequences.  Border collies, for instance, are famous for obeying the EYE pattern. I, in fact, once owned an Akita that employed FOREFOOT-STAB with astonishing expertise to capture mice foraging deep beneath the snow.

Border collie "eye" rule.

The Border collie eye rule.

Nevertheless, say Coppinger and Feinstein, “certain commonalities have long persisted in the predatory motor-pattern sequences of all carnivores, reflecting their shared ancestry” and “an intrinsic ‘wired-in’ program of rules.” Learning is neither necessary nor optional.  Indeed, as soon as their foraging sequences are interrupted for whatever reasons, some wild-types are rendered incapable of continued pursuit.  Pumas can’t consume an animal that’s already dead, for example, and, although wolves generally can enter their foraging sequences at any point, they often can’t perform GRAB-BITE if interfered with following expression of the partial EYE > STALK > CHASE sequence.

Dogs have similar limitations. Coppinger and Feinstein recall two conversations with different sheep ranchers.  The first shepherd commended his livestock-guarding dog for independently standing watch over a sick ewe for days without consuming it.  The second, however, complained because his guarding dog ate a lamb that tore itself open on a barbed-wire fence.  To the ethologists, these seemingly inconsistent behaviors were anything but.  Livestock-guarding dogs generally do not express the DISSECT motor-pattern. In fact, their only foraging rule is CONSUME. The first dog wasn’t a “good” dog, necessarily—it was just an unlucky dog.  And the second animal wasn’t really a “bad” dog—it simply performed its intrinsic program when afforded the opportunity to do so.

Accommodating Environment.

However, that many motor-patterns are stereotyped and non-modifiable does not imply that dogs and other animals are mere automata driven solely by internal programs. Certain behaviors can arise as well from an accommodation of the intrinsic to the contingencies of external forces.  Under the “right” circumstances, in other words, animals commonly act in species- or breed-specific manners.  But when exposed to other environmental conditions, their behaviors can look very different (Twitty 1966).

Indeed, if animals encounter such conditions during a developmentally “critical” or “sensitive” period—that is, a species-specific, time-bound stage of growth—they might never display certain typical behaviors. For example, many prospective service dogs flunk out merely because they can’t negotiate stairs, curbs, or even sewer grates.  Why not?  According to Coppinger and Feinstein, their vision systems never fully developed because they were raised in kennels that were sterile and spacious, but nevertheless lacking in three-dimensional structures.

Research also suggests that canids have critical periods for social bonding, during which exposure to a given stimulus will reduce the animal’s fear of that stimulus in the future (Scott and Fuller 1998). Some argue further that certain conspicuous behavioral differences between canid species can be explained, at least in part, by distinct onsets and offsets of these periods (Lord 2013).  For instance, the sensitive bonding period for dogs begins at about four weeks and ends at about eight weeks, while the same period begins and ends two weeks earlier for wolves.

Crucially, dogs and wolves develop their sensory abilities at about the same time—sight and hearing at six weeks, smell much earlier. As such, wolves have only their sense of smell to rely on during their sensitive bonding period.  One general result is that more stimuli, including humans, will remain unfamiliar and thus frightening to them as adults.  But dogs can suffer similar consequences when raised in the absence of direct human contact.

With bonding periods in mind, Coppinger and Feinstein invite us to guess why the Maremma guarding dogs they studied in Italy would abandon their human shepherds to trail their flocks. Were they merely obeying their evolved, gene-based intrinsic motor-patterns—or perhaps their training?  Did they actually understand the importance of their job?  None of the above, say the authors: guarding dog behavior can be “explained by accommodation to particular environmental factors during a critical period in the development of socialization.”

Maremma guarding-dogs.

Maremma guarding dog pups.

During his famous, Nobel Prize-winning experiments in 1935, Konrad Lorenz was able to transfer the social allegiance of newly-hatched greylag geese from their mothers to not only Lorenz himself, but to inanimate objects including a water faucet as well. Coppinger and Feinstein produced similar effects with their Maremmas.  When raised with sheep instead of humans, the dogs usually stuck with the sheep.  Interestingly, however, a few Maremmas preferred to remain at home when both the sheep and their shepherds left for the fields.  These dogs had actually bonded with milk cans that no doubt smelled very much like the sheep.

Emerging Complexities.

Yet other canine behaviors cannot be easily explained by reference to either intrinsic motor-patterns or their accommodations to environmental influences. Consider the collaborative hunting of large prey in wolves, for example.  Here, individuals within the pack appear to work closely together according to preconceived plan, synchronizing their movements and relative positions to prevent prey escape.  At first glance, the spectacle tempts us to infer not only extraordinary intelligence, but insight as well.

Coppinger and Feinstein, however, suggest an explanation relying not on naïve anthropomorphisms, but rather on our knowledge of canine behavior plus the intriguing concept of emergence.  Nothing new under the intellectual sun, emergence proposes that complex and novel phenomena can arise from the accidental, “self-organizing” interaction of far simpler rules and processes.

Two classic examples illustrate the principle. Known for their towering, complicated, yet surprisingly well-ventilated structures, termite mounds obviously are not designed and erected by hyper-intelligent insects.  Similarly, many species of migrating birds, Canada geese in particular, tend to fly in a conspicuous V-pattern, but not because individual geese possess advanced senses of aesthetics.  The more likely explanation, say the authors, is that members of each species act only according to very simple rules.  Termites transport sand grains to a central location.  Perhaps their movements are sensitive to humidity levels and the relative concentration of gasses.  Geese evolved to fly long distances and to draft behind others to lessen their burdens.  The impressive results were never planned; they simply emerged from the interaction of much humbler, species-specific rules.

The practice of collaborative hunting among wolves is no different, according to Coppinger. He and his colleagues recently created a computational model including digital agents representing both pack and prey (Muro et al. 2011).  When they imposed three basic rules on individual predators—move toward the prey, maintain a safe distance, and move away from other wolves—the model produced a successful pattern of prey capture appearing remarkably similar to the real thing.  But in no way were Coppinger’s results dependent on agent purpose, intelligence, or cooperation.

Collaborative hunting among wolves.

Collaborative hunting among wolves.

Consider dog “play” as well. One popular explanation of play generally is that it evolved as a “practice” motor-pattern to prepare animals for escape.  But play only partially resembles any given adult motor-pattern sequence.  And to be even minimally effective, escape has to be performed correctly the first time, which is precisely why motor-patterns are intrinsic, stereotyped, and automatic—as Coppinger and Feinstein observe, “no practice is ever required.”

As any dog owner will attest, canine play is commonly manifested in the “play bow”—a posture in which the animal halts, lowers its head, raises its rear-end, and stretches its front legs forward. Many have interpreted the bow as a purposeful invitation to engage in play.  But more careful observations and experiments suggest otherwise.  Play bows often result when dogs and wolves enter into an EYE > STALK motor-pattern sequence only to be interrupted by their subjects’ failures to react—that is, to run. As such, the bow might actually reveal a combination of two conflicting rules: stalk and retreat.  If so, the posture itself is neither an adaptive motor-pattern nor a signal of intent.  Rather, say Coppinger and Feinstein, “it is an emergent effect of a dog (or wolf) simultaneously displaying two motor-pattern components when it is in multiple or conflicting states.”

None of which should diminish the love and allegiance we typically bestow upon our dogs. That they have no desire to please us—indeed, that their conscious goals are severely limited in general—is no reason to deny ourselves the great pleasure we so often derive from their company.  Even so, our failure to pursue a more objective understanding of dog behavior frequently results in disaster, for both ourselves and our pets.  For some, ignorance might be bliss.  But it’s never a solution for anyone or any thing.

References:

Coppinger, R. and M. Feinstein. 2015. How Dogs Work. Chicago: University of Chicago Press.

Lord, K.A. 2013. A comparison of the sensory development of wolves and dogs. Ethology 119:110-120.

Lorenz, K. 1982. The Foundations of Ethology: The Principle Ideas and Discoveries in Animal Behavior. NY: Simon and Schuster.

Muro, C., R. Escobedo, L. Spector, et al. 2011. Wolf-pack hunting strategies emerge from simple rules in computational simulations. Behavioral Processes 88: 192-197.

Scott, J.P. and J.L. Fuller. 1998. Genetics and the Social Behavior of the Dog. Chicago: University of Chicago Press.

Twitty, V. 1966. Of Scientists and Salamanders. San Fransisco: W.H. Freeman.

Cat

The Serengeti Rules.

by Kenneth W. Krause.

[Notable New Media]

Kenneth W. Krause is a contributing editor and “Science Watch” columnist for the Skeptical Inquirer.  Formerly a contributing editor and books columnist for the Humanist, Kenneth contributes frequently to Skeptic as well.  He can be contracted at krausekc@msn.com.

Serengeti

Science has saved countless lives in strangely uncelebrated ways. How did military doctors first learn to treat shock? Well, that’s another interesting story.

In the early 20th century, Harvard physiologist, Walter Cannon, coined the term “fight-or-flight” following his observations in animal studies that digestive functions were strongly affected by stress. The sympatheric nervous system, he surmised, works in concert with the adrenal glands to modulate body organs during tough times.

As casualties mounted during WWI, Cannon was asked to figure out why the wounded so often went into shock and died. These soldiers exhibited some of the same symptoms as his beleauguered animal subjects–rapid pulse, dilated pupils, and heavy sweating. He quickly volunteered to treat injured casualties overseas in the Harvard Hospital Unit.

Cannon decided to measure the soldiers’ blood pressure, instead of just their pulse. Shock patients, he discovered, had abnormally low BPs–usually under 90 mmHg. After measuring the concentration of bicarbonate ions in their bloodstreams, he found it similarly lacking. The patients’ normally alkaline blood had become more acidic, and the more acidic it was, the lower the patients’ BPs.

So, to raise their pH levels, Cannon began adminsitering sodium bicarbonate to shock victims. And it worked. Innumerable soldiers were saved before WWI finally came to a grisly end. Later emphasizing how most bodily organs receive dual nervous system inputs that generally oppose one another, he coined another term–“homeostasis.” This dual regulation, he concluded, “is the central problem of physiology,” and thus the physician’s role was to reinforce or restore homeostasis.

University of Wisconsin-Madison professor of molecular biology, Sean B. Carroll, uses this story and others to illustrate a worthy point. Regulation is critical to not just human health, but the health of entire ecosystems as well. Also the author of “Endless Forms Most Beautiful” (one of my all-time favorites), Carroll’s new book, The Serengeti Rules: The Quest to Discover How Life Works and Why It Matters (Princeton University Press 2016), explains why the overarching logic of the small and familiar also applies to the large and far-flung.

Carroll

CRISPR-Cas9: Not Just Another Scientific Revolution (Special Report).

by Kenneth W. Krause.

Kenneth W. Krause is a contributing editor and “Science Watch” columnist for the Skeptical Inquirer.  Formerly a contributing editor and books columnist for the Humanist, he writes regularly for Skeptic magazine as well.  He may be contacted at krausekc@msn.com.

Poised to transform the world as we know it, a new gene-editing system has bioethicists wringing their hands, physicians champing at the bit, and researchers dueling with demons.

CRISPR6

Is it possible to overstate the potential of a new technology that efficiently and cheaply permits deliberate, specific, and multiple genomic modifications to almost anything biological? What if that technology was also capable of altering untold future generations of nearly any given species—including the one responsible for creating it?  And what if it could be used, for better or worse, to rapidly exterminate entire species?

Certain experts have no intention of veiling their enthusiasm, or their unease. Consider, for example, biologist David Baltimore, who recently chaired an international summit dedicated primarily to the technology’s much-disputed ethical implications.  “The unthinkable has become conceivable,” he warned his audience in early December.  Powerful new gene-editing techniques, he added, have placed us “on the cusp of a new era in human history.”

If so, it might seem somewhat anticlimactic to note that Science magazine has dubbed this technology its “Breakthrough of the Year” for 2015, or that its primary developers are widely considered shoo-ins for a Nobel Prize—in addition, that is, to the US$3 million Breakthrough Prize in Life Sciences already earned by two such researchers.  All of which might sound trifling compared to the billions up for grabs following imminent resolution of a now-vicious patent dispute.

Although no gene-editing tool has ever inspired so much drama, the new technology’s promise as a practical remedy for a host of dreadful diseases, including cancer, remains foremost in researchers’ minds. Eager to move beyond in vitro and animal model applications to the clinical setting, geneticists across the globe are quickly developing improved molecular components and methods to increase the technology’s accuracy.  In case you haven’t heard, a truly profound scientific insurrection is well underway.

Adapting CRISPR-Cas9.

Think about a film strip. You see a particular segment of the film that you want to replace.  And if you had a film splicer, you would go in and literally cut it out and piece it back together—maybe with a new clip.  Imagine being able to do that in the genetic code, the code of life.—biochemist Jennifer Doudna (CBS News 2015).

Genetic manipulation is nothing new, of course. Classic gene therapy, for example, typically employs a vector, often a virus, to somewhat haphazardly deliver a healthy allele somewhere in the patient’s genome, hopefully to perform its desired function wherever it settles.  Alternatively, RNA interference selects specific messenger RNA molecules for destruction, thus changing the way one’s DNA is transcribed.  Interference occurs, however, only so long as the damaging agent remains within the cell.

Contemporary editing techniques, on the other hand, allow biologists to actually alter DNA—the “code of life,” as Doudna suggests—and to do so with specific target sequences in mind.  The three major techniques have much in common.  Each involves an enzyme called a programmable nuclease, for example, which is guided to a particular nucleotide sequence to cleave it.

Then, in each case, the cell’s machinery quickly repairs the double-stranded break in one of two ways. Non-homologous end joining for gene “knock out” results when reconstruction, usually involving small, random nucleotide deletions or insertions, is performed only by the cell.  Here, the gene’s function is typically undermined.  By contrast, homology-directed repair for gene “knock in” occurs when the cell copies a researcher’s DNA repair template delivered along with the nuclease.  In this case, the cleaved gene can be corrected or a new gene or genes can be inserted (Corbyn 2015).

But in other ways, the three editing techniques are very distinct. Developed in the late 1990s and first used in human cells in 2005, zinc-finger nucleases (ZFN) attach cutting domains derived from the prokaryote Flavobacterium okeanokoites to proteins called zinc fingers that can be customized to recognize certain three-base-pair DNA codes.  Devised in 2010, transcription activator-like effector nucleases (TALENs) fuse the same cutting domains to different proteins called TAL effectors.  For both ZFN and TALENs, two cutting domains are necessary to cleave double-stranded DNA (Maxmen 2015).

The third and most revolutionary editing technique, and subject of this paper, consists of clustered regularly interspaced short palindromic repeats (CRISPR) and a CRISPR-associated protein-9 nuclease (Cas9). Introduced as an exceptionally precise editing technique in 2012 by Doudna at the University of California, Berkeley, and microbiologist Emmanuelle Charpentier at the Max Planck Institute for Infection Biology in Berlin, CRISPR-Cas9 is actually the bacterium Streptococcus pyogenes’ adaptive immune system that confers resistance to foreign elements, like phages and plasmids.

CRISPR3

CRISPR thus refers to short bits of DNA seized from invading viruses and stored in the bacterium’s own genome for future reference, and Cas9 is the enzyme S. pyogenes uses to cleave a subsequent invader’s double helix.  In other words, in its native setting, CRISPR-Cas9 is the system a certain bacterium uses to recognize and disable common biological threats.  Unlike ZFN and TALENs, CRISPR-Cas9 does not rely on the F. okeanoites cutting domain and, as such, can cleave both strands of an interloper’s double helix simultaneously with a single Cas9 enzyme.

But what makes the CRISPR system so special, in part, and so adaptable to the important task of gene-editing, is its relative simplicity. Only three components are required to achieve site-specific DNA recognition and cleavage.  Both a CRISPR RNA (crRNA) and a trans-activating crRNA (tracrRNA) are needed to guide the Cas9 enzyme to its target sequence.  What Doudna and Charpentier revealed six years ago, however, were the seminal facts that an even simpler, two-component system could be developed by combining the crRNA and tracrRNA into a synthetic single guide RNA (sgRNA), and that researchers could readily modify a sgRNA’s code to redirect the Cas9 enzyme to almost any preferred sequence (Jinek et al. 2012).  Today, a biologist wanting to edit a specific sequence in an organism’s genome can quickly and cheaply design a sgRNA to match that sequence, order it from a competitive manufacturer for US$65 or less, and have it delivered in the mail (Petherick 2015).

None of which is to suggest that a CRISPR system is always the best tool for the gene-editing job, at least not yet. Critically, CRISPR-Cas9 is relatively easy to program and remains the only technique allowing researchers to “multiplex,” or edit several genomic sites simultaneously.  But TALENs have the longest DNA recognition domains and, thus, tend so far to result in the fewest “off-target effects,” which occur when nucleotide sequences identical or similar to the target are cut unintentionally.  And ZFNs are much smaller than either TALENs or CRISPR-Cas9, especially the most popular version derived from S. pyogenes, and are therefore more likely to fit into the tight confines of an adeno-associated virus (AAV)—currently the most promising vector for the delivery of gene-editing therapies.

Even so, CRISPR research continues to progress at breakneck speed. In 2014, the number of gene-editing kits ordered from Addgene, a supplier based in Cambridge, Massachusetts, for research using ZFN and TALENs totaled less than 1000 and less than 2000, respectively.  During that same year—only two years after the new technology was introduced, the number of kits ordered for CRISPR research totaled almost 20,000 (Corbyn 2015).  More importantly, rapidly increasing orders seem to have translated into significant results.  As 2015 ended and a new year began, new studies announcing the creation of smaller guide RNAs and, especially, the reduction of off-target effects began to dominate science headlines.

Building a Better Mousetrap.

At some point everyone needs to decide how specific is specific enough. The idea that you would make a tool that has absolutely no off-target effects is a little too utopian.—bioengineer Charles Gersbach (Ledford 2016).

It’s cheap, easy to use, and remarkably efficient, but CRISPR-Cas9 is not perfect. In early experiments, in fact, pathologist Keith Joung at the Massachusetts General Hospital in Boston, discovered that his enzymes were cutting unintended as often as targeted sequences (Servick 2016).  The U.S. Food and Drug Administration has yet to announce requirements for clinical use of the new technology.  But to help future clinicians safely repair defective, disease-causing genes, for example, researchers are exploring various means of reducing off-target effects that could harm patients in any number of ways, including through uncontrolled cellular growth and cancer.

A CRISPR-Cas9 system “licenses” a DNA sequence for cleavage through a two-stage recognition process (Bolukbasi et al. 2016). Even the most basic details are somewhat technical, of course, but very illuminating.  First, a Cas9-sgRNA complex will attach and remain attached to a DNA sequence only if an appropriate protospacer-adjacent motif (PAM) is nearby.  PAM sequences are very short, often only a few base-pairs long.  In the case of an S. pyogenes Cas9, an NGG PAM is much-preferred, but NAG and NGA PAMs are sometimes inefficiently recognized (“N” represents any nucleobase followed by two guanine, or “G” nucleobases).

CRISPR2

Second, and only if an appropriate PAM is recognized, the sgRNA will interrogate the neighboring DNA sequence through Watson-Crick base pairing in a 3′-to-5′ direction. For an S. pyogenes Cas9, the guide sequence will measure twenty nucleotides long.  If the 3′ end of the programmed guide sequence is complementary to the DNA sequence near the PAM element, “R-loop” formation is initiated.  In zipper-like fashion, further complementarity of the DNA is assessed through extension of the R-loop.  If a complete target sequence is confirmed, allosteric activation of the Cas9 enzyme—actually, activation of Cas9’s two nuclease domains, RuvC and HNH—will result in dual cleavage and, accordingly, a complete double-stranded break in the target sequence.

Unsurprisingly, then, the specificity of a CRISPR-Cas9 system is determined in two ways. In large part, off-target effects are managed through careful design of the sgRNA.  Ideally, the guide sequence would match the target sequence perfectly, and show no homology elsewhere in the genome.  More realistically, however, at least partial homology will often occur at other genomic sites where, unfortunately, off-target cleavage could ensue.  Researchers have developed algorithms that help predict sufficient homology, but have yet to clearly and comprehensively define how closely guide and DNA sequences must harmonize before licensing occurs.  Nevertheless, nuclease activity has been observed at off-target sites displaying up to four or five nucleotide mismatches.

So, careful design of the sgRNA is critical. But one team of researchers, including Joung, recently confirmed that truncating the guide sequence can also help (Fu et al. 2014).  Shortening their guides to as few as seventeen nucleotides, instead of the usual twenty, Joung’s group was able to not only decrease nuclease activity at many off-target sites, but to preserve nearly thorough activity at the majority of intended sites as well.

Other groups have achieved similar success by inactivating one of the two nuclease domains, thus creating a “nickase” that cleaves only one strand of the target sequence (Ran et al. 2013). Here, a double-stranded break can still be achieved by joining two Cas9 nickases with two different sgRNAs targeting adjacent sites on opposing DNA strands.  Importantly, the obligatory use of two active nickases decreases the likelihood of off-target cleavage.

Perhaps the latest and most significant progress in this area, however, has been achieved through modification of the unaltered, or “wild-type,” Cas9 nuclease. Last December, for example, synthetic biologist Feng Zhang at the Broad Institute of MIT and Harvard University announced that he and his colleagues had engineered the Cas9 to render it less likely to act at genomic sites presenting mismatches between RNA guides and DNA targets (Slaymaker et al. 2015).  Appropriately, Zhang dubbed his new enzyme an “enhanced specificity” S. pyogenes Cas9, or eSpCas9 for short.

Feng Zhang

Feng Zhang

Knowing that negatively charged DNA binds to a positively charged groove in the Cas9 enzyme, Zhang’s team predicted that by replacing only a few among the 1400 or so positively charged amino acids with neutral equivalents they could temper the wild-type Cas9’s enthusiasm for binding to and cutting off-target sites. They created and tested several new versions of enzyme that reportedly reduced unintended activity at least tenfold, while maintaining robust on-target cleavage.

Earlier this year, however, Joung and colleagues claimed to have bested Zhang’s results by bringing “off-target-effects to levels where we can no longer detect them, even with the most sensitive methods” (McGreevey 2016). Like Zhang, Joung focused on points of interaction between Cas9 and DNA sequences.  His team created fifteen new enzyme variants by replacing up to four long amino acid side-chains that bind to DNA with shorter chains that do not (Kleinstiver et al. 2016).

Joung then tested each of his Cas9 variants in human cells, and found that one three-substitution and one four-substitution version rejected mismatched sites while maintaining full on-target activity. The latter variant, subsequently named SpCas9-HF1—“HF” denoting “high-fidelity,” induced targeted activity as reliably as a wild-type Cas9 when deployed with eighty-five percent of the thirty-seven different guide RNAs tested.  Similarly, SpCas9-HF1 generated no detectable off-target mutations with six of seven guide RNAs (and only one mutation with the seventh) compared to twenty-five such effects produced by the wild-type Cas9.

Keith Joung

Keith Joung

Joung’s group also tested their hi-fi creations at less typical genomic locations that are particularly difficult to control for off-target effects due to the inclusion of repeat sequences. But even there, his supplemental variants, since designated HF2, HF3, and HF4, appeared to eliminate off-target activity that tended to persist following use of the HF1 version.

It’s too early to judge which of these innovations will prove most valuable or, in fact, whether all of them will soon be superseded by modifications or entirely different systems yet to be introduced. But much progress has already been made and, importantly, at this point, many of the foregoing strategies and designs can be used in concert to bring us closer yet to the day when CRISPR gene-editing becomes a clinical convention.

Breaking Barriers.

This is now the most powerful system we have in biology. Any biological process we care about now, we can get the comprehensive set of genes that underlie that process. That was just not possible before.—biochemist David Sabatini (Yong 2015).

CRISPR-Cas9, of course, is only one among many prokaryotic CRISPR systems that could, at some point, prove useful for any number of human purposes. Use of Cas9 variations, however, has already resulted in successes far too numerous to review liberally here.  Even so, two recent applications in particular reveal the extraordinary, yet strikingly simple, means by which researchers have achieved previously unattainable outcomes.

In the first, three different teams confronted Duchenne muscular dystrophy (DMD), a terrifying disease that affects about one in every 3500 boys in the U.S. alone (Long et al. 2015, Nelson et al. 2015, and Tabebordbar et al. 2015). DMD typically stems from defects in a gene containing seventy-nine protein-coding exons.  If even a single exon suffers a debilitating mutation, the gene can be rendered incapable of producing dystrophin, a vital protein that protects muscle fibers.  Absent sufficient dystrophin, both skeletal and heart muscle will deteriorate.  Patients usually end up confined to wheelchairs and dead before the age of thirty.

CRISPR12

Traditional gene therapy, stem cell treatments, and drugs have proven mostly ineffective against DMD. Scientists have corrected diseased cells in vitro, or in a single organ—the liver.  But treating muscle cells throughout the body, including the heart, is a far more daunting task, because they can’t all be removed, treated in isolation, and then replaced.  And given current ethical concerns, most researchers are prohibited from even considering the possibility of editing human embryos for clinical purposes.

As such, researchers here decided to employ CRISPR-Cas9 technology to excise faulty dystrophin gene exons in both adult and neonatal mice by delivering it directly into their muscles and bloodstreams using non-pathogenic adeno-associated viruses. AAVs, however, are too small to accommodate the relatively large S. pyogenes Cas9, so each team opted instead to deploy a more petite Cas9 enzyme found in Staphylococcus aureus.

Neither group’s interventions resulted in complete cures. But dystrophin production and muscle strength was restored, and little evidence of off-target effects was observed, in treated mice.  One lead researcher later suggested that, although clinical trials could be years away, up to eighty percent of human DMD victims could benefit from defective exon removal (Kaiser 2015).

Remarkably, each of the three teams obtained results comparable to those of the others. Perhaps most impressively, however, these experiments marked the very first instances of using CRISPR to successfully treat genetic disorders in fully-developed living mammals.

But an ever-growing population needs to protect its agricultural products too. Plant DNA viruses, for example, can cause devastating crop damage and economic crises worldwide, but especially in underdeveloped regions including sub-Saharan Africa.  More specifically, the tomato yellow leaf curl virus (tomato virus) is known to ravage a variety of tomato breeds, causing stunted growth, abnormal leaf development, and fruit death.

CRISPR11

Like DMD, the tomato virus has proven an especially intractable problem. Despite previous efforts to control it through breeding, insecticides targeting the vector, and other engineering techniques, we currently know of no effective means of managing the virus.  Undeterred, another group of biologists decided to give CRISPR-Cas9-mediated viral interference a try (Ali et al. 2015).

In this study, the investigators chose to manipulate a species of tobacco plant, well-understood as a model organism, which is similarly vulnerable to tomato virus infection. The experiment was completed in two fairly predictable stages.  First, the group designed sgRNAs to target certain tomato virus coding and non-coding sequences and inserted them into different, harmless viruses of the tobacco rattle variety.  Second, they delivered the newly loaded rattle viruses into their tobacco plants.  After seven days, the plants were exposed to the tomato virus and, after ten more days, they were analyzed for symptoms of infection.

The group agreed that the CRISPR-Cas9 system had reliably cleaved and introduced mutations to the tomato viruses’ genomes. Fortuitously, every plant expressing the system had either abolished or significantly attenuated all symptoms of infection.  The investigators concluded further that the technique was capable of simultaneously targeting multiple DNA viruses with a lone sgRNA, and that other transformable plant species, including tomatoes, of course, would be similarly affected.

One can only guess, at this point, how certain interests might receive these and other types of genome-edited crops. Will nations eventually classify them as GMO or, alternatively, as organisms capable of developing in nature?  Will applicable regulations focus on the processes or products of modification?  Regardless, one can hardly ignore these commodities’ potential windfalls, especially for those in dire need.

Given recent innovations in specificity, for example, CRISPR-based disease research will likely continue to advance quickly toward clinical and other more practical applications. So long as it affects only non-reproductive somatic cells, such interventions should remain largely uncontroversial.  Human gametes and embryos, on the other hand, have once again inspired abundant debate and bitter division among experts.

Moralizing Over Science.

Genome editing in human embryos using current technologies could have unpredictable effects on future generations. This makes it dangerous and ethically unacceptable.—Edward Lanphier et al. (2015).

To intentionally refrain from engaging in life-saving research is to be morally responsible for the foreseeable, avoidable deaths of those who could have benefitted.—bioethicist Julian Savulescu et al. (2015).

The results of the first and, so far, last attempt to edit human embryos using CRISPR-Cas9 was published by a team of Chinese scientists on April 18 of last year (Liang et al. 2015). Led by Junjiu Huang, the group chose to experiment on donated tripronuclear zygotes—non-viable early embryos containing one egg and two sperm nuclei—neither intended nor suitable for clinical use.  Their goal was to successfully edit endogenous β-globin genes that, when mutated, can cause a fatal blood disorder known as β-thalassemia.

Junjiu Huang

Junjiu Huang

By his own admission, Huang’s outcomes were less than spectacular. Eighty-six embryos were injected with the Cas9 system and a molecular template designed to affect the insertion of new DNA.  Of the seventy-one that survived, fifty-four embryos were tested.  A mere twenty-eight were successfully spliced and, of those, only four exhibited the desired additions.  Rates of off-target mutations were much higher than expected too, and the group would likely have discovered additional unintended cuts had they examined more than the protein-coding exome, which represents less than two percent of the entire human genome.

In all fairness, however, the embryos’ abnormality might have been responsible for much of the total off-target effect. And, of course, Huang was unable to take advantage of many specificity-enhancing upgrades to the CRISPR system yet to be designed at the time of his investigations.  In any case, his team acknowledged that their results “highlight the pressing need to further improve the fidelity and specificity” of the new technology, which in their opinions remained immature and unready for clinical applications.

Nevertheless, the Chinese experiment ignited a brawl among both scientists and bioethicists over the prospect of human germline modification with the most powerful and accessible editing machinery ever conceived. Similar quarrels had accompanied the proliferation of technologies involving recombinant DNA, in vitro fertilization, gene therapy, and stem cells, for example.  But never had the need to address our capacity to reroute the evolution of societies—indeed, of the entire species—seemed so real and immediate.

Leading experts, including Baltimore and Doudna, had previously met in Napa, California, on January 24, 2015 to discuss the bioethical implications of rapidly emerging technologies. In the end, they “strongly discouraged … any attempts at germline genome modification for clinical application in humans,” urged informed discussion and transparent research, and called for a prompt global summit to recommend international policies (Baltimore et al. 2015).  A surge of impassioned literature ensued.

A small group led by Sangamo BioSciences president, Edward Lanphier, was one of the first to weigh in (Lanphier et al. 2015). Calling for a “voluntary moratorium” on all human germline research, Lanphier first expressed concerns over potential off-target effects and the genetic mosaicism that could result, for instance, if a fertilized egg began dividing before all intended corrections had occurred.  He also found it difficult to “imagine a situation in which use of human embryos would offer therapeutic benefits over existing and developing methods,” suggesting as well that pre-implantation genetic diagnosis (PGD) and in vitro fertilization (IVF) were far better options than CRISPR for parents carrying the same mutation for a genetic disease.  In any case, he continued, with so many unanswered questions, clinicians remained unable to obtain truly risk-informed consent from either parents looking to modify their germlines or from affected future generations.  Finally, Lanphier implied that even the best intentions could eventually lead societies down a “slippery slope” toward non-therapeutic genetic enhancement and so-called “designer babies.”

Edward Lanphier

Edward Lanphier

Francis Collins, evangelical Christian and director of the National Institutes of Health (which currently refuses to fund human germline research), expressed similar views regarding the sufficiency of PGD and IVF, the impossibility of informed consent, and non-therapeutic enhancement (Skerrett 2015). Additionally, Collins worries that access to the technology would be denied to the economically disadvantaged and that parents might begin to conceive of their children “more like commodities than precious gifts.”  For the director, given the “paucity of compelling cases” in favor of such research, and the significance of the ethical counterarguments, “the balance of the debate leans overwhelmingly against human germline engineering.”

On the other hand, Harvard Medical School geneticist, George Church, urges us to ignore pleas for artificially imposed bans, “encourage the innovators,” and focus more on what he deems the obvious benefits of germline research (Church 2015). Responding to Lanphier and Collins, he argues as well that, without obtaining consent, parents have long exposed future generations to mutagenic forces—through chemotherapy, residence in high-altitudes, and alcohol intake, for example.  We have also consistently chosen to enhance our offspring and future generations through mate choice, among many other things.  Church also points out that PGD during the IVF procedure is incapable of offering solutions to individuals possessing two copies of a detrimental, dominant allele, or to prospective parents who both carry two copies of a harmful, recessive allele.  Moreover, in most instances, PGD cannot be used to avoid more complex polygenic diseases, including schizophrenia.   Nor can we presume that new technology costs will always create treatment or enhancement inequities.  In fact, according to Church, the price of DNA sequencing, for example, has already plummeted more than three million fold.  Finally, germline editing is probably not irreversible, Church contends, and certainly not as error-prone at this point as many have suggested.  “Senseless” bans, he concludes, would only “put a damper on the best medical research and instead drive the practice underground to black markets and uncontrolled medical tourism.”

George Church

George Church

Taking a slightly different tack, Harvard cognitive scientist, Steven Pinker, censures bioethicists generally for getting bogged down in “red-tape, moratoria, or threats of prosecution based on nebulous but sweeping principles such as ‘dignity,’ ‘sacredness,’ or ‘social justice’” (Pinker 2015a). Imploring the bioethical community to “get out of the way” of CRISPR, Pinker reminds them that, once decried as morally unacceptable, vaccinations, transfusions, artificial insemination, organ transplants, and IVF have all proven “unexceptional boons to human well-being.”  Further, the specific harms of which moratorium proponents warn, including cancer, mutations, and birth defects, “are already ruled out by a plethora of existing regulations and norms” (Pinker 2015b).  In the end, he advises, both scientists and everyday people need and deserve a well-diversified research portfolio.  “If you ban something, the probability that people will benefit is zero.  If you don’t ban it, the probability is greater than zero.”

Such were among the arguments considered by a committee of twelve biologists, physicians, and ethicists during the December, 2015 International Summit on Human Genome Editing, organized by the U.S. National Academies of Science and Medicine, the Royal Society in London, and the Chinese Academy of Sciences. The Summit was chaired by David Baltimore.  Doudna and Charpentier, winners of the US$3 million Breakthrough Prize in Life Sciences, attended with Zhang—a now much-celebrated trio considered front runners for a Nobel Prize, though also entangled through their institutions in a CRISPR patent dispute potentially worth billions of dollars.

Doudna, Charpentier, and Zhang

Doudna, Charpentier, and Zhang

After three days of discussion, the Summit’s organizing committee issued a general statement rejecting calls for a comprehensive moratorium on germline research (NAS 2015). The members did, however, advise without exception against the use of edited embryos to establish pregnancy.  “It would be irresponsible to proceed,” they added, “with any clinical use of germline editing” until safety and efficacy issues are resolved and there exists “a broad societal consensus about the appropriateness of the proposed application.”  In conclusion, the committee called for an “ongoing forum” to harmonize the current global patchwork of relevant regulations and guidelines and to “discourage unacceptable activities.”  This forum, the members judged, should consist not only of experts and policymakers, but of “faith leaders,” “public interest advocates,” and “members of the general public” as well.

Wasting little time, the UK’s Human Fertilization and Embryology Authority approved on February 1, 2016, the first attempt to edit healthy human embryos with the CRISPR-Cas9 system.  The application was filed last September by developmental biologist, Kathy Niakan, of the Francis Crick Institute in London.  Niakan intends to use CRISPR to knock out one of four different genes in a total of 120 day-old, IVF-donated embryos to investigate the roles such genes play in early development.

Kathy Niakan

Kathy Niakan

Her research could help identify genes crucial to early human growth and cell differentiation and, thus, lead to more productive IVF cultures and more informed selection practices. It could also reveal mutations that lead to miscarriages and, one day, allow parents to correct these problems through gene therapy.  Following careful observation, Niakan intends to destroy her embryos by the time they reach the blastocyst stage on the seventh day.  Under British law, experimental embryos cannot be used to establish pregnancy.

But the human germline is not the only, or even most pressing, subject of CRISPR controversy. Some, for example, warn of the creation of dangerous pathogens and biological warfare (Greely 2016).  But many others, including Doudna, urge that we quickly address “other potentially harmful applications … in non-human systems, such as the alteration of insect DNA to ‘drive’ certain genes into a population” (Doudna 2015).

Driving DNA.

Clearly, the technology described here is not to be used lightly. Given the suffering caused by some species, neither is it obviously one to be ignored.—evolutionary geneticist Austin Burt (2003).

In broad terms, a “gene drive” can be characterized as a targeted contagion intended to spread through a population with exceptional haste. Burt pioneered the technology through his study of transposable elements—“selfish” and often parasitic DNA sequences that exist merely to propagate themselves.  Importantly, transposons can circumvent the normal Mendelian rules of inheritance dictating that any given gene has a fifty percent chance of being passed from parent to offspring.

Thirteen years ago, Burt envisioned the use of a microbial transposon-like element called a “homing endonuclease” for humanity’s benefit. When inserted into one chromosome, the endonuclease would cut the matching chromosome inherited from the other parent.  The cell would then quickly repair the cut, often using the first chromosome as a template.  As such, the assailed sequence in the second chromosome would be converted to the sequence of the selfish element.  In a newly fertilized egg, the endonuclease would likewise convert the other parent’s DNA and, eventually, drive itself into the genomes of nearly one-hundred percent of the population.

CRISPR1

 

Burt believes we can use gene drives to weaken or even eradicate mosquito transmitted diseases like malaria and dengue fever. If scientists engineered just one percent of a mosquito population to carry such a drive, he calculates, about ninety-nine percent would possess it in only twenty generations.  In fact, Burt announced five years ago that he had created a homing endonuclease capable of locating and cutting a mosquito gene (Windbichler 2011).  But his elements were difficult to program for precise application.

Enter CRISPR-Cas9. As we’ve seen, Cas9 is an eager endonuclease and guide RNAs are easy to program and can be quickly synthesized.  In April of last year, biologists Valentonio Gantz and Ethan Bier revealed that they had used CRISPR-Cas9 to drive color variation into Drosophila fruit flies (Gantz and Bier 2015).  Though they labeled it a “mutagenic chain reaction” at the time, it was the first gene drive ever deployed in a multicellular organism.

Today, researchers sort potential gene drives into two major groups. Replacement drives seek only to displace natural with modified populations.  Suppression drives, by contrast, attempt to reduce or even eradicate populations.  At this point, no drives have been released into the wild.  Nevertheless, researchers have lately designed one of each type to affect mosquitos carrying the deadly human malaria parasite, Plasmodium falciparum.

The first study was led by microbiologist Anthony James, who collaborated on the project with Gantz and Bier (James et al. 2015). Focusing on the prevention of disease transmission, this group engineered Anopheles stephensi mosquitos, highly active in urban India, to carry two transgenes producing antibodies against the malaria parasite, a CRISPR-Cas9-mediated gene drive, and a marker gene.  Because the very lengthy payload rendered insertion a challenging process, James was able to isolate only two drive-bearing males among 25,000 larvae.  But when mated with wild-type females, these and subsequent transgenic males spread their anti-malaria genes at an impressive rate of 99.5 percent.  Transgenic females, on the other hand, processed the drive quite differently and passed it on at near-normal Mendelian ratios.

Despite its overall success, James doesn’t imagine that his team’s replacement drive could eliminate the malaria parasite independently. Instead, he envisions its use to reduce the risk of infection and to compliment other strategies already being employed.  Even so, because such drives would not exterminate P. falciparum or its mosquito vector, they would potentially allow the parasite to one day evolve resistance to their transgene components.

mosquito-anopheles

The second study’s goal was quite different. Here, molecular biologist, Tony Nolan, along with Burt and others, first identified three genes in the Anopheles gambiae mosquito, active in sub-Saharan Africa, that when mutated cause recessive infertility in females (Hammond et al. 2016).  Second, they designed a CRISPR-Cas9 gene drive to target and edit each gene.  Following insertion, they bred their transgenic mosquitos with wild-types and found that nearly all female offspring were born infertile.  In a subsequent experiment, Nolan released 600 vectors—half transgenic, half wild-type—into a cage.  After only four generations, seventy-five percent of the population carried the mutations, exactly what one would expect from an effective gene drive.

A suppression drive like Hammond’s could, in theory, eliminate a parasite’s primary vector. In such a scenario, the parasite might find another means of conveying the disease to humans—more than 800 species of mosquito inhabit Africa alone, for example.  But it might not.  The loss would also substantially alter the relevant ecosystem.  But despite other methods of controlling the disease, malaria still claims more than a half million lives every year, mostly among children under five.

Even in theory, no gene drive is a panacea. They function only in sexually reproducing species, and best in species that reproduce very rapidly.  Nor would their effects be permanent—most transgenes would prove especially vulnerable to evolutionary deselection, for example.   But neither would they turn out as problematic as some might imagine. They can be easily detected through genome sequencing, for instance, and are unlikely to spread accidentally into domesticated species.  And if scientists sought for whatever reason to reverse the effects of a previously released drive, they could probably do so with the release of a subsequent drive.

As Church and others have recently suggested, it “doesn’t really make sense to ask whether we should use gene drives. Rather, we’ll need to ask whether it’s a good idea to consider driving this particular change through this particular population”  (Esvelt et al. 2014).

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Bolukbasi, M.F., A. Gupta, and S.A. Wolf. 2016. Creating and evaluating accurate CRISPR-Cas9 scalpels for genomic surgery. Nature Methods 13(1):41-50.

Burt, A. 2003. Site-specific selfish genes as tools for the control and genetic engineering of natural populations. Proceedings of the Royal Society B 270:921-928.

CBS News. 2015. Could Revolutionary Gene-editing Technology End Cancer? Available online at http://www.cbsnews.com/news/crispr-jennifer-doudna-gene-editing-technology-diseases-dangers-ethics/; accessed January 25, 2016.

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Corbyn, Z. 2015. Biology’s big hit. Nature 528:S4-S5.

Doudna, J. 2015. Embryo editing needs scrutiny. Nature 528:S6.

Esvelt, K., G. Church, and J. Lunshof. 2014. “Gene Drives” and CRISPR Could Revolutionize Ecosystem Management. Available online at http://blogs.scientificamerican.com/guest-blog/gene-drives-and-crispr-could-revolutionize-ecosystem-management/; accessed February 6, 2016.

Fu, Y., J.D. Sander, D. Reyon, et al. 2014. Improving CRISPR-Cas nuclease specificity using truncated guide RNAs. Nature Biotechnology 32:279-284.

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Gantz, V.M., N. Jasinskiene, O. Tatarenkova, et al. 2015. Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi. Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1521077112.

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Jinek, M., K. Chylinski, I. Fonfara, et al. 2012. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337:816-821.

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Kleinstiver, B.P., V. Pattanayak, M.S. Prew, et al. 2016. High-fidelity CRISPR-Cas9 nuclease with no detectable genome-wide off-target effects. Nature 529:490-495.

Lanphier, E., F. Urnov, S.E. Ehlen, et al. 2015. Don’t edit the human germline. Nature 519:410-411.

Ledford, H. 2016. Enzyme Tweak Boosts Precision of CRISPR Genome Edits. Available online at http://www.nature.com/news/enzyme-tweak-boosts-precision-of-crispr-genome-edits-1.19114; accessed January 28, 2016.

Liang, P., Y. Xu, X. Zhang, et al. 2015. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell 6(5):363-372.

Long, C., L. Amoasii, A.A. Mireault, et al. 2015. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science DOI: 10.1126/science.aad5725.

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Ran, F.A., P.D. Hsu, C. Lin, et al. 2013. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154:1380-1389.

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Sherkow, J.S. 2015. The CRISPR Patent Interference Showdown Is On. Available online at https://law.stanford.edu/2015/12/29/the-crispr-patent-interference-showdown-is-on-how-did-we-get-here-and-what-comes-next/; accessed January 29, 2016.

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Tabebordbar, M., K. Zhu, J.K.W. Cheng, et al. 2015. In vivo gene editing in dystrophic mouse and muscle stem cells. Science DOI: 10.1126/science.aad5177.

Windbichler, N., M. Menichelli, P.A. Papathanos, et al. 2011. A synthetic homing endonuclease-based gene drive system in the human malaria mosquito. Nature 473:212-215.

Yong, E. 2015. The New Gene-editing Technique that Reveals Cancer’s Weaknesses. Available online at http://www.theatlantic.com/science/archive/2015/11/a-revolutionary-gene-editing-technique-reveals-cancers-weaknesses/417495/; accessed on January 30, 2016.

Biological Race and the Problem of Human Diversity (Cover Article).

by Kenneth W. Krause.

Kenneth W. Krause is a contributing editor and “Science Watch” columnist for the Skeptical Inquirer.  Formerly a contributing editor and books columnist for the Humanist, Kenneth contributes regularly to Skeptic as well.  He may be contacted at krausekc@msn.com.

Race 1

Some would see any notion of “race” recede unceremoniously into the dustbin of history, taking its ignominious place alongside the likes of phlogiston theory, Ptolemaic geocentricism, or perhaps even the Iron Curtain or Spanish Inquisition.  But race endures, in one form or another, despite its obnoxious, though apparently captivating dossier.

In 1942, anthropologist Ashley Montagu declared biological race “Man’s Most Dangerous Myth,” and, since then, most scientists have consistently agreed (Montagu 1942).  Nevertheless, to most Americans in particular, heritable race seems as obvious as the colors of their neighbors’ skins and the textures of their hair.  So too have a determined minority of researchers always found cause to dissent from the professional consensus.

Here, I recount the latest popular skirmish over the science of race and attempt to reveal a victor, if there be one.  Is biological race indeed a mere myth, as the academic majority has asked us to concede for more than seven decades?  Is it instead a scandalously inconvenient truth—something we all know exists but, for whatever reasons, prefer not to discuss in polite company?  Or is it possible that a far less familiar rendition of biological race could prove not only viable, but both scientifically and socially valuable as well?

Race Revived.

The productive questions pertain to how races came to be and the extent to which racial variation has significant consequences with respect to function in the modern world.—Vincent Sarich and Frank Miele, 2004.

I have no reason to believe that Nicholas Wade, long-time science editor and journalist, is a racist, if “racist” is to mean believing in the inherent superiority of one human race over any other.  In fact, he expressly condemns the idea.  But in the more limited and hopefully sober context of the science of race, Wade is a veritable maverick.  Indeed, his conclusions that biological human races (or subspecies, for these purposes) do exist, and conform generally to ancestral continental regions, appear remarkably more consistent with those of the general public.

In his most recent and certainly controversial book, A Troublesome Inheritance: Genes, Race and Human History, Wade immediately acknowledges that the vast majority of both anthropologists and geneticists deny the existence of biological race (Wade 2014).  Indeed, “race is a recent human invention,” according to the American Anthropological Association (AAA 2008), and a mere “social construct,” per the American Sociological Association (ASA 2003).  First to decode the human genome, Craig Venter was also quick to announce during his White House visit in 2000 that “the concept of race has no genetic or scientific basis.”

But academics especially are resistant to biological race, or the idea that “human evolution is recent, copious, and regional,” Wade contends, because they fear for their careers in left-leaning political atmospheres and because they tend to be “obsessed with intelligence” and paralyzed by the “unlikely” possibility that genetics might one day demonstrate the intellectual superiority of one major race over others.

According to Wade, “social scientists often write as if they believe that culture explains everything and race [indeed, biology] explains nothing, and that all cultures are of equal value.”  But “the emerging truth,” he insists, “is more complicated.”  Although the author sees individuals as fundamentally similar, “their societies differ greatly in their structure, institutions and their achievements.”  Indeed, “contrary to the central belief of multiculturalists, Western culture has achieved far more” than others “because Europeans, probably for reasons of both evolution and history, have been able to create open and innovative societies, starkly different from the default human arrangements of tribalism or autocracy.”

Race 6

Wade admits that much of his argument is speculative and has yet to be confirmed by hard, genetic evidence.  Nevertheless, he argues, “even a small shift in [genetically-based] social behavior can generate a very different kind of society,” perhaps one where trust and cooperation can extend beyond kin or the tribe—thus facilitating trade, for example, or one emphasizing punishment for nonconformity—thus advancing rule-orientation and isolationism, for instance.  “[I]t is reasonable to assume,” the author vies, “that if traits like skin color have evolved in a population, the same may be true of its social behavior.”

But what profound environmental conditions could possibly have selected for more progressive behavioral adaptations in some but not all populations?  As the climate warmed following the Pleistocene Ice Age, Wade reminds, the agricultural revolution erupted around 10,000 years ago among settlements in the Near East and China.  Increased food production led to population explosions, which in turn spurred social stratification, wealth disparities, and more frequent warfare.  “Human social behavior,” Wade says, “had to adapt to a succession of makeovers as settled tribes developed into chiefdoms, chiefdoms into archaic states and states into empires.”

Meanwhile, other societies transformed far less dramatically.  “For lack of good soils, favorable climate, navigable rivers and population pressures,” Wade observes, “Africa south of the Sahara remained largely tribal throughout the historical period, as did Australia, Polynesia and the circumpolar regions.”

Citing economist Gregory Clark, Wade then postulates that, during the period between 1200 and 1800 CE—twenty-four generations and “plenty of time for a significant change in social behavior if the pressure of natural selection were sufficiently intense,”—the English in particular evolved a greater tendency toward “bourgeoisification” and at least four traits—nonviolence, literacy, thrift, and patience—thus enabling them to escape the so-called “Malthusian trap,” in which agrarian societies never quite learn to produce more than their expanding numbers can consume, and, finally, to lead the world into the Industrial Revolution.

In other words, according to this author, modern industrialized societies have emerged only as a result of two evolved sets of behaviors—initially, those that favor broader trust and contribute to the breakdown of tribalism, and, subsequently, those that favor discipline and delayed gratification and lead to increased productivity and wealth.  On the other hand, says Wade, Sub-Saharan Africans, for example, though well-adapted to their unique environmental circumstances, generally never evolved traits necessary to move beyond tribalism.  Only an evolutionary explanation for this disparity, he concludes, can reveal, for instance, why foreign aid to non-modern societies frequently fails and why Western institutions, including democracy and free markets, cannot be readily transferred to (or forced upon) yet pre-industrial cultures.

So how many races have evolved in Wade’s estimation?  Three major races—Caucasian, East Asian, and African—resulted from an early migration out of Africa some 50,000 years ago, followed by a division between European and Asian populations shortly thereafter.  Quoting statistical geneticist, Neil Risch, however, Wade adds Pacific Islanders and Native Americans to the list because “population genetic studies have recapitulated the classical definition of races based on continental ancestry” (Risch 2002).

To those who would object that there can be no biological race when so many thousands of people fail to fit neatly into any discreet racial category, Wade responds, “[T]o say there are no precise boundaries between races is like saying there are no square circles.”  Races, he adds, are merely “way stations” on the evolutionary road toward speciation.  Different variations of a species can arise where different populations face different selective challenges, and humans have no special exemption from this process.  However, the forces of differentiation can reverse course when, as now, races intermingle due to increased migration, travel, and intermarriage.

Race Rejected.

It is only tradition and shortsightedness that leads us to think there are multiple distinct oceans.—Guy P. Harrison, 2010.

So, if we inherit from our parents traits typically associated with race, including skin, hair, and eye color, why do most scientists insist that race is more social construct than biological reality?  Are they suffering from an acute case of political correctness, as Wade suggests, or perhaps a misplaced paternalistic desire to deceive the irresponsible and short-sighted masses for the greater good of humanity?  More ignoble things have happened, of course, even within scientific communities. But according to geneticist Daniel J. Fairbanks, the denial of biological race is all about the evidence.

In his new book, Everyone is African: How Science Explodes the Myth of Race, Fairbanks points out that, although large-scale analyses of human DNA have recently unleashed a deluge of detailed genetic information, such analyses have so far failed to reveal discrete genetic boundaries along traditional lines of racial classification (Fairbanks 2015).  “What they do reveal,” he argues, “are complex and fascinating ancestral backgrounds that mirror known historical immigration, both ancient and modern.”

Fairbanks

In 1972, Harvard geneticist Richard Lewontin analyzed seventeen different genes among seven groups classified by geographic origin.  He famously discovered that subjects within racial groups varied more among themselves than their overall group varied from other groups, and concluded that there exists virtually no genetic or taxonomic significance to racial classifications (Lewontin 1972).  But Lewontin’s word on the subject was by no means the last. Later characterizing his conclusion as “Lewontin’s Fallacy,” for example, Cambridge geneticist A.W.F. Edwards reminded us how easy it is to predict race simply by inspecting people’s genes (Edwards 2003).

So who was right?  Both of them were, according to geneticist Lynn Jorde and anthropologist Stephen Wooding.  Summarizing several large-scale studies on the topic in 2004, they confirmed Lewontin’s finding that about 85-90% of all human genetic variation exists within continental groups, while only 10-15% between them (Jorde and Wooding 2004).  Even so, as Edwards had insisted, they were also able to assign all native European, East Asian, and sub-Saharan African subjects to their continent of origin using DNA alone.  In the end, however, Jorde and Wooding showed that geographically intermediate populations—South Indians, for example—did not fit neatly into commonly conceived racial categories.  “Ancestry,” they concluded, was “a more subtle and complex description” of one’s genetic makeup than “race.”

Fairbanks concurs.  Humans have been highly mobile for thousands of years, he notes.  As a result, our biological variation “is complex, overlapping, and more continuous than discreet.”  When one analyzes DNA from a geographically broad and truly representative sample, the author surmises, “the notion of discrete racial boundaries disappears.”

Nor are the genetic signatures of typically conceived racial traits always consistent between populations native to different geographic regions.  Consider skin color, for example.  We know, of course, that the first Homo sapiens inherited dark skin previously evolved in Africa to protect against sun exposure and folate degradation, which negatively affects fetal development.  Even today, the ancestral variant of the MC1R gene, conferring high skin pigmentation, is carried uniformly among native Africans.

Race 2

But around 30,000 years ago, Fairbanks instructs, long after our species had first ventured out of Africa into the Caucasus region, a new variant appeared.  KITLG evolved in this population prior to the European-Asian split to reduce pigmentation and facilitate vitamin D absorption in regions of diminished sunlight.  Some 15,000 years later, however, another variant, SLC24A5, evolved by selective sweep as one group migrated westward into Europe.  Extremely rare in other native populations, nearly 100% of modern native Europeans carry this variant.  On the other hand, as their assorted skin tones demonstrate, African and Caribbean Americans carry either two copies of an ancestral variant, two copies of the SLC24A5 variant, or one of each.  Asians, by contrast, developed their own pigment-reducing variants—of the OCA2 gene, for example—via convergent evolution, whereby similar phenotypic traits result independently among different populations due to similar environmental pressures.

So how can biology support the traditional, or “folk,” notion of race when the genetic signatures of that notion’s most relied upon trait—that is, skin color—are so diverse among populations sharing the same or similar degree of skin pigmentation?  Fairbanks judges the idea utterly bankrupt “in light of the obvious fact that actual variation for skin color in humans does not fall into discrete classes,” but rather “ranges from intense to little pigmentation in continuously varying gradations.”

To Wade, Fairbanks offers the following reply: “Traditional racial classifications constitute an oversimplified way to represent the distribution of genetic variation among the people of the world. Mutations have been creating new DNA variants throughout human history, and the notion that a small proportion of them define human races fails to recognize the complex nature of their distribution.”

Race 8

A Severe Response.

I use the term scientific racism to refer to scientists who continue to believe that race is a biological reality.—Robert Wald Sussman, 2014.

Since neither author disputes the absence of completely discreet racial categories, one could argue that part of the battle is really one over mere semantics, if not politics. Regardless, critical aspects of Wade’s analysis were quickly and sharply criticized by several well-respected researchers.

Former president of the AAA and co-drafter of its statement on race, Alan Goodman, for example, argues that Wade’s “speculations follow from misunderstandings about most everything, including the idea of race, evolution and gene action, culture and institutions, and most fundamentally, the scientific process” (Goodman 2014). Indeed, he compares Wade’s book to the most maligned texts on race ever published, including Madison Grant’s 1916 The Passing of the Great Race, Arthur Jensen’s 1969 paper proposing racial intelligence differences, and Herrnstein’s and Murray’s 1994 The Bell Curve.

But Wade’s “biggest error,” according to Goodman, “is his inability to separate the data on human variation from race.” He mistakenly assumes, in other words, “that all he sees is due to genes,” and that culture means little to nothing. A “mix of mysticism and sociobiology,” he continues, Wade’s simplistic view of human culture ignores the archeological and historical fact that cultures are “open systems” that constantly change and interact. And although biological human variation can sometimes fall into geographic patterns, Goodman emphasizes, our centuries-long attempt to force all such variation into racial categories has failed miserably.

Characterizing Wade’s analysis similarly as a “spectacular failure of logic,” population geneticist Jennifer Raff takes special issue with the author’s attempt to cluster human genetic variation into five or, really, any given number of races (Raff 2014). To do so, Wade relied in part on a 2002 study featuring a program called Structure, which is used to group people across the globe based on genetic similarities (Rosenberg 2002). And, indeed, when Rosenberg et al. asked Structure to bunch genetic data into five major groups, it produced clusters conforming to the continents.

But, as Raff observes, the program was capable of dividing the data into any number of clusters, up to twenty in this case, depending on the researchers’ pre-specified desire. When asked for six groups, for example, Structure provided an additional “major” cluster, the Kalash of northwestern Pakistan—which Wade arbitrarily, according to Raff, rejected as a racial category. In the end, she concludes, Wade seems to prefer the number five “simply because it matches his pre-conceived notions of what race should be.”

Interestingly, when Rosenberg et al. subsequently expanded their dataset to include additional genetic markers for the same population samples, Structure simply rejected the Kalesh and decided instead that one of Wade’s five human races, the Native Americans, should be split into two clusters (Rosenberg 2005). In any event, Rosenberg et al. expressly warned in their second paper that Structure’s results “should not be taken as evidence of [their] support of any particular concept of ‘biological race.’”

Structure was able to generate discrete clusters from a very limited quantity of genetic variation, adds population geneticist Jeremy Yoder, because its results reflect what his colleagues refer to as isolation-by-distance, or the fact that populations separated by sufficient geographic expanses will display genetic distinctions even if intimately connected through migration and interbreeding (Yoder 2014). In reality, however, human genetic variation is clinal, or gradual in transition between such populations. In simpler terms, people living closer together tend to be more closely related than those living farther apart.

In his review, biological anthropologist Greg Laden admits that human races might have existed in the past and could emerge at some point in the future (Laden 2014). He also concedes that “genes undoubtedly do underlie human behavior in countless ways.” Nevertheless, he argues, Wade’s “fashionable” hypothesis proposing the genetic underpinnings of racially-based behaviors remains groundless. “There is simply not an accepted list of alleles,” Laden reminds, “that account for behavioral variation.”

Chimpanzees, by contrast, can be divided into genetically-based subspecies (or races). Their genetic diversity has proven much greater than ours, and they demonstrate considerable cultural variation as well. Even so, Laden points out, scientists have so far been unable to sort cultural variation among chimps according to their subspecies. So if biologically-based races cannot explain cultural differences among chimpanzees, despite their superior genetic diversity as a species, why would anyone presume the opposite of humans?

Race 7

None of which is to imply that every review of Wade has been entirely negative. Conservative journalist Anthony Daniels (a.k.a. Theodore Dalrymple), for example, praises the author lavishly as a “courageous man … who dares raise his head above the intellectual parapet” (Daniels 2014). While judging Wade’s arguments mostly unconvincing, he nevertheless defends his right to publish them: “That the concept of race has been used to justify the most hideous of crimes should no more inhibit us from examining it dispassionately … than the fact that economic egalitarianism has been used to justify crimes just as hideous …”

Similarly, political scientist and co-author of The Bell Curve, Charles Murray warned readers of the social science “orthodoxy’s” then-impending attempt to “not just refute” Wade’s analysis, “but to discredit it utterly—to make people embarrassed to be seen purchasing it in public” (Murray 2014). “It is unhelpful,” Murray predicts, “for social scientists and the media to continue to proclaim that ‘race is a social construct’” when “the problem facing us down the road is the increasing rate at which the technical literature reports new links between specific genes and specific traits.” Although “we don’t yet know what the genetically significant racial differences will turn out to be,” Murray contends, “we have to expect that they will be many.”

Perhaps; perhaps not. But race is clearly problematic from a biological perspective—at least as Wade and many before him have imagined it. Humans do not sort neatly into separate genetic categories, or into a handful of continentally-based groups. Nor have we discovered sufficient evidence to suggest that human behaviors match to known patterns of genetic diversity. Nonetheless, because no “is” ever implies an “ought,” the cultural past should never define, let alone restrain, the scientific present.

Characterizing Biological Diversity.

Instead of wasting our time “refuting” straw-man positions dredged from a distant past or from fiction, we should deal with the strongest contemporary attempts to rehabilitate race that are scientifically respectable and genetically informed.—Neven Sesardic, 2010.

To this somewhat belated point, I have avoided the task of defining “biological race,” in large measure because no single definition has achieved widespread acceptance. In any event, preeminent evolutionary biologist, Ernst Mayr, once described “geographic race” generally as “an aggregate of phenotypically similar populations of a species inhabiting a geographic subdivision of the range of that species and differing taxonomically from other populations of that species” (Mayr 2002). A “human race,” he added, “consists of the descendants of a once-isolated geographic population primarily adapted for the environmental conditions of their original home country.”

Sounds much like Wade, so far. But unlike Wade, Mayr firmly rejected any typological, essentialist, or folk approach to human race denying profuse variability and mistaking non-biological attributes—especially those implicating personality and behavior—for racial traits. Accepting culture’s profound sway, Mayr warned that it is “generally unwise to assume that every apparent difference … has a biological cause.” Nonetheless, he concluded, recognizing human races “is only recognizing a biological fact”:

Geographic groups of humans, what biologists call races, tend to differ from each other in mean differences and sometimes even in specific single genes. But when it comes to the capacities that are required for the optimal functioning of our society, I am sure that any racial group can be matched by that of some individual in another racial group. This is what population analysis reveals.

So how might one rescue biological race from the present-day miasma of popular imparsimony and professional denialism, perhaps even to the advancement of science and benefit of society? Evolutionary biologist and professor of science philosophy, Massimo Pigliucci, thinks he has an answer.

Race 3

More than a decade ago, he and colleague Jonathan Kaplan proposed that “the best way of making sense of systematic variation within the human species is likely to rely on the ecotypic conception of biological races” (Pigliucci and Kaplan 2003). Ecotypes, they specify, are “functional-ecological entities” genetically adapted to certain environments and distinguished from one another based on “many or a very few genetic differences.” Consistent with clinal variation, ecotypes are not always phylogenetically distinct, and gene flow between them is common. Thus, a single population might consist of many overlapping ecotypes.

All of which is far more descriptive of human evolution than even the otherwise agreeable notion of “ancestry,” for example. For Pigliucci and Kaplan, the question of human biological race turns not on whether there exists significant between-population variation overall, as Lewontin, for example, suggested, but rather on “whether there is [any] variation in genes associated with significant adaptive differences between populations.” As such, if we accept an ecotypic description of race, “much of the evidence used to suggest that there are no biologically significant human races is, in fact, irrelevant.”

On the other hand, as Pigliucci observed more recently, the ecotypic model implies the failure of folk race as well. First, “the same folk ‘race’ may have evolved independently several times,” as explained above in the context of skin color, “and be characterized by different genetic makeups” (Pigliucci 2013). Second, ecotypes are “only superficially different from each other because they are usually selected for only a relatively small number of traits that are advantageous in certain environments.” In other words, the popular notion of the “black race,” for example, centers on a scientifically incoherent unit—one “defined by a mishmash of small and superficial set of biological traits … and a convoluted cultural history” (Pigliucci 2014).

So, while the essentialist and folk concepts of human race can claim “no support in biology,” Pigliucci concludes, scientists “should not fall into the trap of claiming that there is no systematic variation within human populations of interest to biology.” Consider, for a moment, the context of competitive sports. While the common notion that blacks are better runners than whites is demonstrably false, some evidence does suggest that certain West Africans have a genetic edge as sprinters, and that certain East and North Africans possess an innate advantage as long-distance runners (Harrison 2010). As the ecotypic perspective predicts, the most meaningful biological human races are likely far smaller and more numerous than their baseless essentialist and folk counterparts (Pigliucci and Kaplan 2003).

So, given the concept’s exceptionally sordid history, why not abandon every notion of human race, including the ecotypic version? Indeed, we might be wise to avoid the term “race” altogether, as Pigliucci and Kaplan acknowledge. But if a pattern of genetic variation is scientifically coherent and meaningful, it will likely prove valuable as well. Further study of ecotypes “could yield insights into our recent evolution,” the authors urge, “and perhaps shed increased light onto the history of migrations and gene flow.” By contrast, both the failure to replace the folk concept of race and the continued denial of meaningful patterns of human genetic variation have “hampered research into these areas, a situation from which neither biology nor social policy surely benefit.”

References:

American Anthropological Association. 2008. Race continues to define America. http://new.aaanet.org/pdf/upload/Race-Continues-to-Define-America.pdf (last accessed November 12, 2015).

American Sociological Association. 2003. The importance of collecting data and doing social scientific research in race. http://www.asanet.org/images/press/docs/pdf/asa_race_statement.pdf (last accessed November 12, 2015).

Clark, E. 2007. A farewell to alms: a brief economic history of the world. Princeton, NJ: Princeton University Press.

Daniels, A. 2014. Genetic disorder. http://www.newcriterion.com/articleprint.cfm/Genetic-disorder-7903 (last accessed November 19, 2015).

Edwards, A.W.F. 2003. Human genetic diversity: Lewontin’s fallacy. BioEssays 25(8):798-801.

Fairbanks, D.J. 2015. Everyone is African: how science explodes the myth of race. Amherst, NY: Prometheus Books.

Goodman, A. 2014. A troublesome racial smog. http://www.counterpunch.org/2014/05/23/a-troublesome-racial-smog/print (last accessed November 17, 2015).

Harrison, G.P. 2010. Race and reality: what everyone should know about our biological diversity. Amherst, NY: Prometheus Books.

Jorde, L.B. and S.P. Wooding. 2004. Genetic variation, classification and ‘race.’ Nature Genetics 36(11):528-533.

Laden, G. 2014. A troubling tome. http://www.americanscientist.org/bookshelf/id.16216,content.true,css.print/bookshelf.aspx (last accessed November 16, 2015).

Lewontin, R. 1972. The apportionment of human diversity. Evolutionary Biology 6:397.

Mayr, E. 2002. The biology of race and the concept of equality. Daedalus 131(1):89-94.

Montagu, A. 1942. Man’s most dangerous myth: the fallacy of race. NY: Columbia University Press.

Murray, C. 2014. Book review: ‘A Troublesome Inheritance’ by Nicholas Wade: a scientific revolution is under way—upending one of our reigning orthodoxies. http://www.wsj.com/articles/SB10001424052702303380004579521482247869874 (last accessed November 19, 2015).

Pigliucci, M. 2013. What are we to make of the concept of race? Thoughts of a philosopher-scientist. Studies in History and Philosophy of Biological and Biomedical Sciences. 44:272-277.

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Pigliucci, M. and J. Kaplan. 2003. On the concept of biological race and its applicability to humans. Philosophy of Science 70:1161-1172.

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Nature, Nurture, and the Folly of “Holistic Interactionism.”

[Notable New Media]

by Kenneth W. Krause.

Kenneth W. Krause is a contributing editor and “Science Watch” columnist for the Skeptical Inquirer.  Formerly a contributing editor and books columnist for the Humanist, Kenneth contributes regularly to Skeptic as well.  He may be contacted at krausekc@msn.com.

Most contemporary scientists, according to Harvard University experimental psychologist, Steven Pinker, have abandoned both the nineteenth-century belief in biology as destiny and the twentieth-century doctrine that the human mind begins as a “blank slate.”  In his new anthology, Language, Cognition, and Human Nature: Selected Articles (Oxford 2015), Pinker first reminds us of the now-defunct blank slate’s political and moral appeal:  “If nothing in the mind is innate,” he chides, “then differences among races, sexes, and classes can never be innate, making the blank slate the ultimate safeguard against racism, sexism, and class prejudice.”

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Even so, certain angry ideologues, for example, continue to wallow in blank slate dogma.  Gender differences in STEM professions, for example, are often attributed entirely to prejudice and hidden barriers.  The mere possibility that women, on average, are less interested than men in people-free pursuits remains oddly “unspeakable,” says Pinker (but see a recent exception here).  The point, he clarifies, is not that we know for certain that evolution and genetics are relevant to explaining so-called “underrepresentation” in high-end science and math, but that “the mere possibility is often treated as an unmentionable taboo, rather than as a testable hypothesis.”

A similar exception to the general rule centers around parenting and the behavior of children.  It may be true that parents who spank raise more violent children, and that more conversant parents produce children with better language skills.  But why does “virtually everyone” conclude from such facts that the parent’s behavior causes that of the child?  “The possibility that the correlations may rise from shared genes is usually not even mentioned, let alone tested,” says Pinker.

Equally untenable for the author is the now-popular academic doctrine he dubs “holistic interactionism” (HI).  Carrying a “veneer of moderation [and] conceptual sophistication,” says Pinker, HI is based on a few “unexceptional points,” including the facts that nature and nurture are not mutually exclusive and that genes cannot cause behavior directly.  But we should confront this doctrine with heightened scrutiny, according to Pinker, because “no matter how complex the interaction is, it can be understood only by identifying the components and how they interact.”  HI “can stand in the way of such an understanding,” he warns, “by dismissing any attempt to disentangle heredity and environment as uncouth.”

HI mistakenly assumes, for example, that hereditary cannot constrain behavior because genes depend critically on the environment.  “To begin with,” says Pinker, “it is simply not true that any gene can have any effect in some environment, with the implication that we can always design an environment to produce whatever outcome we value.”  And even if some extreme “gene-reversing” environment can be imagined, it simply doesn’t follow that “the ordinary range of environments will [even] modulate that trait, [or that] the environment can explain the nature of the trait.”  The mere existence of environmental mitigations, in other words, does not render the effects of genes inconsequential.  To the contrary, Pinker insists, “genes specify what kinds of environmental manipulations will have what kinds of effects and with what costs.”

Although the postmodernists and social constructionists who tend to dominate humanities departments in American Universities especially, continue to tout HI as a supposedly nuanced means of comprehending the nature-nurture debate, it is in truth little more than a pseudo-intellectual “dodge,” Pinker concludes: a convenient means to “evade fundamental scientific problems because of their moral, emotional, and political baggage.”

Among intellectually honest, truly curious, and consistently rational thinkers (a diminutive demographic indeed), Pinker’s reputation is and has long stood as something perhaps just short of heroic, in no small part due to his defense of politically incorrect but nonetheless scientifically viable hypotheses.  What a shame it is that only academics of similar status (and tenure) can safely rise and demand the freedom required to mount such defenses.  And what a tragedy that so few in such privileged company actually do.