Potential Approaches To Genetic Engineering

We are fast approaching the point where the transhumanist goal of intentionally modifying humans to further our own objectives with tools that include genetic engineering is possible.

There are several approaches that could be taken to doing this that are easier and less sophisticated than simply synthesizing whole genomes, or large parts of them from scratch. And, these are the approaches the would probably dominate the early days of transhumanist genetic engineering that seeks to improve the human genome. 

Of course, each approach also comes with its own particular risks. The risks mostly flow from the fact that biological systems are highly interrelated and tweaking any one part of them can have unintended consequences if we don't perfectly understand those interrelationships (which will probably won't for the foreseeable future).

Fixing Existing Simple Genetic Disorders

The first wave of genetic engineering, which is just starting to be utilized medically, is to change single genes that cause Medellin genetic disorders like sickle cell anemia or achromatopsia, to cure these disorders.

This is among the lowest risk forms of genetic engineering. A known harm is alleviated. But it isn't completely without side effects. The sickle cell anemia gene also creates resistance to malaria when only one rather than two copies of it are present. But removing this benefit from someone's descendants is a small price to pay in someone who had sickle cell anemia and doesn't live in a place where malaria is a problem (or when someone who can be protected from malaria by other means such as a malaria vaccine).

Purging Recessive Genetic Disorder Genes

Everyone has some recessive genes for genetic disorders. And, as long as you don't have children with someone else who has the same recessive genes, this is basically harmless.

The main reason that inbreeding is fitness reducing is that it increases that likelihood that a couple's children will end up with both copies of recessive genes for genetic disorders.

But, in addition to genetic engineering to remove genes that cause genetic disorders from people who already have genetic disorders, essentially the same approach could be used to remove recessive genes that cause genetic disorders from people who are merely carriers for those genetic disorders.

This might be particularly attractive for participants in a space colonization mission that would have a low effective population size and, necessarily, a higher inbreeding coefficient.

This kind of genetic engineering is particularly low risk, because we would be replacing the recessive gene known to present a risk of a genetic disorder, with genes found in the vast majority of the population that are known to be harmless.

Genetic Engineering With Existing Human Coding Genes

It is elementary that there is genetic diversity among humans. Some people have genes that make you tall or smart. Other people have genes that make you short or stupid. People have different blood types, different skin and eye and hair colors, different skin and hair textures, different ability to tolerate high altitudes, etc.

One fairly straightforward, if not necessarily technically easy, form of genetic engineering is to take genes from people who have a desirable genetic trait and place them in people who do not have that trait (often replacing a gene that codes an alternative to that trait).

In other words, basically doing that same thing that could be accomplished with selective breeding, but much more rapidly, directly, and precisely.

This is higher risk than simply removing recessive genes that cause genetic mutations (and even the example of sickle cell anemia which also confers malaria resistance illustrates the trade offs of that), because it could be that a known desirable gene interacts with other genes in an important unknown way that is disrupted when the known desirable gene is transplanted. But it is still lower risk than giving someone a gene that isn't found in humans at all.

Tweaking Top Level Designs That Utilize Existing Coding Genes

Our DNA devotes lots of its coding genes to the blueprints for a mix of proteins, and how to combine those proteins into particular kinds of tissues, and how to combine those tissues into particular organs and structures in the human body. By comparison, our DNA devotes a far smaller share of our genome to specifying which organs and structures go where, and how many of those structures we have.

A genetic modification that hacks this small portion of our DNA governing which organs and structures go where and how many of them we have could create noticeable macroscopically observable changes with comparatively minor tweaks to our DNA and with less risk of adverse side effects on the complex, multifaceted biochemical interrelationships of other parts of our bodies.

For example, a tweak to our DNA that gave us four figures or six, instead of five, would be much easier to accomplish than a tweak to our DNA that gave humans the organ that electric eels use to create electromagnetic shocks which we don't have the blueprints for in our genome.

Similarly, tweaks to our DNA to give us an extra pair of eyes in the sides of our heads, or an extra pair of kidneys, or to rearrange the location of the internal organs in our torsos, ought to be possible with a fairly modest amount of DNA modification.

Genetic Engineering With Pseudo-Genes

Pseudo-genes are genes in our DNA that are no longer part of our coding DNA and have been deactivated by mutations.

At this point, their main practical use is that they allow us to trace historically what genes organisms have lost due to mutations, approximately when that happened, and what those genes looked like immediately prior to being deactivated.

For example, one deactivated gene allowed predecessors to primates to produce their own Vitamin C, which was no longer critical since fruit supplied it. Another allowed us to better break down uric acid in our blood, which has bad aspects since this can cause gout, but also helps us turn fructose into fat which helps us weather fruit scarcity in the winter. We've also lost taste receptors for bitter tastes, in part, because we've learned to distinguish safe and unsafe plants culturally so we don't need the receptors as much.

The thing about pseudo-genes, though, is that often a single slight mutation can undo the mutation that deactivated them in the first place, can reactivate the ability of the pseudo-gene to make the very complex molecule that was genetic fitness enhancing at some point in our evolutionary history.

Mutations that reactive pseudo-genes are extremely rare as a matter of random chance. But if one is engaged in intentional genetic engineering in order to do a transhuman biohack because you believe that the pseudo-gene might be fitness enhancing at our current level of technology and in current environmental conditions, it would often be easier to reactivate a pseudo-gene than it would be to insert all of the genetic code necessary to code a molecule into someone's DNA with a much more complex custom designed retrovirus.

A catalog of pseudo-genes in humans is basically a menu of biological functions that could easily be added to people with a simple biohack.

The risk here is that pseudo-genes were usually purged from the genome to the point of fixation for a fitness enhancing reason. Sometimes the circumstance that enhanced fitness at the time is no longer present, but sometimes it is and we just don't understand it well enough.

Another possibility to consider is that if much of the 90% of the human genome that is non-coding really is literally "junk DNA" that doesn't serve any fitness enhancing function, there might be some form of benefit to simply purging it from our genomes.

The risk of purging junk DNA, of course, is that some of it might have purposes that we just don't understand yet that are still important. So far as we know, simply having junk that does nothing in our DNA isn't a big problem.

Genetic Engineering With Exogenes

Another categories of genes that code molecules which are out there are genes that aren't present in either the coding or non-coding DNA of humans, but are present as coding DNA in other organisms. I don't actually know what the proper scientific name for them is, but I'll call them for convenience in this post, "exogenes."

Suppose, for example, that a honey bee produces a pheromone not found in human genes or pseudo-genes that it would be nice for humans to have. You could cut that gene out of the honey bee genome, splice it onto a retrovirus, infect a human with that retrovirus, and then that human and that human's descendants could produce that pheromone too.

Of course, inserting exogenes into a human could potentially be harmful in all sorts of hard to see ways, because we have no good way of knowing if the exogenes are incompatible with our existing genome until we try it.

Genetic Engineering With Derived Genes

There are some genes in humans that share a common ancestor with different genes in another species, even though the human genes now code for a different molecule with a different purpose than the non-human gene with which it shares a common ancestor.

For example, some of the biochemicals in human saliva are derived from the same ancestral biochemicals that evolved in some snakes into a kink of snake venom.

If you wanted to make it possible for humans to produce that venom, it might be easier to genetically modify human DNA that makes those biochemicals in saliva into DNA that produces snake venom, than it would be to insert the entire snake venom exogene into a human through a much larger retrovirus than one that would merely tweak our existing salvia biochemical gene.

This is less risky that a straight out exogene, because humans already have something similar, but it is still far from risk free.

For example, maybe snakes have genes that give them immunity from their own venom, in addition to the genes that create the venom, that a human with a tweaked salvia gene that creates the same venom would not have.

Small Tweaks To Create Chemically Similar Molecules

Similar to genetic engineering of genes with a common origin is genetic engineering of genes that produce a molecule that is chemically similar to another molecule, even if the genes that produce the two different biochemicals do not share a recent common origin.

For example, the caffein molecule and the chocolate molecule differ by only a single atom. So, it probably wouldn't be too hard to engineer a cocoa bean that was caffeinated instead of chocolaty, or a coffee bean that was chocolaty instead of caffeinated.

The general concern about unintended consequences that is present throughout genetic engineering is present here, but to the extent that tweak is small, and we understand what the purpose of the molecule being tweaked is in the original organism, the risk can be fairly modest.

Another Path For Transhumanism: Design Improvements

When one thinks about the prospects of genetic engineering and other ways of improving the human body and mind, which is basically what "transhumanism" is about, cosmetic improvements and functional improvements come to mind. (The engineering challenges of actually writing and not merely reading a genome are not insubstantial but they are not entirely insurmountable either.)

But many people fail to appreciate the many design flaws in the human body from wisdom teeth, to tail bones, to the appendix, to the design flaws in the human eye, to immune system gaps that have to be addressed with vaccines. Improving these flaws is one obvious and not very ethically troubling task for genetic engineering.

The human eye is marvelous but also very poorly designed. The poor design is evidence against intelligent design and in favor of the “unguided, unplanned, messy, quirky, and historically contingent” process of evolutionary design. A short piece from 2008, Suboptimal Optics: Vision Problems as Scars of Evolutionary History, does a nice job explaining.

Most well known is that the wiring is backwards.

The most obvious design flaw of the retina is that the cellular layers are backwards. Light has to travel through multiple layers in order to get to the rods and cones that act as the photoreceptors. There is no functional reason for this arrangement—it is purely quirky and contingent.

Even in a healthy and normally functioning eye, this arrangement causes problems. Because the nerve fibers coming from the rods and cones need to come together as the optic nerve, which then has to travel back to the brain, there needs to be a hole in the retina through which the optic nerve can travel. This hole creates a blind spot in each eye. Our brains compensate for this blind spot so that we normally do not perceive it—but it is there.

From a practical point of view, this is a minor compromise to visual function, but it is completely unnecessary. If the rods and cones were simply turned around so that their cell bodies and axons were behind them (oriented to the direction of light), then there would be no need for a blind spot at all.

Cephalopod’s like octopuses took a slightly different evolutionary path and have a better design:

But the reversal of the wiring isn’t the only design flaw.

The arrangement of the extraocular muscles—the muscles that move the eyes—is also difficult to explain without appealing to evolutionary contingency. There are more muscles than are minimally necessary and yet there is no functional redundancy. In order to move a sphere in any direction, only three muscles would be necessary, evenly spaced like the legs of a tripod. The human eye has six—the superior, inferior, lateral, and medial rectus, and the superior and inferior oblique. And yet, despite the extra three muscles, the loss of function of any one muscle causes an impairment of eye movement and results in double vision or displaced vision. A more frugal design with only three muscles would be more efficient and less prone to malfunction, as there are fewer components to break down.

If the eye were to be designed with more than the minimal three muscles, then it would make sense to arrange the muscles so that the loss of one or even more would not impair eye movement.

From here via Marginal Revolution which also has some interesting comments.

Medical Advances Can Reverse Cell Death

Biomedical researchers have discovered that cell deaths from infections can be halted even when they reach a point that had previously been thought to be a point of no return at which treatment was hopeless. 

Researchers report a new method for analyzing pyroptosis -- the process of cell death that is usually caused by infections and results in excess inflammation in the body -- and show that the process, long thought to be irreversible once initiated, can in fact be halted and controlled. The discovery means that scientists have a new way to study diseases that are related to malfunctioning cell death processes and infections that can be complicated by out-of-control inflammation. . . .

[S]cientists have a new way to study diseases that are related to malfunctioning cell death processes, like some cancers, and infections that can be complicated by out-of-control inflammation caused by the process. These infections include sepsis, for example, and acute respiratory distress syndrome, which is among the major complications of COVID-19 illness.

(Source).

Quote Of The Day

[T]he brain accounts for about 2–3% of total body weight, but it consumes 25% of the body’s energy [at rest].

 - Sapiens, Yuval Noah Harari.

Thinking burns calories.

Making Sour Beer

The science of yeast fermentation in sour beer production is sophisticated stuff explored in a new preprint. There are hundreds of strains of beer yeast and some are particularly well suited to the task.

Truth Can Be As Strange As Fiction

There exists a weird kind of cancer called a teratoma, whose cells seem to think that they are in an embryo. These cancers differentiate; develop hair, teeth, skin, all manner of messy things. They exist in humans and animals. Some very odd guy wondered if teratoma cells, which seem to want to be an embryo, would actually become one if given a favorable environment. He implanted teratoma cells into an early-stage rat embryo; the teratoma cells there experienced the proper chemical cues and developed into part of a rat. He ended up with a piebald rat – some of the cells had a regular rat mom and dad, while other parts were descended from a cancer propagated in a tissue culture. The rat was fine.

Via G. Cochran at West Hunter.

Along the same vein, researchers have found biochemical similarities between the growth of an embryo in a pregnant woman and the biochemical mechanism associated with many cancers. They are trying to figure out how this biochemical process works in order to create a treatment that confounds that mechanism and interrupts cancer-cell specific growth.

Cure For Some Kinds Of Previously Lethal Leukemia Discovered; Aging Better Understood

In a small study, an experimental treatment that genetically modifies part of the human immune system cured all but one of eight cases of a type of leukemia (one of several kinds of blood cancer) that is usually fatal in everyone who contracts it.  Note that a treatment that appears to entirely cure someone's cancer, as opposed to merely forcing it into remission for the duration of the treatment, is particularly exceptional.

Moreover, this new approach to cancer therapy provides a template for many potential future cures of other kinds of cancers (or even other kinds of diseases).

This subtype of leukemia isn't the only circumstance in which cancer treatment has made great strides, although it is one of the most dramatic.  From 1960-1964, the five year survival rate for leukemia was 14%.  From 2004 to 2010, it was more than four times that rate, at 60.2%, and progress has continued since then.

Progress In Understanding Aging

In other impressive medicinal biochemistry news, scientists have made great progress in understanding the role of a key hormone called growth differentiation factor eleven (GDF11) first described in 2014, in the genetically determined component of aging.

This hormone's effects are truly impressive in mouse models.  "Restoration of GDF11 reverses cardiovascular aging in old mice and leads to muscle and brain rejuvenation . . . . GDF11 levels decrease over time and also showed that most of the depletion occurs by middle age."  Seven genes associated with GDF11 levels in mice were identified and much of that information can be used to identify parallel genes in humans.

As I noted recently in another post, the biochemistry of other completely independent aspects of the human aging progress are also increasingly well understood.  And, we have made progress toward identify one of the environmental causes of Alzheimer's disease (copper exposure).

Depression Is A Huge Problem For Roundworms. Who Knew?

In a new study, researchers administered an antidepressant called mianserin to Caenorhabditis elegans, a type of roundworm used frequently in research. In 2007, they discovered that the drug increases the lifespan of roundworms by 30-40 per cent.

From here.

The study also notes that most of the lifespan extension occurs during the prime of roundworm life, during their years of peak fertility.

Obviously, this drug probably isn't really treating depression in roundworms, but scientists aren't really certain why it does work either, although they'd love to know. The results sound somewhat less miraculous when you learn that roundworms reach adult level fertility at an age of about one day old and typically live in all until they are fourteen to twenty-one days old.

The title of the journal article in which this result is reported also deserves special credit for being utterly vacuous:

Rangaraju, et al., "Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality." eLife, 2015; 4.

I ask you, is there a means of extending lifespan that does not involve the postponing the onset of mortality?

Short Takes

* Spinal fluid biomarkers can distinguish between people suffering from Lyme disease (a tick carried infectious agent), Chronic Fatigue Syndrome (probably a viral condition with a long latency period), and uninfected individuals. This is important first, because Lyme disease and Chronic Fatigue Syndrome can present with similar symptoms, and second, because diagnosing Chronic Fatigue Syndrome and even finding ways for sufferers to convince people that they have a genuine biologically caused disease rather than simply being lazy, is a major challenge.

* The Kalash people in a remote part of the Hindu Kush Mountain range are one of the most genetically distinct populations in the world. When one has a computer break the world's autosomal genetics into the most distinct possible seven clusters, the clusters that you get are: African, European, South Asian, East Asian, Papuan, indigenous American and Kalash.

Their Y-DNA haplogroups (from a sample of about 43 people) are as follows:
L3a 22.7% (most common in Pakistan)
H1* 20.5% (most common in South Asia)
R1a 18.2% (most common in Eastern Europe and South Asia)
G 18.2% (most common in Southern Europe, Anatolia, Druze, Brahui and Pashtuns)
J2 9.1% (most common in Anatolia and where Indo-Europeans have had an impact)
R* 6.8% (most common in Thailand, Indonesia, the Phillipines and Australian aborigines)
R1* 2.3% (most common in indigenous Americans)
L* 2.3%. (most common in South Asia)

Their mtDNA haplogroups (from a sample of 44 people) are as follows:
pre-HV 22.7% (most common in Socotri, North Africa, Iran and Arabia)
HV* 4.5%
H 4.5% (the modal haplogroup of Europe)
U2e 15.9% (most common in South Asia)
U4 34.1% (most common in Central Asia)
U7 2.3% (most common in South Asia)
J1 2.3%
J2 9.1%
T* 4.5%

They speak a language from the Dardic branch of the Indo-European family (one of the more basal of the Indo-Iranian part of the late language family), and practice a polytheistic religion.

They are between areas that areas typically Central Asian and areas that are typically South Asian in genetic makeup. Their traditions place them as a lost contingent of Alexander the Great's army, but given their uniparental markers, the genetic makeup, their particularly contingent would have had to have picked up members mostly from the area from Anatolia to the Hindu Kush. Their Dardic language is also an anomaly for an isolated community claiming to descend from the Greeks, they lack common distinctively Greek uniparental markers, and their religion is close to Hinduism than it is to Greek pantheistic beliefs. An origin a millennium or two earlier (if not much more ancient) would seem to be a better fit for the facts.

Given their autosomal makeup, any new arrivals in the region from somewhere would have had to either admixed substantially with a relict population that was largely wiped out or overwhelmed genetically elsewhere such as Europe and Central Asia's pre-Neolithic hunter-gatherers, or South Asian hunter-gatherer populations disrupted by Munda, Dravidian, and Indo-Aryan populations respectively. Alternately, they might have undergone significant selectively driven evolution analogous to that found in Tibetans as a result of living at high altitudes. The case for incorporation of a relict Central Asian hunter-gatherer population is most strongly supported by the modal mtDNA haplogroup U4, which was one of the second most common types found in ancient DNA from Central Asian hunter-gatherers.

* There are a couple of kinds of invasive ants that have an unusual reproductive system. Future queens are clones of the current queen. Future drones (reproducing males) are clones of their fathers. Workers, who do not reproduce, have a mix of the queen and the drone's genes similar to that of ordinary sexually reproducing animals. (I'll try to find a reference later).

* As a thought experiment, it is interesting to consider would it would look like to have a society where a human or near human species with reproduction system in which only half of women had children, but they had an average of four and a half surviving descendants, assuring the replacement of the species. There are several different permutations of this that would be possible. Half of children could be gay. Half of the children could be infertile (perhaps clones of their same sex parent, or perhaps surgically or chemically neutered). Half of females could be in "harems" like those of alpha dominated gorillas or lions, and only alphas might have the pheromones necessary to trigger reproduction. One imagines that such a society might resemble the Byzantine courts.

Alternately, one could imagine a society where half the women were in a social class that averaged surviving three children, while the other half the women were in a social class that average one surviving child. A study of the vital statistic of a Bronze Age society in Spain based on its burials and the inferred diets of the dead, which showed a minority elite with a high protein diet surviving at much greater rates than a "middle class" (perhaps soldiers) or an even more deprived underclass (perhaps servants or slaves), with this kind of demographics.

* There is a tendency in Anglo-American political economy to imagine a society with strong property rights and weak governments as a "state of nature" against which political action should be measured. But, this sense is to a great extent ahistorical, particularly in farming and more urbanized societies. The oldest Minoan Linear A script is preserves administrative records of ration distribution systems, basically welfare states, that had strong parallels in Sumeria, Egypt, the Hebrew Bible and Rome - i.e. all of the major civilizations of the Mediterranean of the Copper Age, Bronze Age and Iron Age, and arguably via feudal societies into to the Middle Ages. There also seems to be evidence that these were command economies in which soldiers played an integral economic part, perhaps along the lines of the large role played by military owned enterprises in the civilian economies of modern Egypt and China. Likewise, fedual societies were basically agrarian economies run on a military footing with involuntary serf labor.

Decentralized market driven economies with contract rights and private property as an important organizing principle doesn't really emerge as the predominant component of the economy until after the Middle Ages end in Europe.

* NPR made some notable observations about the Middle Eastern oil states that are experiencing revolutions at the moment. Generally speaking, these states don't impose significant taxes on non-petroleum activities. Oil money funds government operations including strong military forces and a significant welfare state. This helps explain why the oil rich states of the Middle East have managed to survive while being so undemocratic. Historically, constitutional monarchy and republican government in cases like Rome, England and France have their roots in the need of a monarch to obtain consent of representatives of people who were going to be required to pay taxes to support the state. Taxes are the price of democracy.

* Some of the dates assigned to remains used to argue for an early presence of modern humans in Europe engaged in relatively primative economic industry have been revised upon further examination to more recent dates. Remains previously touted as more than 30,000 years old, which had "long been considered to be the earliest evidence of the remains of modern Homo sapiens anywhere in Europe" in Southern France and Southwest Germany have been re-examined within the last decade and determined to have actually been less than 10,000 years old.

This also influences how one conceptualizes the Chatelperronian lithic industry in Europe, which in turn relates to how smart we think the Neanderthals were. The prior and more primative Mousterian industry is clearly associated with Neanderthals. The industry that follows the Chatelperronian is associated clearly with modern humans. The Chatelperronian has traditionally been associated with Neanderthals as well, but some researchers have argued for it as "an independent development by Neanderthals (d'Errico et al. 1998)" while others "see the Chatelperronian as the result of the acculturation of Neanderthals by modern humans (Mellars 2005)." People care, because if the Chatelperronian was an independent Neanderthal invention, then maybe they were pretty smart and advancing their technology just as the humans did when climate conditions improved. In contrast, the opposite extreme would be to argue that admixture of modern human traits into Neanderthal populations is the only reason that they were able to innovate as much as they did even in the relatively primate Chatelperronian era. Between the two extremes is the possibility that the Neanderthals were capable of mimicing modern human Upper Paleolithic lithic industries, even if they would have been hard put to develop it themselves.

John Hawks, approaching the same underlying question of Neanderthal intelligence from another angle wonders if the ability of people born blind to repurpose their visual centers for language doesn't suggest that language is less hard wired, and hence, less likely to require genetic evolution, than has been often assumed: "Kaschube and colleagues showed that the apparent developmental robusticity of the visual cortex could be maintained by simple rules of self-organization. It doesn't take specialized genetic control to create a visual cortex, it just takes information structured in the right way to flip a few genetic triggers" and the right kind of environmental exposures. As he explains:

The blind subjects tell us that the ground for language processing is almost as fertile elsewhere in the cortex. Many brain areas have the genetic equipment to recruit and organize neurons into useful circuits for language processing. Language development is developmentally robust because it can rely on a rich language environment, not because of genetic standardization. The basic problems of language evolution must be explained by showing how robust language communities emerged. I don't preclude genetics, far from it -- weaker language environments may have become stronger because of evolutionary change. But that evolution must have been substantially domain-general, because language processing is not specifically canalized by genetics.

I like this scenario because it means we shouldn't be looking for lots of language-specific genetic changes in the last few hundred thousand years. The Neandertal genome suggests that there may not have been any at all.

My second speculation: If the language environment determines the instantiation of language processing, then brains must be substantially different in the way they process language. Children experience different language environments -- not only different languages, but different microenvironments within language communities. Only strong genetic controls could canalize brains despite the differences in their language environments. In brains where language processing emerges readily in the visual cortex, genetic controls cannot possibly synchronize brains in the face of environmental variation.

* A case is being made that the strong genetic discontinuity between South Asia and Southeast Asia, despite the lack of an obviously inpenetrable geographic barrier is attributable to the effects of the Toba volcano erruption, that while not wiping out the modern human population in South Asia, did seriously disrupt and reshape it:

Oppenheimer . . . [suggests] that the prolonged ash cloud could have devastated all or most of India, especially both M and N related populations in the east and south, closest to the volcano. He hypothesizes that this area could then have been repopulated by M dominated groups immigrating from the east, who might then have spread, in a cline, to the rest of the subcontinent, while N-related groups to the west could have repopulated India from that region. This could have left India populated by more recent M and N hapolotypes than those found farther east[.]

He also associates this event with the distribution of tone languages which are found in Africa, "scattered among so many indigenous peoples of Southeast Asia, southern China, Indonesia, Taiwan, the Philippines, and Melanesia" and in "northernmost reaches of the Indus valley . . . "would have been a likely spot where a branch of the Out of Africa migrants, who could have broken from the main group to travel north along the banks of the Indus, might have been able to survive the effects of Toba with their African traditions more or less intact. If tone language was part of their HMC inheritance, then that could explain the prevalence of tone language in this area today." Suggested musical linkages that might be legacies of this connection are discussed here.

Neuroscience of Binge Drinking Better Understood

[M]anipulating two receptors in the brain, GABA receptors and toll-like receptor 4 (TLR4), "caused profound reduction" of binge drinking for two weeks in rodents that had been bred and trained to drink excessively." The study was published online the week of Feb. 28 in the journal the Proceedings of the National Academy of Sciences.

About 30 percent of Americans who drink do so excessively, and about 75,000 people die each year from the effects of excessive drinking. Current treatments for excessive alcohol drinking include prescription drugs Revia and Campral for controlling cravings. To ease withdrawal symptoms, doctors often prescribe medications such as Valium and Librium that carry their own risks of addiction. Valium and Librium reduce the anxiety alcoholics feel when they stop drinking but do not reduce cravings for alcohol.

The new study found that treatments that manipulate both the GABA receptor and toll-like receptor 4 have the potential to reduce anxiety and control cravings, with little to no risk for addiction[.] . . .

GABA receptors are a class of receptors in the brain that react to the neurotransmitter GABA and act as inhibitory receptors, calming down or inhibiting the activity of neurons in the brain. GABA receptors react to alcohol, giving drinkers a calm and euphoric feeling and reinforcing excessive drinking behavior. . . . This is the first scientific study to document GABA receptors' key involvement in binge drinking specifically, though scientists already believed that the receptors had a role in excessive drinking in general. . . .

Science has traditionally considered TLR4 to be an innate immunity receptor involved with neuroinflammation in the brain. Scientists associated TLR4 with microglia, cells that support inflammatory responses in the brain. "What makes this finding particularly important for the field of neuroscience is that we're showing that TLR4 plays a significant role in neurons, specifically, the neurons that are connected to the GABA receptor," . . . . To establish the connection between the GABA receptors, TLR4 and alcohol, the scientists manipulated this pathway in the binge drinking rodents . . . [with] a herpes viral vector . . . to deliver a gene-modifying agent directly to the neurons in the brain, to target TLR4 and GABA receptors. The scientists found that when they artificially stimulated the GABA receptors and TLR4 in order to simulate the good feelings binge drinkers feel when drinking alcohol, the rats lost interest in alcohol for two weeks after the procedure.

Compounds exist that would stimulate the receptors in the same way the scientists did in the study. "It's very likely that, down the road, these compounds could become new therapies for binge drinking . . . These compounds would act like a substitute for alcohol, much like methadone acts as a substitute for heroin. They would help alcoholics stop drinking, giving them relief from their cravings and from the anxiety that they try to alleviate with drinking."

From here.

So, drugs to end a predisposition to binge drink may be on the horizon in our near future, and there is a methodological precedent for determining a cause and developing a treatment for other kinds of substance addictions.

Given the strong connection between alcoholism and other kinds of substance abuse, and a wide range of socially unacceptable behavior and crimes, the next question is whether these treatments promise a world in which those social ills are dramatically less of problem.

Also, if such drugs existed, what would it take to get binge drinkers to take it? Will drug testing for probationers cease to become a matter of seeing that they aren't taking illegal drugs and become a matter of confirming that they are taking drugs that treat their vulnerabilities?

Given the poor track record of science at observing ethical standards with vulnerable or institutionalized populations, there is also good reason to fear abuses along the same lines in the future.

There may also be an upside to the complexity of many polygenetic mental health traits. While it may take just a single disruption of one of thousands of genes that go into a health functioning brain, if dysfunctional processes are equally complex, a single way to disrupt that process may deal with problems that have a wide variety of causes. This seems to be the story of modern psychiatry. We have found drugs that can manipulate a handful of neurochemicals in the brain, but those drugs treat a large number of patients with neurochemical imbalances in the neurochemical systems that most commonly go awry.

Drugs that act on neurochemical receptors and reuptake channels seems to address a great many mental health conditions. This part of the brain seems particularly succeptable to treatment with drugs. There may be other parts of the brain that are equally important, perhaps miswired neurons, for example, but we don't understand how to treat them as well.

Epigenetic Link To Body Mass Index Found

First, cold viruses are implicated as playing a major role in obesity. Now, another study of 74 adults over the age of 57 years old, is finding that epigenetics ("changes in gene activity that do not involve mutations to DNA, but manage to survive through cell replication . . [and] govern gene expression") play an important role in obesity.

So, what is your epigenome again?

Though most of your epigenome is static and determined at birth, a small subset changes over time, and these changes are now being ascribed to environment factors and even behavior — whether you smoke, feel stressed or eat an unhealthy diet, for instance. Some scientists argue that epigenetic changes — the most common type is known as DNA methylation — can be passed onto future generations.

And, what exactly did the researchers find?

The team began by mapping 4.5 million areas of the human genome. Of the 4.5 million locations, researchers found that 227 were distinct between people — like an epigenetic fingerprint. Two-thirds of those distinct locations remained constant over time, but one-third changed over the course of the 11-year study. Feinberg attributes these changes to environmental and behavioral influences. . . . [S]ome of the genetic methylation that occurred over the course of the study — involving the expression of 13 genes — was in fact related to BMI.

Multiple observations:

1. All but one in 19,823 areas of the epiggenome studies were exactly the same in 74 different subjects. The part of a person's epigenome that differs from person to person could be described in a shorthand notation that would fit in a couple of text messages. Indeed, since there are far fewer than 40 different possible values at any distinct epigenome location studied, and it is likely that not all possible combinations may actually manifest themselves, one could probably devise a code that would describe a person's entire epigenome in a single text message.

2. The parts of the epigenome relevant to BMI are a small subset of the total variable portion of the epigenome studied. This could be described with a code about the length of the typical e-mail password.

3. It is possible to distinguish between epigenomic profiles that people are basically stuck with and can't change through behavior, and those that your environment can change.

4. From a potential medical perspective, changing someone's epigenome is probably easier than changing someone's genes.

5. This study is one more nail in the coffin of the conventional wisdom, common among physicians and other people who deal with obesity problemes professionally, that obesity is a simple product of how many calories you eat per day and how much you exercise.

6. Knowledge of the particular role played by the genes whose activity is epigenetically influenced in ways linked to BMI helps us understand the biochemistry of obesity and may suggest novel approaches to controlling obesity with drugs or diet.

7. Testing of BMI relevant epigenetic locations may make it possible to profile people's natural tendencies with regard to obesity and learn which approaches work best with different kinds of obesity.

8. It is possible that cold virus infections linked to obesity have a mechanism that changes someone's epigenome. Knowing the mechanism by which cold virus infections can lead to obesity would allow researchers to know which treatments would be or would not be likely to be effective.

Erowid

One handy reference source that I rediscovered this summer was the website Erowid, which is a non-profit, donor and grant supported reference site that covers all aspects of psychoactive materials. Not all of the information provided is simply a matter of scientific fact, although it does have the available scientific facts, but the statements available are largely compilations of the insights and opinions of others, so that people interested in knowing about psychoactive drugs, be they in law enforcement, experimenting users, or policy makers, can start from the same page in terms of what basic reference sources have said about the issues.

In addition to its more slowly updated reference oriented materials, the site also has mechanisms that allow for new user generated information to be quickly generated with the caveat that it is user generated information. Thus, it performs the public service of helping to identify, for example, potential outbreaks of problems in the unregulated illegal drug markets that could pose a public health risk.

It is a good first stop for anyone wanting to gather up basic information about a variety of psychoactive materials before getting sucked into a search routine that will obscure important voices in any part of the discussion.

Life Without Oxygen

Life with an alternative biochemistry based upon sulfer instead of oxygen has been identified in Antarctica.

Gamma Synthesis

Ordinary green plants turn ordinary light into an energy source for the plant using photosynthesis. Now, it turns out that some fungi can harness high energy gamma rays to help them grow using another process.

Born To Be Addicted?

Rat studies show that there may be a physical predisposition to cocaine addiction, characterized by a shortage of dopamine receptors. The abstract:

Stimulant addiction is often linked to excessive risk taking, sensation seeking, and impulsivity, but in ways that are poorly understood. We report here that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine (DA) function before drug exposure. Using positron emission tomography, we demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of DA release. These data demonstrate that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.

In other words, rats, and quite possibly people, becomce thrill seekers and addicts because it takes more to thrill them.

Brain's Fat Control Regulator Identified

The fat mouse lacks protein SH2B1.

Once again, it's good to be a mouse, if you get assigned to the right group, until they dissect you.

You probably know that dopamine plays a key role in your brain's pleasure centers, and that other chemicals in your brain, like melatonin and serotonin play a key role in governing brain functions like sleep and mood, respectively.

Now, it appears that a protein, with the unpronouncable name SH2B1, plays "a key role in the flurry of signals that govern fat storage, sugar use, energy balance and weight." Mice that lack the protein "become obese, diabetic, and unable to stop eating." Its roles includes allowing the brain to receive the "I'm full" signal that molecules leptin and insulin send to the brain.

Principal investigator Liangyou Rui, Ph.D., Postdoc Decheng Ren, Ph.D, and other investigators at the University of Michigan Medical School have published their latest research in the February issue of the Journal of Clinical Investigation. Early research was published in a 2005 edition of Cell Metabolism. The researchers, with University assistance, are seeking to bring the advance to the next level by using it to formula an anti-obesity treatment for humans.