Category Archives: biology

Reflected Glory: Axe Cop

So, you may be familiar with the opening of Nietzsche’s Also sprach Zarathustra, where he describes the three metamorphoses: spirit becomes camel, camel becomes lion (and slays dragon), and lion becomes child. I think that Nietzsche’s metaphor works really nicely in a lot of circumstances. I most strongly associate it with biology graduate training, but I think that similar reasoning probably applies in a lot of other fields.

In the early stages of education, through high school and college, and into the beginning of graduate school, the student is like the camel, who has to develop a strong back by learning to carry all of the received knowledge. Then, starting typically in grad school, you learn that all of the things that are in the textbooks you’ve been using are not strictly true. This is like the transformation into the lion, who has to slay the dragon covered with scales, where each scale has golden letters that read “Thou Shalt!” It is only after passing through these two stages that the third transformation occurs (maybe while you’re a postdoc?), where the lion becomes the child. The child is innocence and creativity, and it is this child who advances knowledge by possessing skills and knowledge, but no longer being beholden to them.

Now, one of the problems with the system is that not everyone makes it all the way through the transformations. Many scientists never fully shed the camel phase. They are quite skilled at the type of incremental research that NIH and NSF love to fund, and are often successful, but are excessively (IMHO) tied to the dogma and assumptions that define their discipline.

Other people get stuck in the lion phase. These are the compulsive paradigm shifters. They are Don Quixotes who spend their lives slaying imaginary windmill-dragons. In evolutionary biology this is the phenomenon responsible for the perennial “Darwin was WRONG!!” headlines.

That last step is really the hardest one. It requires us to recapture the innocence and creativity of childhood, but to wield it tempered with skill and knowledge. Unfortunately, the implementation of most science education is such that the camel and lion stages are coupled with a soul-crushing strangulation of the childlike curiosity that we are all born with.

So, what does this all have to do with Axe Cop? Axe Cop is a web comic (and now a book) written by a pair of brothers, Ethan and Malachai Nicolle. The twist? Ethan is 29 years old, and Malachai is 5. Ethan has clearly absorbed the illustrating and storytelling skills of the comic-book camel, and has slain the comic-book dragon. The comic itself is just bursting with a child-like creativity that is easy to recognize but difficult to produce. How do they do it? I suspect that Ethan was able to retain and/or recapture his creativity and innocence better than most, but the biggest thing is probably the co-authorship with Malachai, who has not yet entered the camel phase.

There is undoubtedly a lesson here about how to do great science, although I can’t quite figure out the mechanics. One possibility is this.

So, in the spirit of understanding Nietzsche, and biology graduate school, and education reform, and dragons, and ninjas, unicorns, avocados, vampires, dinosaurs, and robots, go read Axe Cop.

Also, it’s AWESOME!

Genomic Imprinting III: The Loudest Voice Prevails

So, it’s been a while since the last installment of the Primers on Imprinting feature, but they should be posted with greater regularity in the upcoming weeks. This time we’re going to introduce something that we will see again in future installments: small differences in selection lead to large differences in behavior.

Last time, we introduced the most widely discussed and most successful explanation of the evolutionary origins of genomic imprinting, the “kinship” or “conflict” theory. According to this theory, imprinted gene expression is a consequence of the fact that natural selection acts differently on alleles depending on their parent of origin. There are several ways to think about the origin of this differential selection, but we talked about it in terms of the framework that I find most intuitive: inclusive fitness.

As we also noted last time, even in the cases where the asymmetry in selection on maternally and paternally derived alleles is sufficiently large to drive the evolution of imprinted gene expression, the actual magnitude of this asymmetry is actually incredibly small. Why? Well, even for a allele with large effects on the survival and reproduction of related individuals, the dominant factor in the inclusive fitness of that allele is still going to be the survival and reproduction of the individual organism carrying that allele around.

But, the standard pattern observed with imprinted genes is that the allele-specific expression is all or nothing. For example, an allele might be expressed when it is inherited from a male, but completely silent when inherited from a female. So this small difference in the optimal expression levels of the maternally and paternally derived alleles leads to – in a way – the largest possible difference in the realized expression levels of the two alleles.

I like to think of this in terms of an analogy. Imagine that Pat and Chris share an office, and that they have a slight disagreement over the temperature they want the office at. Say Pat wants the office to be at 71 degrees (Fahrenheit), while Chris wants it to be 70. Each of them has control over a small space heater, and this is the only mechanism that they have for manipulating the temperature. [1]

What’s going to happen? Let’s say the temperature is 70 degrees. Pat will turn up his/her space heater until the temperature reaches 71. In response, Chris will turn his/her space heater down until the temperature comes down to 70. They will go back and forth like this until, eventually, Chris’s space heater is completely turned off. Pat will then turn his/her space heater up to get the room to 71. Then we’re done. Chris is unhappy about the temperature of the room, but no longer has any ability to make it any cooler.

Two things about this outcome. First, a small disagreement over the ideal temperature has led to a large divergence in the strategies: Chris’s space heater is all the way off, while Pat’s is on and doing all the work. Notice that the outcome would be exactly the same, in principle, if Chris’s ideal temperature were 70.9 degrees, or even 70.999 degrees. [2]

Second, Pat wins. This is a consequence of the fact that we are talking about space heaters, and that Pat prefers the higher temperature. If, instead of space heaters, Pat and Chris each had control of an air conditioner, Chris would be the winner. At equilibrium, Pat’s air conditioner would be all the way off, and the room would be at 70 degrees.

This is also the way it works with alleles at an imprinted locus. Let’s consider the case of a gene where increased expression results in increased prenatal growth. The inclusive fitness argument says that the optimal amount of this growth factor is higher for an allele when it is paternally inherited than when it is maternally inherited. Say this patrilineal optimum is 105 units, while the maternal optimum is 95 units.

If the gene is not imprinted we might expect it to produce about 100 units, with each allele producing 50. However, once the evolutionary dynamics of imprinting take over, the pattern of expression will evolve to one where alleles are transcriptionally silent when maternally inherited, but where a paternally expressed allele is making 105 units.

For a growth-suppressing gene, where increased expression actually reduces prenatal growth, we expect the opposite pattern, where alleles are silenced when paternally inherited, but are expressed when maternally inherited. This set of predictions – that imprinted growth enhancers will be paternally expressed, and imprinted growth suppressors will be maternally expressed – matches the empirically observed pattern by and large, although there are a few counterexamples that are not fully understood at the moment.

This pattern of allele silencing has been dubbed the “loudest voice prevails” principle. The phenotype evolves to the optimum of the allele favoring higher expression. Now, you can argue that this is the sort of thing that does not really need its own name. Fair enough. It’s really just saying that the evolutionarily stable state of the system is an edge solution. But, “loudest voice prevails” is sort of catchy, and has the advantage of reminding us which allele is expressed at equilibrium.

The Haig 1996 citation is the paper that introduces the phrase. The other three citations are papers published around the same time that use different mathematical frameworks to address the evolution of gene expression at an imprinted locus. Generically speaking, the answer is the one described here, although the Spencer, Feldman, and Clark paper identifies certain regimes in parameter space where apparently different results can be obtained. In a future post, we will delve into the differences in the assumptions and conclusions of different modeling frameworks as they have been applied to imprinting.

Now, what if you consider more than one imprinted gene? What if Pat and Chris each have a space heater and an air conditioner? We’ll talk about that next time.

Haig, D. (1996). Placental hormones, genomic imprinting, and maternal-fetal communication Journal of Evolutionary Biology, 9 (3), 357-380 DOI: 10.1046/j.1420-9101.1996.9030357.x

Mochizuki A, Takeda Y, & Iwasa Y (1996). The evolution of genomic imprinting. Genetics, 144 (3), 1283-95 PMID: 8913768

Haig, D. (1997). Parental antagonism, relatedness asymmetries, and genomic imprinting Proceedings of the Royal Society B: Biological Sciences, 264 (1388), 1657-1662 DOI: 10.1098/rspb.1997.0230

Spencer HG, Feldman MW, & Clark AG (1998). Genetic conflicts, multiple paternity and the evolution of genomic imprinting. Genetics, 148 (2), 893-904 PMID: 9504935


[1] Of course, in the real-life situation, we might assume that Pat and Chris would discuss the situation and come to some sort of agreement. This is a key difference between people interacting in strategic situations and genes evolving under natural selection. Alleles at a locus are like people sharing an office, where both of them are incredibly passive aggressive. If it helps, imagine that Pat and Chris won’t talk to each other.

[2] In practice, of course, there is going to be some minimum level of disagreement required in order to trigger this passive-aggressive escalation. In this analogy, the minimum level will be set by a combination of things such as the sensitivity of Pat and Chris to small changes in temperature, the precision with which the space heaters control the temperature of the room, and the extent to which they care about each other’s comfort. Similar reasoning holds in the case of genes, and we will address this in a future installment of the series, where we ask why there are any genes that are not imprinted.

The Genetical Book Review: Middlesex

So, welcome to the first installment of Lost in Transcription’s newest feature: The Genetical Book Review. For the maiden voyage, we’ll cover the 2002, Pulitzer-prize-winning Middlesex by Jeffrey Eugenides.

You’re surprised? Because you assume that an eight-year-old Pulitzer winner must already have been reviewed?

Fair enough. But, here’s the gimmick: we’ll use the genetics angle to talk about some things that have not already been covered extensively elsewhere.

First, though, the precis and value judgement. If you’ve not read the book, or read about it, it follows three generations of the Greek-American Stephanides family, who traipse through a slice of historical events in Smyrna and Detroit over the course of nearly a century. It’s sort of a Forrest Gump for the NPR set. Cal Stephanides and his relatives witness genocide at the hands of the Turks, emigrate to America, build cars for Henry Ford, and run booze during prohibition. They are present for the founding of the Nation of Islam and the 1967 Detroit race riots. They flee to the suburbs and watch Watergate unfold on the television.

As in Forrest Gump, some of the historical context feels a bit like pandering, an attempt to draw the reader in through nostalgia. On the other hand, many of the events are local enough to be only passingly familiar to most readers, so there’s learning to be had. More importantly, those events are always portrayed through the lens of how they shaped the trajectories of the characters in the book. And, they are charmingly and engagingly written, with a varied style that is pleasurable to read.

Basically, if your book group has not already read this book, and you’re sick of plodding stories about alcoholic mothers and victims of sexual abuse, but want something with some literary gravitas (so that you don’t lose social status by suggesting it to your book-group frenemies), this is the book for you!

There you have it. Hit the jump for the role of genetics in the book.

The book is written in a memoir style, told by Cal, who periodically takes on the persona of a chromosome being passed down, or an egg sitting in an ovary as s/he relates the events from previous generations. I say “s/he” because – and I’m not giving anything away here – the key twist to the coming-of-age story is that Cal is intersex, having ambiguous genitals as a result of a recessive, genetic 5-alpha-reductase deficiency.  For reasons reaching back to Smyrna, Cal’s condition is not identified at birth, and our protagonist is raised as a female, Calliope. It is not until puberty hits that Calliope discovers her condition and transforms into her male alter ego, Cal.

The 5-alpha-reductase gene encodes an enzyme that converts testosterone into dihydrotestosterone (DHT). In early development, testosterone is responsible for certain internal male reproductive structures, such as the vas deferens, while DHT is responsible for the external genitalia. Upon the onset of puberty, testosterone drives the male increase in muscle mass and deepening of voice, while DHT is responsible for the growth of facial hair. One of the reasons for the female-to-male switch that happens at puberty is that there are actually two different 5-alpha reductases. The type 2 enzyme is the one that is primarily responsible for DHT production, particularly in early development, and it is this enzyme that Cal lacks. The other one, the type 1 enzyme, is substantially upregulated at puberty, which results in an uptick in DHT production.

So, there are two things that combine at puberty to drive the sudden appearance of male characteristics: (1) Testosterone and DHT start sharing the load for creating external male-typical characteristics, and (2) a second pathway appears for the generation of DHT.

I have to say, as I have read about this disorder, I have been impressed with the depth of understanding that Eugenides seems to have brought to the novel.

[As a side note, this disorder was first identified in the remote village of Salinas in the Dominican Republic, where it occurred in about 2% of live births. Locally, these individuals are known as “guevedoces.” Whenever I have seen reference to the guevedoces, it is followed by the phrase “literally ‘penis at twelve.'” Actually, it turns out that ‘gueve’ is derived from ‘huevos,’ which is slang for ‘balls.’ Thus, a better translation might be “balls at twelve.” Although, if you’re going to precede your translation with “literally,” you would need to acknowledge that this slang for ‘balls’ is literally the word for ‘eggs.’ Of course, referring to the appearance of male sexual characteristics at the onset of puberty as “eggs at twelve” is just weird and confusing, because it sounds like something you would order at Denny’s, and because it is sort of the exact opposite of what is going on.]

Incest is one of the recurring themes in the book, which traces the paths through which Cal came to inherit two defective copies of the 5-alpha-reductase gene. This particular disorder is straight-up recessive, so if you have one functional copy of the gene, you develop normally.

Cal’s grandparents on his/her father’s side are brother and sister. They hailed from the same tiny village outside of Smyrna, were orphaned, and fell in love. Their immigration to America permitted them the opportunity to fabricate a non-consanguinous past. The interesting thing is that the inbreeding involving Cal’s grandparents bears absolutely no responsibility for Cal’s condition. Their son, Milt is unaffected, which means that he inherited one defective gene copy from one of his parents. It doesn’t actually matter whether the other parent carried a copy or not.
More specifically, what is required for the story is that Milt be a carrier, but not express the condition. If one of his parents is a carrier, the probability that he is a non-expressing carrier is 1/2. If both of his parents are carriers, the probability that he is a non-expressing carrier is 1/2. It will not have escaped your attention that 1/2 = 1/2.

There is a second case of inbreeding, however, that does contribute to Cal’s condition. Milt and his wife, Tessie, are second cousins, and each of them is heterozygous for the deficiency. Now, statistically speaking, the fact that Milt and Tessie are second cousins barely counts as incest. For a rare disorder such as 5-alpha-reductase deficiency, the elevation in risk due to a second-cousin marriage is small. How small? Let’s see.

Assume that the frequency of the defective version of the gene is q = 0.001, or one in a thousand. This is in the ballpark of what we might expect for a recessive mutation maintained at mutation-selection balance. The probability that an outbred individual inherits two defective copies is approximately q2, or one in a million. What if the mother and father are related? If their degree of relatedness is r, then the probability that their child will inherit two copies is:

         p = q (r/2q (1 – r/2))

What is this r thing? Well, if they are brother and sister, r = 1/2, so the probability p would be about 0.00025. For first cousins, r = 1/8, and p = 0.0000634. For second cousins, r = 1/32, and p = 0.0000166.

That is, for second cousins, the probability goes from one in a million to about one in 60,000. Basically, you will have a bigger impact by taking prenatal vitamins.

Diane Paul and Hamish Spencer published an interesting piece a couple of years ago about the history of the stigmatization of first-cousin marriage, particularly in the United States. They make a number of interesting points, and I recommend the article, which can be found here. It is short, fascinating, open access, and requires no background in genetics to follow.

One of the points they make is that there is pretty much no way to interpret a ban on first-cousin marriage as anything other than eugenics. And yet, somehow, this prohibition has managed to escape that label. Another of their points is that the genetic risks associated with first-cousin marriage are actually small compared with a lot of behaviors that are completely acceptable in our society, such as women having children over the age of 40, or the use of in vitro fertilization techniques. (That second one was not mentioned by them, but it’s true.) So, there is some inconsistency there, which they trace to nineteenth century misconceptions about heredity and prejudice against immigrants and the rural poor.

But, back to the book.

To recap, in terms of causal things leading to Cal’s genetic composition, the fact that his/her parents are second cousins matters. The fact that the grandparents are brother and sister does not. Why, then, does the story, much of which is driving towards Cal’s conception, spend so much more attention on the (genetically) irrelevant grandparental love story?

Obviously, I can’t speak to the author’s intention, but to me, having two separate incidents provides a nice, clean separation between the psychological and genetic consequences of incest. Cal’s grandmother is wracked with guilt about her transgression, and this guilt drives the story in several places. In fact, one of the motifs in the book is that action (or, often, lack of action) is often motivated by superstitious beliefs. –– Sorry about the vagueness here. I’m in spoiler-avoidance mode. –– Hypothetically speaking, let’s say one of the characters is eating toast, and then that character’s mother falls down and breaks her hip. The character would blame him/herself for eating toast and refuse to eat toast again for a long time. You get the idea.

Anyway, my point is that by having two separate incests, we are able to distinguish more clearly between the genetic consequences of consanguinity from the EWWWW consequences of knocking boots with your sister.

Paul, D., & Spencer, H. (2008). “It’s Ok, We’re Not Cousins by Blood”: The Cousin Marriage Controversy in Historical Perspective PLoS Biology, 6 (12) DOI: 10.1371/journal.pbio.0060320

Buy it now!!

What’s that? You say you want to buy this book? And you want to support Lost in Transcription at the same time? Well, for you, sir and/or madam, I present these links.

Buy Middlesex now through:


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The Cost of Christmas

So, if you haven’t already, you’ll probably soon receive the credit card bill with all of your Christmas purchases on it. Was it worth it? Well, was it, punk?

If you’re like most people, some of your presents were probably intended to impress someone. The question is, what’s the best kind of present for that? Should I give the girl from math class diamond earrings, or new batteries for her calculator? Should I give my boss a mug, or a gift certificate to Glamour Shots?

Fortunately, Science!™ has the answer. Today’s journal club entry concerns a model of gift-giving that considers three different types of gift that differ in their cost to the giver and their value to the recipient. “Cheap” gifts are, well, cheap. “Valuable” gifts are expensive to give, and have value to the recipient. The interesting category is the third one, the “extravagant” gifts, which are expensive to give, but have little inherent value to the recipient.

The specific context is gift-giving and mating. The model is of a sequential game with three or four stages. First, the male offers a gift to the female. Second, the female either accepts or rejects the gift. Third, she chooses whether or not to mate with the male. Then, in one version of the game, the male decides whether or not to stick around and contribute to the care of the offspring.

This $305 luxury frisbee is an example of an extravagant gift.

The conclusion of the paper is that there are many combinations of parameter values that will lead to males giving extravagant gifts. There are two critical features of the model that seem to be necessary in order to get this result.

First, there is uncertainty. The female has a guess about the quality of the male (or, equivalently, in the version of the model with paternal care, the probability that he will stick around after mating). By accepting the gift, she gains additional information about his quality or intentions. Similarly, the male is uncertain about the quality and intentions of the female – whether it is worth it for him to stick around after mating, and whether or not she is a gold-digger, who will just take his gift and skip town with his cousin.

[Editorial note: the term “gold-digger” is from the paper. Those of you who know me know me know that I would never have gone with such a politically incorrect term. I would have used “■■■■■■■■■■”.]

[[Meta-editorial note: parts of the previous editorial note have been redacted.]]

The other key feature is that there must be some cost to the female in accepting the gift.

Now, there are lots of parameters in a model like this, and several equilibrium solutions are possible. The interesting one is the one where males give cheap gifts to unattractive females (females whom they judge, with some uncertainty, to be of low quality), and give extravagant gifts to attractive females.

The key to getting the interesting equilibrium is that the ability or willingness to provide and extravagant gift has to correlate with the male’s quality or intentions. For example, a male can’t afford to spend two-months salary on a diamond ring every time he wants to have a one-night stand. Therefore, an extravagant engagement ring becomes a reliable indicator of his intentions. Ideally, the gift has to have no inherent value to the female, for example, if it were impossible to sell the engagement ring for cash money. Recall also that it has to cost her something to accept the gift. Then, taking the gift constitutes a commitment on her part as well. Otherwise, she benefits most from accepting the gift and walking away.

In the salacious application-to-human-mating case, this cost to the female is easiest to envision as a reputation cost (e.g., the risk of being labeled as a ■■■■■■■■■■). In certain species, where females mate with multiple males, store the sperm, and then use it selectively, there may be direct opportunity costs that do not require catty moralizing.

Just one last point.

The paper starts with, “Gift-giving is a feature of human courtship”. The authors cite Geoffrey Miller’s 2000 book, The Mating Mind. If the paper were being written today, I assume they would have cited more recent work by Hefner and Harris.

Sozou, P., & Seymour, R. (2005). Costly but worthless gifts facilitate courtship Proceedings of the Royal Society B: Biological Sciences, 272 (1575), 1877-1884 DOI: 10.1098/rspb.2005.3152

The Distribution of Dominance

So, as you have no doubt surmised from the title of this post, the cash-strapped Republican Party is going to start using their abundant frequent “flyer” points to pay their debts.

I’m kidding, of course. The GOP doesn’t pay its debts!

Actually, we’re going to talk about a paper just out in Genetics by Aneil Agarwal and Michael Whitlock. They provide a very thorough analysis of data on the fitness effects of homozygous and heterozygous gene deletions in yeast.

But let’s back up for a minute first.

The authors are interested in understanding the distribution of dominance, in the population-genetic sense. Traditionally, the dominance is represented by h, and the strength of selection by s. Usually, we define the fitness of the wild-type (hypothetically not carrying any mutations) as 1. Then, we consider the fitness effect of a mutation in a particular gene. In this case, we’re going to focus on deleterious, or harmful mutations, which reduce fitness. If an individual carries two copies of the deleterious mutation, they have a fitness of 1-s, so that small values of s mean weak selection, and large values of s mean strong selection. The dominance refers to the relative fitness of an individual carrying only one copy of the deleterious mutation. This heterozygous fitness is 1-hs. If h equals 1, the deleterious mutation is completely dominant, meaning that having one copy of it is just as bad as having two. If h equals 0, the deleterious mutation is completely recessive, and having one defective copy of the gene is just as good as having two functional copies.

So, what is a typical value of h? Does it depend on s? How much does it vary from gene to gene? The conventional wisdom is that most deleterious mutations are recessive. This is why you should not have children with close relatives. I carry a bunch of recessive mutations, as does my wife. As long as we have different ones, our son inherits a bunch of mutations – but only one copy of each – so they’re recessive in him as well. If we were closely related, we would carry many of the same mutations, and there would be a decent chance that our son would inherit two defective copies of the same gene, which could have various health consequences.

Charles Darwin and his first cousin Emma Wedgwood were married in 1839. 170 years later, they were portrayed by real-life-non-first-cousin couple Paul Bettany and Jennifer Connelly (not pictured).

However, population geneticists don’t care about things like this just because of the implications for human disease. Dominance has a major impact on the eventual fates of individual mutations, and can influence other evolutionary processes, like speciation. Often, in order to model some other process, we have to make some sort of assumption about the distribution of fitness effects of mutations. Traditionally, a researcher would pull this distribution out of his or her asc. This is one of the biggest contributions that this paper will make to the field. It provides a nice, empirically based distribution of dominance effects that can feed into other evolutionary studies.

The results also confirmed (with much greater confidence than was previously the case) the relationship between h and s which had been suggested by some previous studies. They find that larger values of s tend to go with smaller values of h. Consistent with the conventional wisdom about not marrying your cousin, strongly deleterious genes tend to be pretty recessive. More surprisingly, most mildly deleterious mutations had fairly high h values. In fact, the mean value of h over all deleterious mutations was 0.8 – quite dominant. However, when the average is weighted by the fitness effect s, it drops to 0.2.

The authors also point out that this negative relationship between h and s has implications for the evolution of dominance. This pattern is most consistent with theories in which dominance is shaped by indirect selection. For example, deleterious mutations might be recessive if the protein produced by the gene were selected for overexpression to enhance a metabolic pathway, or to buffer the performance of that pathway in certain environments. Then, loss of one copy of the gene encoding that protein might not have a major effect on function (half of too much being still enough). Alternatively, recessiveness could come from feedback mechanisms that upregulate the functional copy of the gene when not enough of the gene product is being made.

The point is that in either of these cases (among others), recessiveness is driven by selection to maintain the function of the gene. The more important the gene is (the larger the value of s associated with it), the stronger this selection will be, and the more recessive deleterious mutations will become. Therefore, mechanisms like these predict the observed negative relationship between h and s.

On a historical note, this type of buffering process was proposed by one of the giants of population genetics, J. B. S. Haldane way back in 1930. Haldane passed away on December 1, 1964.

R. I. P., J. B. S.

Agrawal, A., & Whitlock, M. (2010). Inferences About the Distribution of Dominance Drawn from Yeast Gene Knockout Data Genetics DOI: 10.1534/genetics.110.124560

Concerning a Way for the Prolongation of Humane Life

So, Deare Readers of this Blogue, I hope that you will indulge me in reporting on an Interesting Idea published by the Royal Society in their Philosophical Transactions. I hope, Deare Reader, that you may also see fit to join me in Lauding said Society for having made their entyre back catalogue freely available to the publick this Month of November.

The Publication in Question, titled An Extract of a Letter Written by Monsieur de Martel of Montauban to the Publisher, Concerning a Way for the Prolongation of Humane Life, together with Some Observations Made in the Southern Parts of France, English’d as Follows, contains the author’s reflections on the Causes of the Debilitation of Nature’s strength in the course of man’s life, and how these Causes might be Ameliorated, leading, naturally, to a means of achieving Eternal Youth through Medical Science.

The author agrees with the illustrious Messrs. Bacon and Sanctorius that the extinction of the natural heat and dessication of the Radical humour, as previously understood by Philosophers, seem not sufficient explanation for the causes of Age. However, Monsieur de Martel disagrees with Sanctorius’s assertion that “the Fibres do dry up, that they can no more be renew’d,” noting that even old Oxen have at certain times more or less marrow (though not, he is quick to point out, owing to the cycles of the moon).

Blood, claims Monsieur de Martel, is the Principle of Life, but notes that a Man typically has no Shortage of Blood when he dies. What causes this man to age, then, is that the Veins and Arteries which inclose the Blood, much like the Chymists Furnace, develop apertures, which, being insufficiently repair’d, do ease the dissipation of the igneous particles, such that they abandon the Blood. He reasons, then

 As in Stuffs and Cloth (whose woof is in manner like that of the Tunicles) the Threds by wearing do loosen and break, insomuch that many holes are made in it as in a Sieve. So that, if we had the Art to reinforce and to strengthen anew those Coats and Membranes, that they might not let slip what maketh the blood vital, the life would be preserved perpetually. . . . There is no reason to despair of finding out such Medicins, or Ailments, as are proper to strengthen the Coats and Membranes of the Vessels, so that they may at all times retain the fiery and spirituous corpuscules of the blood, as well as in the time of Youth.

The author also reports on the method of making Muscadin Wine in Frontignac.

For those wishing further to pursue Monsieur de Martel’s ideas on the Acquisition of Eternal Youth through preservation of the blood’s vital igneous particles, or those wishing to instruct their Slaves on how best to produce a nice Muscadin, the citation information is:

de Martel, M. (1670). An Extract of a Letter Written by Monsieur de Martel of Montauban to the Publisher, Concerning a Way for the Prolongation of Humane Life, together with Some Observations Made in the Southern Parts of France, English’d as Follows Philosophical Transactions of the Royal Society of London, 5 (57-68), 1179-1184 DOI: 10.1098/rstl.1670.0020

Irony Alert: Marc Hauser on moral judgments

So, PNAS has just published a brief exchange on the nature of moral judgments, including a letter where one of the coauthors is the man who put the a** in a**ertainment bias.

Marc Hauser is a Professor in the Psychology Department at Harvard. He made a name for himself publishing a variety of behavioral and cognitive studies on both humans and non-human primates, with the goal of understanding the evolutionary origins of human cognition, including complex traits such as language, economic decision-making, and moral judgments. More recently, he has made a name for himself by allegedly falsifying data and allegedly bullying the people in his lab who naively thought that the data published by the group should be . . . I don’t know . . . NOT falsified. I won’t repeat what this more recent name that he’s made for himself is, as it would violate the norms of internet civility. Over his career, Hauser has published something like 200 articles and 6 books, many of which probably contain certain things that are not entirely false. At the moment, he is on leave from Harvard, following an investigation’s finding him solely responsible for 8 counts of scientific misconduct. Presumably, he is working on his next book, allegedly titled Evilicious: Explaining Our Evolved Taste for Being Bad.

Snarking aside, the two letters that were just published follow from an interesting article published in PNAS earlier this year, where Hauser is the third of four co-authors. For those not familiar with authorship conventions in biology and related fields, here is what is typically implied by the order of authorship on a four-author paper. The first author probably did all of the experiments. The second author helped with some of the experiments, and/or some of the data analysis. The third author probably didn’t directly participate, but contributed ideas and/or reagents and/or equipment. The last author probably runs the lab where the experiments were done. In fact, the other three authors are all at the other Cambridge, in England, where the experiments were actually done. I point all this out just because I don’t want to leave the impression that we should be suspect of the results in the paper just because Hauser’s name is on it.

The original paper, which can be found and freely downloaded here, tests the effect of enhancing serotonin activity on a variety of tasks or decisions, some of which had a moral flavor. Serotonin enhancement was achieved by giving some of the subjects the drug citalopram, which is a selective serotonin reuptake inhibitor (SSRI), like Prozac or Zoloft. The finding was that enhancing serotonin made subjects less willing to take an action that required them to inflict harm on another individual in an emotionally salient context.

This work fits in with a substantial literature on moral dilemmas. I’ll just briefly outline the gist of that literature here in the context of one particular dilemma that often makes an appearance in these studies. The scenario is this: there are five people tied to a train track, and there is a train rushing towards them. You have the opportunity to save them, by stopping the train or switching it to a different track, but the only way to do it involves killing one person. What do you do?

Most people find that they have two conflicting impulses. On the one hand, killing one person to save five makes sense from a utilitarian perspective. That’s four fewer dead people. On the other hand, you are the one who has to kill the one person, and most people feel a moral repulsion to killing someone, even if it is for the greater good.

In these studies, which of the two impulses seems to win depends on how personal the killing is. If all you have to do is pull a switch, and the train will go on another track, which, for unknown reasons, has one person tied to it, the killing is fairly impersonal, and many people will choose this utilitarian, four-fewer-dead-people option. On the other hand, if the only way to stop the train is to chop off someone’s head and throw it through a magical basketball net woven of human entrails (I’m making this up), many people will find this too emotionally and morally problematic, and will let the train go on its merry five-corpse-making way. Researchers have mapped out a whole continuum between these two extremes: pushing someone off a bridge with your hands is more emotionally salient (and therefore less morally acceptable) than pushing someone off a bridge with a stick, and so forth.

What the original paper finds is that giving someone an SSRI does not have much effect on decisions that are morally neutral, or where the harm that must be inflicted is impersonal (like throwing a switch to divert the train). However, in cases where one decision would require the subject to harm someone in a personal and emotionally salient way (like pushing them off the bridge with their bare hands), the SSRI seems to enhance the emotional/moral aversion to taking that action.

So, in addition to nausea, insomnia, and diarrhea, add to the list of possible side effects of antidepressants: “may reduce willingness to harm others in emotionally charged situations.” Maybe Charlie Sheen should be on one of these.

The letters commenting on the original paper can be found here and here, but require a subscription to PNAS to access. I wouldn’t go to great lengths to get them, however. There is some quibbling about terminology – driven more by a commentary on the original article than by the article itself – and some tiresome academic “Get off my lawn!” moments, but probably nothing of interest to most of the reader(s) of this blog.

Crockett MJ, Clark L, Hauser MD, & Robbins TW (2010). Serotonin selectively influences moral judgment and behavior through effects on harm aversion. Proceedings of the National Academy of Sciences of the United States of America, 107 (40), 17433-8 PMID: 20876101

Neural compensation and autism

So, a study just published in the Proceedings of the National Academy of Sciences uses fMRI to compare the neural response to biological motion in three groups of subjects: people with autism, unaffected siblings of people with autism, and a control group, who have neither autism nor family members with autism. This is a fairly standard sort of thing to do when people study disorders that, like autism, have high heritability, and therefore presumably a significant genetic component. There were some interesting findings in this paper, though, that make it stand out. In particular, the authors identify a set of brain regions that show elevated activity specifically in the group of unaffected siblings, and call these “compensatory” regions.

The idea is this. People with autism have a set of genetic variants that give them a predisposition for developing autism. Straightforward, right? Presumably, the siblings of people with autism carry many of these same genetic variants, but there is some reason why they don’t develop the disorder. Of course, one possibility is that they do not, in fact, carry the autism-causing genetic variants. Another possibility, raised by this paper, is that they do have genes that predispose them to autism, but that some compensatory mechanism has maintained normal neural development in the face of this genetic predisposition. This compensation could be developmental – in that some sort of canalization mechanism sets in when it somehow senses that brain development is going off track. Or, it could be genetic, in that the unaffected siblings also possess genetic variants (presumably at other genetic loci) that shift them back towards normal development.

Here’s Figure 3 from the paper. The top panel shows the “state” regions. Those are brain regions that show differential activation in the autism group (reduced activity in response to viewing biological motion). The middle panel shows the “trait” regions, which are the regions with reduced activity in both the autism group and the group of unaffected siblings. The bottom panel shows the “compensatory” regions, which show elevated activity specifically in the group of unaffected siblings.

The brain regions identified as “state” regions are those that are typically identified as regions of reduced activity in autism – a nice validation. The two “compensatory” regions are the right posterior superior temporal sulcus (pSTS) and ventromedial prefrontal cortex (vmPFC). Both of these regions have been associated with social perception and cognition. Note that both of these regions also appear in the “state” category.

So what does that mean? Well, that means that there are certain regions within these two structures that show reduced activity in cases of autism. There are other regions within the same two structures that are not impaired in autism, but show enhanced activity in unaffected siblings.

Like much of the most interesting science, this paper raises more questions than it answers, and there are many conceivable explanations of these patterns. The results suggest a number of interesting avenues for future research, however.

The paper can be found here. It is an open-access article, so you don’t need a subscription to PNAS to get it.

Update: Full citation

Kaiser MD, Hudac CM, Shultz S, Lee SM, Cheung C, Berken AM, Deen B, Pitskel NB, Sugrue DR, Voos AC, Saulnier CA, Ventola P, Wolf JM, Klin A, Vander Wyk BC, & Pelphrey KA (2010). Neural signatures of autism. Proceedings of the National Academy of Sciences of the United States of America PMID: 21078973

Snake parthenogenesis III: The final chapter

So, I really had no intention of doing three separate posts on virgin birth in snakes, and I sincerely hope – for your sake as well as mine – that this finishes off the topic for the time being. In the first installment, we talked about this Boa constrictor that had given parthenogenetic birth to 22 babies, and some of the interesting genetics raised by that observation. In the second installment, we noted some species that undergo paternal genome exclusion, which seems like a similar phenomenon.

I was then pointed toward the case of the whip-tail lizard in a note from John Wilkins, who not only has an AWESOME name, but also runs possibly the best blog out there on philosophy and evolution. If you’re not already reading his blog, I highly recommend it.

The phenomenon of non-virgin virgin birth may not be all that rare or unexpected among herps (amphibians and reptiles). For example, in the case of the whip-tail lizards, some species consist only of females, all of whom reproduce parthenogenetically. The interesting thing is that mating is required in order to trigger this parthenogenetic developmental process. So, how does that work, if there are no males? What happens is that these females will mate with males of another species, and it is likely that the diploid, parthenogenetic egg starts developing only when it receives a biochemical signal that depends on physical contact with the sperm.

I spoke about this with Andrew Singson, who studies cell-cell interactions, particularly between gametes. He noted that the requirement for physical stimulation of the egg by sperm is actually quite widespread. In many birds, for example, polyspermy, where more than one sperm interacts with the egg, is required. Only one of these sperm fuses with the egg and contributes genetic material to the offspring. However, that single sperm may not provide enough of a signal to flip the egg’s developmental switch. Before the process of embryonic development can start, many other sperm have to physically interact with the egg in a sort of wing-man role. Opportunities for analogy abound, but fortunately – for your sake as well as mine – other demands prohibit me from plumbing their depths at the moment.

Snake parthenogenesis II: Non-virgin virgin birth

So, in the last post, we went through some of the strange and interesting things associated with the Boa constrictor that gave parthenogenetic birth to 22 baby Boas. It turns out there’s yet another crazy thing going on here. Etymologically speaking, parthenogenesis means “virgin birth.” It is a combination of parthenos (παρθένος), meaning “virgin,” like the parthenon, and genesis (γένεσις), meaning, well, genesis.

The thing is, though, while it seems clear that the baby Boas’ genetic material comes entirely from the mother, she’s likely not really a virgin. I don’t mean that she’s a born-again virgin who had some had some wild times back in snake college, repented, then ran for Senate. Instead, it appears that she only gave birth after being housed with a male snake. Of course, it’s only two litters, so it could well be a coincidence. On the other hand, it could be that fertilization was required to initiate development of the diploid eggs produced by the female.

There is a somewhat related phenomenon of paternal genome loss that has been identified in several different species of creepy crawlies, including at least some species of Phytoseiid mites (click here for non-English text, but drawings of them preying on other mite species), scale insects, and sciarid flies. Typically, paternal genome exclusion is limited to males, which start of diploid, but then lose their paternally inherited genome at some point during development, often living much of their lives in a haploid state. These and related phenomena are nicely covered in chapter 10 of Genes in Conflict by Austin Burt and Robert Trivers. Of course, the difference here is that the snakes have two full maternal genomes. Also, we don’t really know if they received, and then jettisoned paternal genes, or never got them in the first place.

It also bears some similarities to one of the mechanisms by which uniparental disomies arise in humans (among others). Normally, meiosis results in one copy of each chromosome going into each gamete. With some frequency, though, they don’t sort out correctly, and two aneuploid gametes wind up being produced, one with an extra copy of one chromosome, and one that is missing that chromosome altogether. If one of these gametes winds up contributing to the offspring, that offspring may wind up missing one copy of a chromosome (e.g., the X chromosome in Turner’s syndrome), or with an extra copy of a chromosome (e.g., the X chromosome in Kleinfelter’s syndrome, or chromosome 21 in Down syndrome). Another possible outcome for the extra chromosome case is “trisomy rescue,” where the zygote somehow recognizes the presence of the extra chromosome and kicks out one of the three copies.

There are a couple of different ways that this trisomy rescue can happen. Let’s say the extra chromosome came in with the egg. If one of the two maternal copies is kicked out, you wind up back at the standard diploid genome. On the other hand, if the paternal copy gets kicked out, you have the standard number of chromosomes, but a uniparental disomy. If the chromosome contains one or more imprinted genes, this can have various developmental consequences.

So, one possibility is that this female snake, for whatever reason, produces diploid eggs. Fertilization triggers development, but then a triploid rescue mechanism kicks in. The key thing is that it would need to be kicking in before fusion of the maternal and paternal pronuclei, since it seems to be the paternal genome that goes missing in every case.

Or this could all be related to the fact that the males snakes housed with this female in 2009 and 2010 were all huge General Ripper fans.

Update: One more follow-up post here.