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).

References:

Ali, Z., A. Abulfaraj, Ali Idris, et al. 2015. CRISPR/Cas9-mediated viral interference in plants. Genome Biology 16:238 DOI:10.1186/s13059-015-0799-6.

Baltimore, D., P. Berg, M. Botcham, et al. 2015. A prudent path forward for genomic engineering and germline gene modification. Science 348(6230):36-38.

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.

Church, G., 2015. Encourage the innovators. Nature 528:S7.

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.

Gantz, V.M., and E. Bier. 2015a. The mutagenic chain reaction: A method for converting heterozygous to homozygous mutations. Science 348(6233):442-444.

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.

Greely, H.T. 2016. Are We Ready for Genetically Modified Animals? Available online at http://www.weforum.org/agenda/2016/01/are-we-ready-for-genetically-modified-animals; accessed February 3, 2016.

Hammond, A. R. Galizi, K. Kyrou, et al. 2016. A CRISPR-Cas9 gene drive system targeting female reproduction in the malaria mosquito vector Anopheles gambiae. Nature Biotechnology DOI: 10.1038/nbt.3439.

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

Kaiser, J. 2015. CRISPR Helps Heal Mice With Muscular Dystrophy. Available online at http://www.sciencemag.org/news/2015/12/crispr-helps-heal-mice-muscular-dystrophy; accessed January 30, 2015.

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.

Maxmen, A. 2015. Three technologies that changed genetics. Nature 528:S2-S3.

McGreevey, S. 2016. High-fidelity CRISPR. Available online at https://hms.harvard.edu/news/high-fidelity-crispr; accessed January 29, 2016.

National Academies of Science. 2015. International Summit Statement. Available at http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=12032015a; accessed January 2, 2016.

Nelson, C.E., C.H. Hakim, D.G. Ousterout, et al. 2015. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science DOI: 10.1126/science.aad5143.

Petherick, A. 2015. Nature outlook genome editing. Nature 528:S1.

Pinker, S. 2015a. The Moral Imperative for Bioethics. Available online at https://www.bostonglobe.com/opinion/2015/07/31/the-moral-imperative-for-bioethics/JmEkoyzlTAu9oQV76JrK9N/story.html; accessed February 2, 2016.

Pinker, S. 2015b. Steven Pinker Interview. Available online at https://www.ipscell.com/2015/08/stevenpinker/; accessed February 2, 2016.

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.

Savulescu, J., J. Pugh, T. Douglas, et al. 2015. The moral imperative to continue gene editing research on human embryos. Protein Cell 6(7):476-479.

Servick, K. 2016. Researchers Rein In Slice-happy Gene Editor, CRISPR. Available online at http://www.sciencemag.org/news/2016/01/researchers-rein-slice-happy-gene-editor-crispr; accessed January 28, 2016.

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.

Skerrett, P., 2015. First Opinion. A Debate: Should We Edit the Human Genome? Available online at http://www.statnews.com/2015/11/30/gene-editing-crispr-germline/; accessed February 2, 2016.

Slaymaker, I. M., L. Gao, B. Zetsche, et al. 2015. Rationally engineered Cas9 nucleases with improved specificity. Science 351(6268):84-88.

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.

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Out of Southern East Asia: The Origin and Evolution of the Domestic Dog.

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.

Evoltion dogs

Despite biologists’ great interest and effort, a detailed history of the domestic dog’s evolution has remained elusive. Scientists have estimated the date of divergence between dogs (Canis lupus familiaris) and wolves (or wolf-like canids) at anywhere between 10,000 and 32,000 years ago.  Similarly, using maternally transmitted mitochondrial DNA and haplotype analyses, researchers have proposed a number of possible regions as the dog’s birthplace, including Europe and the Middle East.

But a new study on dog origins suggests a more definitive answer.  An international team of biologists led by geneticist Ya-Ping Zhang recently collected the whole genome sequences of 58 canids, including 12 grey wolves from Europe, 11 dogs from southern East Asia, 12 dogs from northern East Asia, 4 dogs from Nigeria, and 19 diverse dog breeds from across the Old World and the Americas (Wang et al. 2015).

Following examination of these sequences, Zhang’s team discovered that the highest genetic diversity—a strong signal of species origination—occurred among dogs indigenous to southern East Asia. Other populations demonstrated a progressive gradient in ancestry away from wolves beginning in southern East Asia.  These findings, the group noted, tend to corroborate earlier work based on mitochondrial DNA and paternally transmitted Y-chromosomal DNA.

As for the timing of dog-wolf divergence and the subsequent dispersal of dogs globally, Zhang and colleagues used various genomic techniques that, in their estimation, revealed a two-step process. First, dog and wolf populations began to separate about 33,000 years ago in southern East Asia.  Then, around 15,000 years ago, dog subgroups began to radiate westward, reaching the Middle East, Africa, and finally Europe about 10,000 years ago.  Meanwhile, one Asian population backtracked to northern China, they suggest, mixed with northern East Asian dogs, and eventually made its way to the New World.

So how and when were dogs actually domesticated? A number of non-exclusive evolutionary theories of varying plausibility have been advanced over the years.  According to Hungarian ethologist Adam Miklosi, however, only a handful of these theories are consistent with the scientific evidence.  In his new book, Miklosi specifies that early humans might have plucked canid cubs from their dens, for example, selecting only those with the most affiliative temperaments.   Or perhaps humans and canids co-evolved, each species by exerting selective pressures on the other.  Group selection may have played a role as well, if early dogs somehow boosted the survival rate and reproductive fitness of some human groups over that of others (Miklosi 2015).

Zhang’s group, however, favors the scenario in which an ancient dog-wolf split comprised the first step in both the domestication of wolves and evolution of domestic dogs. Humans and the ancestors of dogs probably shared an ecological niche in southern East Asia, they argue, that offered refuge to both species during the last glacial period, which peaked between 26,500 and 19,000 years ago.  The long process of domestication may have began with a group of wolves that became “loosely associated and scavenged with” humans before undergoing “self-domestication”—that is, “waves of selection for phenotypes [in other words, behaviors and physical traits] that gradually favored stronger bonding with humans.”

References:

Miklosi, Adam. 2015. Dog behavior, evolution, and cognition (second edition). Oxford, UK: Oxford University Press.

Wang, G., W. Zhai, H. Yang, et al. 2015. Out of southern East Asia: the natural history of domestic dogs across the world. Cell Research 15 December 2015; doi:10.1038/cr.2015.147.

Evolution dogs3

The Underappreciated Role of Physical Activity in the Battle Against Obesity—Part 3: Adults and the Relationship Between Physical Activity and Adiposity.

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.

Exercise adult 4

Is physical activity, including structured exercise, an effective strategy in the battle against overweight and obesity? Some have recently suggested that successful weight loss and weight maintenance are the results of improved diet alone.

In part one of this article, I reviewed evidence suggesting that, despite popular media misinformation, most people who maintain weight loss do so through a combination of diet and physical activity. Nor does it appear true, as many have reported, that exercisers completely compensate for energy expenditure through increased sedentary time or energy intake.  In part two, I examined evidence showing that both moderate-to-vigorous physical activity and television viewing time significantly affect adiposity in children.

The National Academies’ Institute of Medicine recently gathered preeminent experts in several relevant fields to summarize the current science exploring “the impact of physical activity in the prevention and treatment of overweight and obesity” (IOM 2015). Here, I discuss the panel’s conclusions relating specifically to adults.

Robert Ross, professor in the School of Kinesiology and Health Studies at Queen’s University, Kingston, Ontario, Canada, presented the most credible evidence on the subject from randomized controlled trials. Before doing so, however, he distinguished between efficacy trials, which ask what happens physiologically when adults actually do exercise, and effectiveness trials, which investigate instead what occurs in terms of behavior change when adults are in one way or another encouraged to exercise.

In terms of efficacy trials, Ross described the results of his own extensive work. First, he found that when previously active male and female participants increased their exercise time and caloric intake, they either did not gain weight or found it challenging to avoid weight loss (Ross et al. 2000, 2004).  As such, exercise appears at the very least to prevent weight gain, even when accompanied by an increase in consumption.

Second, in a study of 300 mostly inactive obese adults who were asked to maintain caloric intake but to add five days of supervised exercise per week for six months, Ross’s team observed an impressive loss of body weight along with decreased waist circumference among all treatment groups (which varied in terms of exercise amount and intensity) (Ross et al 2015). Importantly, they revealed as well that participants did not compensate for elevated energy expenditure through increased sedentary time.

Such results appear to bode very well for those committed to an intelligent and consistent exercise program. “I just don’t think there is any ambiguity here,” Ross commented.  Even for the obese, unless one eats more, an increase in exercise will translate to lost weight.

Exercise adult 8

But what happens in terms of behavior change when people are simply asked to lose weight? The results of effectiveness trials are encouraging, but, sadly, less than spectacular.  For example, in a systematic review of nine diet and exercise trials including 1595 women and 375 men and involving a variety of behavior change strategies, investigators found a significant but modest difference in weight gain in only five trials, largely due to gain among control group members (Lombard et al. 2009).

In another diet and exercise trial incorporating three distinct interventions—one clinic-based, one correspondence-based, and one informational only (the control group)—researchers discovered trends among women toward weight gain in the informational and correspondence groups, and toward gain prevention only in the clinic group (Levine et al. 2007).  According to Ross, most prevention effectiveness trials have demonstrated success in achieving a similarly modest yet significant goal, but of course have been unable to distinguish between the effects of improved diet and increased exercise.  Higher quality trials have yet to be conducted.

From these results, researchers including Ross have concluded that prevention of weight gain, rather than substantial weight loss, appears to be the most achievable goal. Which might seem intuitive, given that overweight and obesity renders effective exercise a much more difficult, though certainly not impossible, prospect.  On the other hand, a commitment to weight gain prevention requires considerable foresight and, at least during the earliest stages, an apparently rare ability to decline immediate gratification in exchange for future health and performance benefits.

But the evidence is clear: exercise works.  Less plain is why that message has failed to fully penetrate developed societies, certain regions of the United States in particular.  Perhaps the answer should be obvious.  The goal of the popular media is seldom to enlighten, after all, and much less to encourage discipline.  Their primary aim, rather, is almost always to manipulate and indulge consumer emotions.  Arguably, it’s a wonder anyone ever succeeds in his or her battle against an unhealthy bulge.

In any case, evidence of “don’t” is not evidence of “can’t,” and the fact that some do succeed tends to show that many more can. Consistent with the evidence presented here, and as I have frequently argued in the past, true success for the obese and overweight is entirely attainable.  But it surely requires extraordinary candor, personal growth beyond the typical, and, in most if not all instances, substantial modifications to life priorities.

References:

IOM (Institute of Medicine). 2015. Physical activity: moving toward obesity solutions: workshop summary. Washington, D.C.: The National Academies Press.

Levine, M.D., M.L. Klem, M.A. Kalarchian, et al. 2007. Weight gain prevention among women. Obesity 15(5):1267-1277.

Lombard, C.B., A.A. Deeks, and H.J. Teede. 2009. A systematic review of interventions aimed at the prevention of weight gain in adults. Public Health Nutrition 12(11):2236-2246.

Ross, R., D. Dagnone, P.J. Jones, et al. 2000. Reduction in obesity and related comorbidity conditions after diet-induced weight loss or exercise-induced weight loss in men: A randomized controlled trial. Annals of Internal Medicine 133(2):92-103.

Ross, R., I. Janssen, J. Dawson, et al. 2004. Exercise-induced reduction in obesity and insulin resistance in women: A randomized controlled trial. Obesity Research 12(5):7898798.

Ross, R., R. Hudson, P.J. Stotz, et al. 2015. Effects of exercise amount and intensity on abdominal obesity and glucose tolerance in obese adults: A randomized controlled trial. Annals of Internal Medicine 162(5):325-334.

dog-situps

The Underappreciated Role of Physical Activity in the Battle Against Obesity—Part 2: Children and the (Bidirectional?) Relationship Between Physical Activity and Adiposity.

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.

Exercising Children 3

Is physical activity, including structured exercise, an effective strategy in the battle against overweight and obesity?  In part one of this article, I reviewed evidence suggesting that, despite popular media misinformation, most people who maintain weight loss do so through a combination of diet and physical activity.  Nor is it true, as many have reported, that exercisers completely compensate for energy expenditure through increased sedentary time or energy intake.

The National Academies’ Institute of Medicine recently gathered preeminent experts in several relevant fields to summarize the current science exploring “the impact of physical activity in the prevention and treatment of overweight and obesity” (IOM 2015).  Here, I discuss the panel’s conclusions relating to children specifically.

The two most common study designs used to examine children’s health are the cross-sectional and prospective longitudinal models.  While the former measures the explanatory variable (physical activity, in this case) and the outcome (adiposity) at the same time, the latter measures those variables on multiple occasions.  While neither “proves” cause and effect, the longitudinal design is especially capable of supporting inferences that compliment randomized controlled trials by providing important information about real-world patterns.

Panelist Kathleen Janz, professor of health and human physiology and associate director of the University of Iowa Obesity Research and Education Initiative, focused initially on the Iowa Bone Development Study (IBDS), a sixteen-year longitudinal program with which she has been intimately involved since its inception (Kwon et al. 2013, 2015).  The IBDS was one of the first to use an accelerometer to more accurately measure physical activity.  Janz’s team also used dual-energy X-ray absorptiometry (DXA) to sort body composition into lean, fat, and bone tissues, and to distinguish between visceral and subcutaneous fat.

In the IBDS, Janz and her team followed 500 children from the age of five and, to date, have conducted at least eight clinical exams of each child.  Defining obesity as 32 percent body fat in girls and 25 percent in boys, twelve percent of study participants were obese from the beginning.  Unfortunately, another ten percent had joined them by the age of nineteen.

Exercising Children 1

So which variables were found to be potentially explanatory?  Total sedentary time did not matter, according to Janz.  But television viewing time (a subset of total sedentary time) and moderate-to-vigorous physical activity (MVPA) did.  Janz explained her findings in the context of a typical eleven-year-old study participant.  Averaging every variable other than MVPA, her group discovered a 7.5 difference in adiposity between females with high and low levels of MVPA, and a five percent distinction in males.  Averaging every variable except TV time, they revealed a five percent difference in adiposity between girls who watched a great deal of TV and very little TV, and a 9.3 percent difference in boys.  When averaging all variables except both MVPA and TV, Janz’s team found an 11.8 percent difference in female adiposity and a whopping 21.3 percent difference in males.

In a recent cross-sectional study of more than 6000 children aged nine to eleven residing at twelve different locations across the world, another group of researchers came to a similar conclusion (Katzmarzyk et al. 2015).  The best predictor of reduced obesity, they found, was MVPA, rather than either sedentary time or vigorous-intensity physical activity.  More specifically, 55 minutes of daily MVPA was the most reliable predictor of lower obesity rates.

But might inferred causality run in the opposite direction as well?  In other words, does higher adiposity predict less physical activity?  If so, one would be forced to question the logic underlying the Health at Every Size (HAES) movement, as well as the increasingly popular claim that physical fitness, but not excess adiposity, is the more accurate predictor of superior health outcomes.

Indeed, one accelerometer study showed that, while MVPA at age seven did not predict decreased body fat between the ages of seven and ten, body fat percentage at age seven did in fact predict decreased MVPA between ages seven and ten (Metcalf et al. 2011).  More specifically, a ten percent increase in adiposity at age seven was associated with four fewer minutes per day of MVPA at age ten.  According to Janz, a “bidirectional relationship” between physical activity and adiposity might signal the existence of a “positive feedback loop.”

Summarizing the data from the IBDS, Janz instructed that children who consistently engaged in at least 45 minutes of MVPA every day “were 60 percent less likely to end up obese at the age of nineteen than children whose level of MVPA decreased as they aged.”  This evidence, she concluded, supports the current national guidelines emphasizing at least 60 minutes of MVPA per day and two hours or less of television.

Exercising Children 2

 

References:

IOM (Institute of Medicine). 2015. Physical activity: moving toward obesity solutions: workshop summary. Washington, D.C.: The National Academies Press.

Katzmarzyk, P.T., T.V. Barreira, S.T., S.T. Broyles, et al. 2015. Physical activity, sedentary time, and obesity in an international sample of children. Medicine & Science in Sports & Exercise 47(10):2062-2069.

Kwon, S., K.F. Janz, T.L. Burns, et al. 2011. Effects of adiposity on physical activity in childhood: Iowa Bone Development Study. Medicine & Science in Sports & Exercise 43(3):443-448.

Kwon, S., K.F. Janz, E.M. Letuchy, et al. 2015. Developmental trajectories of physical activity, sport, and television viewing during childhood to young adulthood: Iowa Bone Development Study. JAMA: Pediatrics 169(7):666-672.

Metcalf, B.S., J. Hosking, A.N. Jeffery, et al. 2011. Fatness leads to inactivity, but inactivity does not lead to fatness: a longitudinal study in children (EarlyBird 45). Archives of Disease in Childhood 96(10):942-947.

The Underappreciated Role of Physical Activity in the Battle Against Obesity (Part 1).

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 regularly to Skeptic as well.  He may be contacted at krausekc@msn.com.

Could it be that Time magazine’s August 17, 2009 cover story announcing “The Myth About Exercise” misled millions of potential exercisers about the true relationship between physical activity (PA) and weight loss and maintenance?  James Hill, professor of pediatrics and medicine at the University of Colorado Denver, and co-founder of the National Weight Control Registry and the America on the Move initiative, seems to think so.

1101090817_400

In the spring of 2015, the National Academies’ Institute of Medicine convened a two-day workshop titled, “Physical Activity: Moving Toward Obesity Solutions.”  Gathering preeminent experts in several relevant fields, the panel’s expressed purpose was to summarize the current science exploring “the impact of physical activity in the prevention and treatment of overweight and obesity and to highlight innovative strategies” for physical fitness.  Their results were recently published by the National Academy of Sciences (IOM 2015).

We all understand that, in the limited context of weight loss and maintenance, those predisposed to excess adiposity cannot outrun, or out-exercise, a poor diet.  And while it might take three minutes to consume a 560-calorie hamburger, for example, one would have to exercise forty-five to sixty minutes, depending on intensity, among other things, to burn it off.  But does that necessarily mean, as the 2009 Time article implied, that PA is a trivial strategy in the difficult battle against an unhealthy bulge?

Not according to Hill, and not according to the science.  Consider first the issue of “compensation.”  Through many popular sources, including Time, we have been led to believe that those who increase their level of PA tend to compensate by either consuming more calories or increasing sedentary behavior.

But, as Hill reveals, a recent systematic review of 30 studies shows that, in most cases, exercisers did in fact not compensate with reductions in non-exercise PA (Washburn et al. 2014).  Another study demonstrated that people who increased their PA tended not to completely compensate with increased caloric intake (Schubert et al. 2013).  In summary, according to Hill, “the scientific literature indicates that when physical activity is added to a weight loss program, the majority of people do not compensate, at least not completely.”  The “net result” of PA, in other words, is “a negative energy balance.”

Between 1960 and 2010, daily occupational (including housework) energy expenditure decreased by 120 calories per day, and more recent statistics suggest a further and continuing decline.  “That is enough,” Hill argues, “to explain most of obesity.”  Every study conducted on highly palatable, energy-dense diets, he continues, has demonstrated less weight gain when PA is added to improved nutrition—“even among people genetically susceptible to weight gain.”

Physical Activity

Here, Doctor Hill draws our attentions to two important concepts.  First, “metabolic flexibility” determines how efficiently our bodies can switch fuels.  During a relative fasting state, a flexible metabolism can quickly suppress glucose oxidation and enhance fat oxidation, whereas an inflexible metabolism maintains “a blunted preference for fat oxidation” and remains unable to suppress the use of glucose.  During an insulin-stimulated state, by contrast, the flexible person can suppress fat oxidation and increase her use of glucose, while the inflexible person is less capable of suppressing fat use and stimulating glucose oxidation.

Metabolic flexibility, Hill contends, is directly related to PA.  While weight loss alone does not necessarily improve the situation, “[w]hen people stop moving, their metabolism loses its flexibility.”  The resulting inflexibility, he reasons, renders people, including calorie-restricting dieters, “more susceptible to storing rather than burning fat.”

Second, some researchers believe that one can control personal energy balance far more efficiently by crossing a “threshold of PA.”  Above that threshold is the “regulated zone,” and below it is the “unregulated zone.”  In the former zone, we would expect to observe “a total compensation of energy intake with increased physical activity” and no weight change.  In such cases, physical activity is “driving the bus” and “food is just along for the ride.”  In the latter, unregulated zone, however, “as physical activity decreases, food intake actually increases.”  Here, a tight coupling between PA and caloric intake collapses, and food is now “driving the bus.”

Physical activity threshold

Hill suspects that decreasing PA “is the reason why most people today occupy the unregulated zone.”  When people do lose weight, of course, their energy needs decrease.  If a 220-pound person, for example, were to lose ten percent of his body weight, his energy demands would also plummet by roughly 170 to 250 calories per day.  What’s the best solution?  Fill that “energy gap,” Hill prescribes, with an increase in PA—which of course is far more sustainable than a decrease in energy intake.

Based on data from Hill’s National Weight Loss Registry, a paltry eight percent of the population will maintain a reduction in weight achieved by improved diet alone.  Despite popular media manipulation and misinformation, most people who maintain weight loss do so through a combination of physical activity and diet.  It is therefore extremely unlikely, Hill stresses, that any individual case of obesity can be resolved with improved nutrition alone, or that the obesity epidemic can be reversed without increasing PA in the broader population.

 

References:

IOM (Institute of Medicine). 2015. Physical activity: moving toward obesity solutions: workshop summary. Washington, D.C.: The National Academies Press.

Schubert, M.M., B. Dresbow, S. Sabapathy, and M. Leveritt. 2013. Acute exercise and subsequent energy intake: a meta-analysis. Appetite 63:92-104.

Washburn, R.A., K. Lambourne, A.N. Szabo, et al. 2014. Does increased prescribed exercise alter non-exercise physical activity/energy expenditure in healthy adults? A systematic review. Clinical Obesity 4(1):1-20.

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.”

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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.

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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.”

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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?

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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.

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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.

Pigliucci, M. 2014. On the biology of race. http://www.scientiasalon.wordpress.com/2014/05/29/on-the-biology-of-race/. (last accessed November 22, 2015).

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

Raff, J. 2014. Nicholas Wade and race: building a scientific façade. http://www.violentmetaphors.com/2014/05/21/nicholas-wade-and-race-building-a-scientific-facade/ (last accessed November 16, 2015).

Risch, N., E. Burchard, E. Ziv, and H. Tang. 2002. Categorization of humans in biomedical research: genes, race and disease. Genome Biology 3(7):1-12.

Rosenberg, N., J.K. Pritchard, J.L. Weber, et al. 2002. Genetic structure of human populations. Science 298(5602):2381-2385.

Rosenberg, N., M. Saurabh, S. Ramachandran, et al. 2005. Clines, clusters, and the effect of study design on the inference of human population structure. PLOS Genetics 1(6):e70.

Sarich, V. and F. Miele. 2004. Race: the reality of human differences. Boulder, CO: Westview Press.

Sesardic, N. 2010. Race: a social deconstruction of a biological concept. Biological Philosophy 25:143-162.

Sussman, R.W. 2014. The myth of race: the troubling persistence of an unscientific idea. Cambridge, MA: Harvard University Press.

Wade, N. 2014. A troublesome inheritance: genes, race and human history. NY: Penguin Press.

Yoder, J. 2014. How A Troublesome Inheritance gets human genetics wrong. http://www.molecularecologist.com/2014/05/troublesome-inheritance/ (last accessed November 16, 2015).

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.