Tag Archives: genetics

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.

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

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

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

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

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“Race” in 2015: Myth or Reality? (part 2)

[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.

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, perhaps, or 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 Everyone is African: How Science Explodes the Myth of Race (Prometheus 2015), 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.  “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.  Later characterizing that conclusion as “Lewontin’s Fallacy” in 2003, Cambridge geneticist A.W.F. Edwards reminded us how easy it is to predict race simply by looking at people’s genes.

So who was right?  Both of them were, according to Lynn Jorde and Stephen Wooding at the University of Utah School of Medicine.  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.  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 revealed 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.  Take 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.

But around 30,000 years ago, 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 west into Europe.  Extremely rare in other native populations, nearly 100% of modern native Europeans carry this variant.  On the other hand, as their varied 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, a process where similar external traits result independently among different populations due to similar environmental pressures.

So how can biology support traditional notions of race when the genetic signatures of those notions’ most relied upon trait–that is, skin color–are so diverse among people sharing the same or similar degree of skin pigmentation?  Fairbanks finds such ideas 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 long-time science journalist, Nicholas Wade, who, in his recent book, A Troublesome Inheritance, judged that biological races are real and can be distinguished genetically at the continental level, 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.”

Why Gay and Lesbian: A New Epigenetic Proposal.

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.

The persistence of homosexuality among certain animal species, including humans, has bewildered scientists at least since the time of Darwin.  Why should same-sex attraction persist when evolution assumes reproductive success?  Does homosexuality—especially among humans—facilitate the intergenerational transfer of genetic material in some other way?  Or perhaps it advances an entirely different objective that justifies it’s more obvious procreative disadvantage.  Such questions have long attracted gene-based explanations for homosexuality.

Consider “kin selection,” for example.  As E.O. Wilson first suggested in 1975, maybe human homosexuals are like sterile female worker bees that assist the queen in reproduction.  One study of homosexual men, known in Independent Samoa as fa’afafine, revealed that gays are significantly more likely than straight men to help their siblings raise children.

But to satisfy the kin selection hypothesis, each gay must account for the survival of at least two sibling-born children for every one he fails to reproduce—a difficult standard to attain accomplish.  In any case, relevant studies in the U.S. and U.K. have failed to provide such evidence.

As a possible explanation for male homosexuality, other researchers have offered the “fertile female” hypothesis.  Here, a genetic tendency toward androphilia, or attraction to males—though problematic for men from an evolutionary perspective—is thought to enhance the reproductive success of their straight, opposite-sex relatives by rendering them hyper-sexual.

At least two studies have claimed results in support of the fertile female model.  Notably, this hypothesis is also capable of explaining why gayness persists at a constant but low frequency of about eight percent in the general global population.

A former faculty member at Harvard Medical School and the Salk Institute, neuroscientist Simon LeVay favors evidence suggesting a suite of several “feminizing” genes (LeVay 2011).  The inheritance of a limited number of these genes, LeVay proposes, will make males, for instance, more attractive to females—and thus presumably more successful in terms of reproduction—by rendering them less aggressive and more empathetic, for example.

But a few men in the family tree will receive “too many” feminizing genes and, as a result, be born gay.  Indeed, one Australian study has discovered that gender-atypical traits do enhance reproduction, and that heterosexuals with homosexual twins achieved more opposite-sex partnerships than heterosexuals without homosexual twins—though statistical significance was observed only among females.

Even so, most explanations are not based solely in genetics.  Evidence suggests as well, for example, that a variety of mental gender traits are shaped during fetal life by varying levels of circulating sex hormones.  Especially during certain critical periods of development, testosterone (T) levels in particular are thought to cause the brain to organize in a more masculine or feminine direction and, later in life, to influence a broad spectrum of gender traits including sexual preference.

For instance, women suffering from congenital adrenal hyperplasia due to elevated levels of prenatal T and other androgens are known to possess gender traits significantly shifted toward masculinity and lesbianism.  Importantly, female fetuses most severely affected by CAH and, thus, most heavily exposed to prenatal androgens are the most likely to experience same-sex attraction later in life.

Similarly, the bodies of male fetuses afflicted with androgen insensitivity syndrome—a condition in which the gene coding for the androgen receptor has mutated—will fail to react normally to circulating T.  As a result, these XY fetuses will later appear as girls and, as adults, share an attraction to men.  In sum, although a number of other factors could be, and likely are, at play, it is now fairly well established that prenatal androgen levels have a substantial impact on sexual orientation in both men and women.

But three researchers working through the National Institute for Mathematical and Biological Synthesis have recently combined evolutionary theory with the rapidly advancing science of both androgen-dependent sexual development and molecular regulation of gene expression to propose a new and provocative epigenetic model to explain both male and female homosexuality (Rice, et. al. 2012).

According to lead author William Rice at the university of California, Santa Barbara, his group’s hypothesis succeeds not only in squaring homosexuality with natural selection—it also explains why same-sex attraction has been proven substantially heritable even though, one, numerous molecular studies have so far failed to locate associated DNA markers and, two, concordance between identical twins—about twenty percent—is far lower than genetic causation might predict.

At the model’s heart are sex-specific epigenetic modifications, or epi-marks.  Generally speaking, epi-marks can be characterized as molecular regulatory switches attached to genes’ backbones that direct how, when, and to what degree genetic instructions are carried out during an organism’s development.  They are created anew during each generation and are usually “erased” between generations.

But because epi-marks are produced at the embryonic stem cell stage of development—prior to division between soma and germline—they can in theory be transmitted across generations.  Indeed, some evidence does suggest that on rare occasions (though not at scientifically trivial rates) they will carry over, and thus mimic the hereditary effect of genes.

Under typical circumstances, Rice instructs, sex-specific epi-marks serve our species’ evolutionary objectives well by canalizing subsequent sexual development.  In other words, they protect sexually essential developmental endpoints by buffering XX fetuses from the masculinizing effects and XY fetuses from the feminizing effects of fluctuating in utero androgen levels.  Significantly, each epi-mark will influence some sexually dimorphic traits—sexual orientation, for example—but not others.

According to the new model, however, when sex-specific epi-marks manage to escape intergenerational erasure and transfer to opposite-sex offspring, they become sexually antagonistic (SA) and thus capable of guiding the development of sexual phenotypes in a gonad-discordant direction.  As such, Rice hypothesizes, “homosexuality occurs when stonger-than-average SA-epi-marks (influencing sexual preference) from an opposite-sex parent escape erasure and are then paired with weaker-than-average de novo sex-specific epi-marks produced in opposite-sex offspring.”

To summarize, Rice’s team argues that differences in the sensitivity of XY and XX fetuses to the same levels of T might be caused by epigenetic mechanisms.  Normally, such mechanisms would render male fetuses comparatively more sensitive and female fetuses relatively less sensitive to exposure.  But if such epigenetic labels pass between generations, they can influence sexual development.  And if they pass from mother to son or from father to daughter, sexual development can proceed in a manner that is abnormal (or “atypical,” if you prefer).  In those very exceptional cases, offspring brain development can progress in a fashion more likely to result in homosexuality.

Rice’s observations and insights are fascinating, to say the least.  Indeed, popular news reports describe a scientific community highly appreciative of the new model’s theoretical power.   Nevertheless, a great deal of criticism has been tendered as well.

LeVay, for example, describes the authors’ hypothesis generally as “a reasonable one that deserves to be tested—for example by actual measurement of the epigenetic labeling of relevant genes in gay people and their parents.”  He reminded me, however, that Rice hasn’t actually discovered anything.  The new model is in fact pure speculation, says LeVay, and it never should have been reported—as some media have done—as “the cause” (or even as “a cause”) of homosexuality.

More specifically, LeVay offers three points of caution.  First, he warns that an epigenetic explanation is not to any degree implied from the current data on fetal T levels.  When based on single measurements, he concedes, male and female fetuses may indeed show some overlap.  But because T levels fluctuate in both males and females throughout development, allegedly anomalous individuals might easily average completely sex-typical T levels over time.  Second, LeVay sees “little or no evidence” that epi-marks ever escape erasure in humans.

Finally, LeVay continues to favor genetic explanations.  The incidence of homosexuality in some family trees, he says, is more consistent with DNA inheritance than with any known epigenetic mechanism.  Moreover, he warns, we should never underestimate the difficulty of identifying genetic influences—especially with regard to mental traits.  In such cases, complex polygenic origins are far more likely to be at play than single, magic genetic bullets.

Other neuroscientists have posed equally important questions.  How can we test whether the appropriate epi-marks—probably situated in the brain—have been erased?  Is it too simplistic to suggest identical or even similar mechanisms for both male and female homosexuality?  Why is it important to isolate the specific biological causes of same-sex attraction?  By doing so, do we run the risk of further stigmatizing an already beleaguered population?

Rice doesn’t deny his new model’s data deficit.  Nor does he portray the epigenetic influence on same-sex attraction as an exclusive one.  His team does, however, insist that epigenetics is “a probable agent contributing to homosexuality.”  We now have “clear evidence,” they maintain, that “epigenetic changes to gene promoters … can be transmitted across generations and … can strongly influence, in the next generation, both sex-specific behavior and gene expression in the brain.”

The authors contend as well that their hypothesis can be rapidly falsified because it makes “two unambiguous predictions that are testable with current technology.”  First, future large-scale association studies will not identify genetic markers correlated with most homosexuality.  Any such associations found, they say, will be weak.

Second, future genome-wide epigenetic profiles will distinguish differences between homosexuals and non-homosexuals, but only at genes associated with androgen signaling or in brain regions controlling sexual orientation.  Testing this second prediction, they admit, may proceed only with regard to lesbianism by comparing profiles of sperm from fathers with and without homosexual daughters.

To my knowledge, Rice and his colleagues have never squarely addressed the question of whether, for philosophical or sociological reasons, we should refrain from delving further into the dicey subject of same-sex attraction.  Such questions do, however, expose a tendency toward communal repression and a general lack of respect for the scientific enterprise.  These decisions should be left to the scientists and those who fund them.

References:

LeVay, Simon. 2011. Gay, Straight, and the Reason Why: The Science of Sexual Orientation. NY: Oxford University Press.

Rice, W., Friberg, U., and Gavrilets, S. 2012. Homosexuality as a consequence of epigenetically canalized sexual development.  The Quarterly Review of Biology 87(4): 343-368.

Change We Can Believe In: “Race” and Continuing Evolution in the Human Genome.

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.

“People, including me, would rather believe that significant human biological evolution stopped between 50,000 and 100,000 years ago, before the races diverged, which would ensure that racial and ethnic groups are biologically equivalent.”—Steven Pinker.

Pinker might be right about what most people would prefer to believe.  But equivalency, I would argue, is a concept better left to mathematicians—should they choose to keep using it.  In any other, less antiseptic context, however, the notion is utterly bankrupt.  That we have had to work so hard in recent centuries to construct and maintain political equality among individuals and classifications of individuals should tell us how persistent and pervasive inequality really is.  We should never confuse the social construct with the scientific reality.  Denial is the least mature and, certainly, the least progressive response to fear.

Like all other species, human beings continue to change.  But until very recently, both the popular and scientific assumptions had been that, if humans were still evolving at all, it was through the very slow and completely random process of genetic drift.  The alternatives, natural and sexual selection, of course, turn on differential reproductive success based on fitness, attractiveness, or both.  So the prevailing argument has long been that, because we civilized humans have for the most part managed to insulate ourselves from the natural environment, to nurse our sick back to health, and to provide mates for nearly all persons among us, the march of Darwinian selection had finally reached an impasse.  Similarly, many have claimed that, because selection had long ago relaxed its discriminating grip on the human genome, our collective abilities to think and to resist disease, for example, have steadily degenerated.

But there have been exceptions—like University of California at San Diego biologist Christopher Wills, who in his 1998 book, Children of Prometheus, defiantly pronounced that “[t]he powerful effects of our culture have, if anything, accelerated our biological evolution.”  Wills’ powerful and prescient hypothesis was that genes and an increasingly rich—or at least complex—culture have combined to create a positive feedback loop in which human minds in particular benefit from frequent adaptive boosts.  Sure enough, recent genome projects and surveys along with new and controversial genetic studies seem to bear Wills out.

In 2005, for example, University of Chicago geneticist Bruce Lahn published a pair of studies concluding that two genes thought to regulate brain growth have continued to evolve under selective pressures until very recently, if not to the present day (Science 309, 1717-1720 and Science 309, 1720-1722).  An intellectual controversy erupted because Lahn, a Chinese-born lifetime member of the NAACP, also discovered that these mutated alleles were less common among sub-Saharan Africans than in other populations.

Different mutations of the Microcephalin and ASPM genes were known to cause primary microcephaly, a positively dreadful condition marked by severely reduced brain size (typically 400 cubic centimeters in affected adults compared to 1200 to 1600 cubic centimeters in normal adults).  It was also commonly understood that phylogenic analyses of both genes had revealed strong positive selection in the primate lineage leading to Homo sapiens.  The question for Lahn, then, was whether certain variants of Microcephalin and ASPM had continued to evolve by natural selection during the last 200,000 years, since humans became anatomically modern.

After sifting through a vast cache of DNA broadly representative of global diversity, Lahn’s team located an allele for each gene that occurred so frequently that it simply had to have been adaptive rather than merely the stray product of genetic drift or group migration.  Then, using past mutation rates as a reliable molecular clock, they estimated the dates when these alleles originated.  Lahn determined that the Microcephalin variant arose only about 37,000 years ago (with a 95 percent confidence interval of 14,000 to 60,000 years) and, much to everyone’s amazement, that the ASPM allele clocked in at about 5800 years ago (with a 95 percent confidence interval of 500 to 14,100 years).  Many, including Lahn’s team, noted that these dates generally corresponded to the explosion of symbolically driven behavior in Europe (the “Upper Paleolithic revolution”), on the one hand, and the development of cities and written language on the other.

But these studies ignited a firestorm of debate over race and intelligence because they concluded as well that these apparently beneficial variants were common in Eurasia (75 percent of some populations), but quite rare in Africa (less than 10 percent among some groups).  Several researchers formally challenged Lahn’s findings of selection generally or of selection for various brain-related abilities in particular (See, e.g., Currat, M., et. al., Science 313, 172a [2006]; Timpson, N., et. al., Science 317, 1036a [2007]; and Rushton, J.P., et. al., Biol. Lett. 3, 157-160 [2007]).  But Lahn defended his work and reemphasized that he had never claimed to have demonstrated a cognitive purpose for these alleles (Science 313, 172b [2006] and Science 317, 1036b [2007]).  He even conceded the remote possibility that their roles might implicate functions completely unrelated to the brain.

In any case, the new genes’ youth and worldwide prevalence clearly evidenced a “selective sweep”—the rapid spread of an advantageous new allele—very much reminiscent of the genetic adaptations that had allowed European adults during the early Holocene to digest milk lactose.  Although LCT, the lactase gene, arose around 8000 years ago, it has subsequently spread to more than 80 percent of Europeans, but less than 28 percent of Africans—the latter of which to a large degree have still not adopted agriculture as a way of life.  But for any kind of selective sweep to occur, the advantage or selective force of the new allele must be dramatic.  Could it be, as Wills suggested back in 1998, that our genes and cultural circumstances were and, in fact, are collaborating to accelerate human evolution?

University of Utah anthropologists Henry Harpending and Gregory Cochran certainly count themselves among the growing number of scientists who think so.  Many will recall their famous—in some circles infamous—2006 study on the natural history of Ashkenazi intelligence (J. Biosoc. Sci. 38, 659-693).  There, they and collaborator Jason Hardy determined that the unusually high IQ scores of European Jews resulted from their forced and intense occupation of a particular professional niche between the 9th and 17th centuries that strongly selected for economic acumen.  Unfortunately for the Ashkenazim, heritable diseases like Tay-Sachs and Gaucher’s accompanied these mutations.

But, by the end of 2007, Cochran, Harpending, and University of Wisconsin at Madison biological anthropologist, John Hawks, had published their analysis of DNA in the International HapMap Project, a mammoth survey of genetic distinctions among populations around the globe.  After scrutinizing 3.9 million single nucleotide polymorphisms (SNPs) from 270 persons, the team concluded that “[t]he rate of adaptive evolution in human populations has indeed accelerated” during recent millennia, especially since the Ice Age ending roughly 10,000 years ago (Proc. Natl. Acad. Sci., USA 104, 20753-20758).  The agricultural revolution initiating the Holocene epoch allowed certain Eurasian populations to explode, says Hawks, and for increasingly complex human cultures to flourish

As population densities increase, he adds, so do the opportunities for genetic mutation—favorable or otherwise.  Indeed, the team found that a minimum of seven percent of the human genome appears to be evolving right now at the highest rate in our species’ history.  But how can we know that some of these changes were adaptive?  Geneticists look to haplotypes—large blocks of linked DNA passed on from one generation to the next—for helpful clues.  An allele resulting from an important adaptive trait will expand to great frequency in a population so rapidly that it will often drag an extended haplotype with it before recombination and mutation can break it down.  In other words, to population geneticists like Hawks, rare SNPs flanked by long stretches of identical DNA in many individuals among a given population strongly suggests recent and robust selection for an especially advantageous trait.

And such were precisely the attributes that Hawks’ researchers discovered in about 1800 human genes.  Although scientists don’t know the identity or function of most of these genes, many appear to be responses to recent changes in diet and to new waves of virulent diseases, including AIDS, malaria, and yellow fever.  Again, the agricultural revolution was the likely catalyst and, again, some populations were more affected than others.  As Hawks notes, “sub-Saharan Africa has no archeological evidence for agriculture before 4,000 years ago,” and “[a]s a consequence, some 2,500 years ago the population of sub-Saharan Africa was likely < 7 million people, compared to European, West Asian, East Asian, and South Asian populations approaching or in excess of 30 million each.”  Contrary to popular belief, Hawks concludes, humans on different continents appear to be evolving away from each other and at quite an impressive clip.

Now, a group of French and Spanish geneticists, led by Lluis Quintana-Murci at the Pasteur Institute in Paris, France, has reinforced the Americans’ results by identifying 582 genes that have evolved differentially in various world populations during the past 60,000 years (Nature Genetics 40(3), 340-345 [2008]).  Attempting to isolate disease-causing variations, Quintana-Murci examined the DNA of 210 persons from Phase II of the HapMap database, including 2.8 million SNPs from Europeans, Asians, and Africans.

Like Hawks, he found compelling indicators of recent positive selection that varied strikingly between geographic populations.  An ENPP1 mutation, for example, which is known to protect against obesity and type II diabetes, is present in about 90 percent of non-Africans but nearly absent in Africans.  A CR1 gene, by contrast, which is known to thwart malarial attacks, is virtually absent in everyone except Africans, who carry it at a rate of about 85 percent.  But Quintana-Murci isn’t interested in any potential political implications.  Rather, he expects his results to “open multiple avenues of research” and to “facilitate genetic explorations of medical conditions by identifying strong candidate genes for diseases in which prevalence depends on ethnic background.”

Even so, many scientists are still concerned about what some non-scientists will do with this information—and understandably so, given our history.  On November 7, 2008, Constance Holden reported a meeting of about 40 scientists and ethicists at the National Human Genome Research Institute in an article titled, “The Touchy Subject of ‘Race’” (Science 322, 839).  Although much debate has already ensued over the medical use of racial distinctions in disease-related alleles, “it won’t be long,” Holden predicts, “before [scientists] have solid leads on much more controversial genes: genes that influence behavior—possibly including intelligence.”

University of Georgia at Athens professor of speech communication, Celeste Condit, apparently criticized Lahn’s work at the meeting, charging that his studies could be seen as embedding a political message.  Lahn denied the accusation and, according to Holden, rejoined that scientists have become “‘almost like creationists in their unwillingness to acknowledge that the brain is not exempt from selection pressures.”  One could argue, in fact, that because the brain is affected by so many genes, it is uniquely situated to sustain adaptation.

The panel wisely agreed that we need to police our language to some extent, by opting for terms like “geographic ancestry” in lieu of “race,” for example.  But I would insist that precision alone should drive our vocabulary, not fear of historical baggage or the specters of inappropriate popular inferences and political agendas.  Although we surely must remain vigilant on behalf of universal political equality, neither social conservatives nor liberals can afford to keep ignoring the differences between populations at the molecular level.

If indeed culture is accelerating human evolution by means of natural selection, perhaps technology and the economic forces of globalism will one day in the very distant future meld many populations into one.  But, until then—for our own benefit—we should let the scientific chips fall where they may.  In his timely and thoughtful new book, Strange Fruit: Why Both Sides Are Wrong in the Race Debate (Oneworld, 2008), British author Kenan Malik acknowledged that the very concept of “race” is both unscientific and irrational.  But so is the current practice of antiracism, he adds, which, on the one hand, tends to impose otherwise alien cultures upon minority individuals and, on the other, seeks to deny them important biological facts that might one day benefit them and their descendants in very profound ways.  “We need to challenge both [concepts],” Malik urges, “in the name of humanism and reason.”

Startling Reflections in the Neanderthal Genome.

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

Considered neither chic nor sleek, Neandertals were once the Richard Nixons of extinct hominins.  But thanks to a newly published draft sequence of our (kissing?) cousins’ nuclear genome, we don’t have Neandertals to kick around anymore.  In fact, one could argue—as Svante Pääbo, paleogeneticist at the Max Planck Institute in Leipzig, Germany, and leader of project recently has—that Neandertals aren’t really extinct at all.

Paabo

Modern humans and Neandertals share a common ancestor that lived from between 270,000 and 400,000 years ago, according to Pääbo’s new estimate.  The latter lived in Europe and Asia—only as far east as Southern Siberia and only as far south as the Middle East.  Fossil evidence suggests the two groups encountered one another in some way in the Middle East from at least 80,000 years ago, and then later in Europe.  But, for reasons highly contested and yet unclear, H. sapiens pressed on as Neandertal remains vanished from the record around 28,000 years ago.

Burly and bell-chested with protruding brow-ridges and feeble chins, Neandertals have suffered much abuse in the popular imagination.  Crude tradition has portrayed them as dullards because of their brutish appearance, for example, or as one-trick-ponies because of their inability to survive irregular climatic circumstances or, alternatively, the invasion of Cro-Magnon man during the late Pleistocene.

But science has recently rehabilitated the Neandertal narrative.  For whatever it’s worth, their brains were probably as large or larger than ours.  Apparently gifted with symbolic thought, they decorated their bodies with jewelry and probably pigment.  They hunted expertly with stone points and implements crafted from wood and bone.  In 2007, Johannes Krause (also a member of Pääbo’s team) reported that Neandertals carried FOXP2, the gene that allows humans to speak.  And whatever the causes of their eventual passing, Neandertals ruled Eurasia’s volatile environs for more than 200,000 years—longer than our species has existed.

But the biggest news has just arrived.  Neandertals, it turns out, are human—or at least a significant portion of most humans.  In the May 7 issue of Science, Pääbo’s international team of scientists published a draft sequence of the Neandertal genome composed of 4 billion nucleotides from three individuals.  And to their great surprise, they discovered that between 1 and 4 percent of the modern, non-African human genome was derived from our maligned and misunderstood relatives.  In other words, Neandertals and modern humans interbred.

The outcome stunned Pääbo and his cohorts because previous analyses of Neandertal mitochondrial DNA consistently fell outside the variation found in contemporary humans.  On the other hand, many paleoanthropologists rather expected the results.  Milford Wolpoff of the University of Michigan and João Zilhão of the University of Bristol in England, argue that fossil evidence has long suggested interbreeding.  Found in Portugal in the late 1990s, for example, the 24,000-year-old Lagar Velho child presents a mixture of Neanderthal and H. sapiens traits.

Pääbo’s team assembled the genome primarily using DNA from three Neandertal limb bones—each from a separate female individual—found in Vindija Cave, Croatia, and dated to 38,000 to 44,000 years old.  They confirmed that sequence with smaller samples from El Sidron, Spain; Neander Valley, Germany; and Mezmaiskaya, Russia—none of which differed significantly from the Vindija specimens.  By contrasting the results with the chimpanzee genome, Pääbo was able to distinguish ancestral genetic variants from their derived counterparts.

To find out whether Neandertals are more closely related to some contemporary humans than to others, Pääbo then compared the derived Neandertal variants to those contained in the genomes of five living humans—a San from Southern Africa, a Yoruba from West Africa, a French European, a Papua New Guinean, and a Han Chinese.  The San and Yoruba were deemed appropriate proxies for genetic diversity in Africa because of their exceptionally ancient heritage. If gene flow between Neandertals and H. sapiens occurred prior to differentiation among human populations, Pääbo hypothesized, the Neandertal alleles would match those of individuals from some regions of the world more often than those of others.

Neanderthal

And the results revealed exactly that.  After ruling out the ever-present possibility of contamination, the team concluded that “Neandertals share significantly more derived alleles with non-Africans than with Africans.”  More specifically, Neandertals shared the same number of derived alleles with both the European and the Asians, but significantly more with either the European or the Asians compared with either African.  Notably, no Neandertal specimen has ever been found as far east as China or New Guinea.

Thus, Pääbo inferred, because Neandertals are more closely related to all present-day non-Africans, and equally so, they must have interbred with their common ancestors shortly after they departed from Africa into the Middle East, but before their further migration into Eurasia.  Such genetic exchange could have taken place about 80,000 years ago when Neandertal remains began to show up in Israeli caves already occupied by humans (Qafzeh, Skhul, and Tabun, for example), or later, about 50,000 to 60,000 years ago, when a second group of H. sapiens set out from Africa.  Even so, the team wouldn’t completely exclude an alternative possibility—that their results might instead reveal an “old substructure” in Africa that lasted from Neanderthal origins until non-African migration.

In any case, a prominent and long-standing debate in paleoanthropology has finally been resolved.  The Neandertal genome does indeed live on in present-day humans.  But “the most interesting development,” Pääbo recently told me, may be “the identification of genes that were positively selected in humans after their divergence from Neanderthals.”  In other words, the Neandertal sequence has begun to reveal some of the recently evolved traits that make us uniquely human.

But there were surprises lurking here too.  Using the chimpanzee, orangutan, and rhesus macaque genomes in addition to those of modern humans and Neandertals, the team located only 78 recent nucleotide substitutions capable of altering the protein-coding capacity of genes where moderns are fixed for a derived state and where Neandertals bear the ancestral, more chimp-like version.  And just five genes had accumulated multiple substitutions—a shockingly small number, given the ample span of time.  Indeed, changes to human accelerated regions (HARs)—conserved throughout most of vertebrate evolution, but altered drastically during hominin evolution—tended to predate the human-Neandertal split.

Even so, Pääbo was able to identify general roles, if not specific functions, associated with some of our newly altered genes.  Three alleles carrying multiple substitutions affect skin physiology, including pigmentation (TRPM1).  Others might pertain to cognitive development, mutations of which are presently implicated in causing autism (CADPS2, AUTS2), schizophrenia (NRG3), and Downs syndrome (DYRK1A).  Still others could be important for gene transcription (TTF1), wound healing (PCD16), energy metabolism (THADA), and the beating of the sperm flagellum (SPAG17).

The team couldn’t say, however, whether these specific substitutions were the result of random drift or positive selection.  But they also searched the modern human sequence for “selective sweeps”—lengthy swaths of DNA including mutations absent in the Neandertal and chimp genomes.  Extensive affected regions, the prevailing theory goes, imply relatively intense selective pressures.  Again through genomic comparisons, Pääbo successfully identified 212 such sweeps in the modern human genome, many surrounding genes commonly thought to involve brain function in some way.

But the new Neandertal sequence is imperfect to say the least.  Although Pääbo’s team decoded roughly 5.3 billion nucleotides in total—the human genome containing about 3 billion—much of that total consists of duplications.  They confess as well that better than a third of the genome remains unsequenced.  Pääbo expects his fair share criticism at some point, but says it’s a bit too early to expect serious reproaches from other scientists.  The religious community remains silent as well, which Pääbo finds somewhat surprising.

Meanwhile, science turns its collective gaze forward.  Pääbo wants to improve the screening process for positive selection and to follow up on specific candidate genes the function of which may have been altered during recent human evolution.  He hopes as well to explore the Neandertal sequence more fully to identify features unique to their species (or subspecies), and to illuminate Neandertal variation by analyzing the remains of additional specimens.  And perhaps his team will scrutinize the genomes of other extinct hominin forms to determine whether they too have contributed to the human blueprint.

Regardless, Pääbo and his colleagues have already advanced humanity’s self-knowledge by meteoric leaps and bounds.  We now have confirmation that the genomes of long-extinct hominins can be reliably salvaged.  We know that the strictest “out of Africa” hypothesis of human origins is untenable, and that the environment—whether natural or man-made—continues to shape the contours our epic evolutionary adventure.  We should appreciate as well that genetic rifts between modern human populations can run quite deep indeed, and, thus, will be ignored only at our common peril.

And hopefully we’ve gained a great deal more respect for our exceptionally intimate relatives, the Neandertals.  Far from ugly, dim-witted, or incompetent, our “sister group,” as Pääbo’s team has dubbed them, will much to teach us in the coming years.  But many of us can’t really talk about Neandertals as “them” anymore, because, in fact, Neandertals are us.

Book Review: Sheldon Krimsky and Kathleen Sloan, eds., Race and the Genetic Revolution: Science, Myth, and Culture. NY: Columbia University Press, 2011.

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.

There’s no point in telling someone that being “black,” for example, no longer matters in the 21st Century.  As history plainly demonstrates, it will continue to matter profoundly so long as “blackness” exists.  The more helpful and, as it turns out, honest approach might be to explain that “race”—like clairvoyance, transcendence, or holiness, for instance—is, in reality, all in our heads.

We have a knotty problem indeed whenever society accepts or even emphasizes what science deems a dangerous myth.  In 1972, geneticist Richard Lewontin told us that more genetic diversity exists among West Africans than between West Africans and Europeans.  We also know that disease polymorphisms are totally inconsistent with the 19th Century notion of taxonomic race, and that blood types don’t sort by geographic region.

Yet the notion of race endures.  Why—and who should be targeted for blame?  Don’t waste all of your arrows on the easiest, most familiar targets—the uneducated or otherwise unworldly xenophobes who will likely never come within spitting distance of this publication or any remotely like it.  Racism is far more inclusive these days, even if seldom referred to as such.

Personal case in point: My former fiancée and I recently applied for a marriage license in Wisconsin.  Upon arrival, the county clerk asked each of us to designate our race.  “None,” we replied in turn, choosing our responses carefully.  But the clerk typed “refused” on our application, nevertheless, as she apparently had been instructed to do.

But the racist bug continues to spread deeper into the well-meaning but wrong-headed bastions of polite society.  Earlier this year, the University of Wisconsin-Madison—notably liberal and otherwise highly respected in scientific circles—was criticized for its admissions policies that intentionally discriminate against two races in favor of two others.

In 2010, the U.S. Census Bureau endeavored to segregate more than 300 million highly intermixed Americans into fourteen discrete racial categories.  And even social scientists routinely employ self-identified race as a variable in international studies—despite the fact that the concept’s meaning varies from country to country.

But, thankfully, we can depend on the “harder” sciences and their more rational practitioners to promote a relatively systematic and objective approach.  Or can we?

In his introduction to Race and the Genetic Revolution, Tufts University community health specialist and co-editor Sheldon Krimsky (along with human rights advocate Kathleen Sloan) confirms that race amounts to nothing more than a “scientific myth,”—a “vestigial cultural artifact” persisting only in our “minds and public policies.”

Race emerged from two projects launched by the Council for Responsible Genetics.  The first examined the effects of expanded DNA databases on racial disparities in criminal justice.  The second, more interesting to me, explored how modern scientific—especially medical—practices have actually revived a dangerous concept that should have been tagged and bagged years ago.

In a concise historical essay, contributor and Drexel University public health expert, Michael Yudell, considers the recent “upsurge” in race-based medicine and its possible drivers.  The genetic revolution, he finds, combined with our noble desire to resolve certain health disparities—especially in hearth disease, cancer, and diabetes, for example—has scientists rummaging for solutions in every possible direction.

Unfortunately, many well-intentioned researchers have reverted to race.  According to Yudell, this reckless trend suggests that “an analysis of the complex relationship between individuals, populations, and health will be surrendered to a simplistic, racialized worldview.”

Enter BiDil, a drug manufactured to treat heart failure.  A small Massachusetts biotech company called NitroMed brought BiDil to the FDA in 2001, expressly requesting race-specific approval.  Based on a trial in which every participant self-identified as “African American,” the FDA acceded in 2005.  The drug was subsequently labeled as indicated only for blacks.

In reality, however, BiDil is just a combination of two generic vasodilators—hydralazine and isosorbide dinitrate—used without regard to race for more than a decade.  Deeply troubled by the BiDil story for a number of reasons, contributor and Hamline University professor of law, Jonathan Kahn, indicts the FDA for opening a “Pandora’s box of racial politics.”

First, he says, no scientific evidence has ever suggested that race has anything to do with how the drug works.  BiDil was never evaluated on a control population of non-blacks, after all.  Nor did common sense support the drug’s designation.  The FDA never approves and companies never market the numerous drugs tested only on white people as “white drugs.”  Second, had NitroMed requested and acquired only race-neutral approval, its patent would have expired in 2007 rather than 2020.  Though scientifically inappropriate, in other words, the company’s strategy was very impressive from a purely economic perspective.

Third, one wonders who counts as “African American”—or “black,” as BiDil’s label designates.  Should we revert to Jim Crow era blood ratios to figure it out?  Are Australian Aborigines or dark-skinned South Asians included?  Fourth, race-based labeling might prevent non-blacks from obtaining beneficial or even life-saving medicine, and, in effect, it might render insurance companies the defining agents of race.  Finally, the author stresses, by granting race-specific approval, the federal government fallaciously endorsed the use of race as a biological category.

Khan’s argument, however, is not that race should never play any role in genetic research.  “There may be occasions where race can be productively used,” he instructs, but we must “differentiate between using a racial group to characterize a gene versus using a gene to characterize a race.”  It is entirely acceptable, for example, to study the Pima Indians of the American Southwest to characterize the genetic basis for diabetes.  But scientists should never employ genetics to brand the Pima as a people burdened with the gene or genes for diabetes.

The proponents of “racialized medicine” thus allege the reliable predictability of a person’s disease predisposition through determination of his or her biological race.  Critics, on the other hand, emphasize the lack of any solid and consistent bases for biological race.  And even if such foundations existed, they say, we could never be certain that members of one race would share specific disease-related genes distinct from those of other races.

Contrastingly, advocates of evolutionary medicine claim that diseases result from combinations of infection, genes, novel environments, design compromises, and evolutionary legacies.  Affecting all humans, the first and the latter two tend not to cause health disparities.

In the United States, these discussions focus on maladies like cancer, stroke, heart disease, and diabetes—all of which are influenced by several genes along with copious environmental factors.  Thus, to address health disparities, according to Joseph Graves, Jr., contributor and biologist at North Carolina A & T University, “we really must utilize the full intellectual arsenal of evolutionary genetics.”

The evolutionary theory of aging informs us that genes causing certain diseases in old age can be either neutral or beneficial early on in life (mutation accumulation or antagonistic pleiotropy, respectively).  Stomach cancer represents one such evolutionary legacy in mammals generally.   In the U.S., however, the disease tends to afflict East Asians at a higher rate than others.  But contrary to common medical opinion, according to Graves, the primary explanation for this disparity is obviously not genetic.  Rather, infection, frequent tobacco use, high salt intake, and low fruit and vegetable consumption are more culpable.

The National Institutes of Health spends $2.7 billion on health disparity research every year.  But much of the resulting literature presumes genetic predisposition—a false paradigm and a “fool’s errand,” Graves concludes, that will persist until both the government and the science it supports choose to abandon the bizarre and highly toxic concept of race.

Book Review: Daniel J. Fairbanks, Relics of Eden: The Powerful Evidence of Evolution in Human DNA (Amherst, NY: Prometheus, 2007). 281 pp.

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.

Science writers frequently report 98 percent similarity between the human and chimpanzee genomes, as if that bald datum alone were enough to sate the scientific wanderlust or to send biblical literalists packing for a one-way trip toward a more stable reality.  But if neither God nor demon lie in the finer details, the overwhelming elegance of natural selection certainly does.  Can small- and large-scale DNA analyses verify the history of evolution?  Do they confirm previous conclusions based on anatomy, physiology, archeology, geology, and, of course, the fossil record?  Can we exploit vast and recently collected DNA sequences to reconstruct evolutionary relationships between man and various other species, non-human primates in particular?  Absolutely, answers Brigham Young University professor and research geneticist, Daniel J. Fairbanks, as he hurls his lay—but no doubt highly motivated—readers into the wondrous, whirling slopes of the double helix.

In 1950, Barbara McClintock detected small segments of DNA that appeared to “jump,” as it were, from one position in the corn genome to another, resulting in major insertion mutations.  Following an extended intellectual uproar, McClintock was finally awarded the 1983 Nobel Prize in Medicine for her then-breakthrough discovery of what geneticists now commonly refer to as transposable elements, approximately three million of which reside somewhere in the human genome.  Only about eleven percent of these elements, called transposons, actually sever themselves from one location and move to another.  By contrast, more typical retroelements, never really skip from place to place, but rather construct RNA copies of themselves that, in turn, are retro-copied back into DNA prior to insertion elsewhere in the genome.  All transposons and nearly all retroelements have become relics—so riddled with mutations, in other words, that they can no longer move or replicate.  Alu retroelements are important exceptions, comprising nearly ten percent of the human genome.

But the crucial evolutionary feature of retroelements generally is that they once could or now can insert themselves anywhere into the vast DNA text.  Therefore, the likelihood that just one would transpose to the same exact position in two different persons by mere chance alone, less said to all members of two or more different species, is infinitesimally small.  Yet, in study after study, transposable elements in the human genome have been found at precisely the same locations in the chimpanzee genome 98 percent of the time, and in the DNA of other apes and monkeys at only slightly decreased rates.  There can be only one coherent explanation, Fairbanks concludes.  These transposable elements, he writes, “became established in the DNA of a common ancestor of humans and chimpanzees, then they mutated in the separate lineages.”

A group of Russian scientists, for example, isolated the fourteen known HERV-K retroelements, decidedly ancient but still transposing in the human genome.  Recognizing that a common ancestor is logically implied when even a single retroelement is found in an identical location among two or more species, the Russians compared our HERV-Ks to those of other apes (chimps, gorillas, orangutans, and gibbons), Old World (African and Asian) monkeys, and New World monkeys.  Of the fourteen elements, three existed only in the human genome, indicating relatively recent insertion.  The other eleven were found at precisely the same positions in both chimps and gorillas.  Orangutans shared nine elements with us, and gibbons seven.  Old World and New World monkeys had just four and two HERV-Ks in common with humans, respectively.  Such evidence is entirely consistent, the author observes, with the primate family tree previously derived from more traditional data, including the fossil record, revealing the tightest ancestral relationship between humans and African apes, followed by Asian apes, and, finally, to a lesser extent, Old and New World monkeys.  Confirming results have emerged from additional studies, including those distinguishing Alu elements contained in DNA segments related to hemoglobin and Charcot-Marie tooth disease.

Equally enlightening are the thousands of mostly useless, dead-end pseudogenes that continue to haunt our chromosomal recesses.  Many animals—dogs and cats, for example—possess a functional, unitary GULO gene that allows them to produce vitamin C, an extremely useful trick for creatures that do not regularly consume fruits and vegetables.  Most primates, on the other hand, have always maintained a vitamin C-rich diet, which explains why human and chimpanzee genomes contain substantially mutated GULO pseudogenes that are 98 percent identical.  Unfortunately for us, however, the need for a functional GULO has returned.  Alas, natural selection (or, more accurately, the relaxation thereof) does not possess the predictive insight of the typically enscriptured all-powerful and all-seeing God.

Darwin

Consider as well glucocerebrosidase, or GBA, sequences in primates.  Squirrel monkeys possess only the original gene.  Orangutans have two functional copies, the first of which resides in the same position as that of monkeys, and the second of which has been copied to a location in close proximity.  Although all gorilla, chimp, and human genomes include both GBA copies, their second pseudogene has suffered a 55 base-pair mutation—again, at precisely identical sites in each species.  The best explanation for the GBA scenario is, first, that the functional gene duplicated in the common ancestor of apes and humans following the split between the monkey and ape lineages, and, second, that the younger copy mutated into a pseudogene in the lineage leading to gorillas, chimps, and humans after those species diverged from the lineage leading to orangutans.  One should infer as well that gorillas, chimps, and humans are more closely related to each other than any of the three is to orangutans, and that all species of ape are more familiar to one another than any ape is to any monkey.  A total of 19,724 human pseudogenes had been identified in 2003, and scientists continue to compare them to those of other species.  “[T]he same pattern emerges over and over,” Fairbanks instructs.  “Once again, we find evidence of our shared evolutionary ancestry with other primates, and more distant shared ancestry with other mammals.”

But even prior to genome sequencing, microscopic examination had yielded similar results.  Human and chimpanzee chromosomes can be perfectly aligned, except at a few notable locations.  These variances, however, are denoted as rearrangements only because, as it turns out, the relevant DNA sequences are essentially the same.  In nine instances, DNA segments were simply inverted over time.  Using both fluorescence in situ and DNA sequence comparison methods, scientists have determined that, in chromosomes 1 and 18, the inversions occurred exclusively in the lineage leading to humans, and that, in chromosomes 4, 5, 9, 12, and 15 through 17, they occurred only in the chimp lineage prior to the chimpanzee-bonobo split.   In other instances, small sections of one species’ chromosome have merely been expanded with repeated sequences.

In the past, opponents of science education have attempted to exploit the fact that chimps possess 24 and humans only 23 chromosomes.  In 1991, however, Yale University scientists resolved the issue by sequencing DNA near the middle of human chromosome 2, discovering that it matched that of the telomeres (DNA segments at the end of chromosomes) of chimpanzee chromosomes 2A and 2B.  In addition, the centromere (a constricted segment of DNA within a chromosome) of human chromosome 2 matches the centromere in chimp chromosome 2A, and the corresponding region of human chromosome 2 matches the DNA contained at the centromere in chimp chromosome 2B.  “The evidence that human chromosome 2 arose from a fusion” of the two shorter chimpanzee chromosomes “is solid and unmistakable,” writes Fairbanks.  “The only reasonable explanation of this evidence is a chromosome fusion that happened after the lineage leading to humans diverged from the lineage leading to the great apes.”

In recent years, human, chimpanzee, and other genome projects have revealed confirming evidence of human evolution that can be characterized only as utterly overpowering.  The sad irony, of course, is that, at the same time, generously funded and proudly uninformed creationists continue to crusade against evolution and, in fact, against all scientific realities that conspicuously threaten their fanatical beliefs.  Describing himself as a person of “deep religious convictions,” Fairbanks includes two final Stephen Jay Gould-esque chapters exploring the clash of faith and reason along with a much more appropriate appendix outlining the history of biological science from Darwin to the human genome project.  Fortunately, however, polemics and politics take a distant back seat to logic and facts in this truly commanding and no doubt timely illumination of human origins, a subject the significance of which simply cannot be overstated.