Not so Studly?

In an interesting article available in Biology Letters; Alastair J. Wilson and Andrew Rambaut apply evilutionary biology to the question of whether race horse studs are worth the money. Racehorses from prized bloodlines can command stud fees upwards of hundreds of thousands of dollars, but according to Wilson and Rambaut, stud fee is a poor predictor of offspring performance.

Using techniques developed in evilutionary biology to answer questions regarding sexual selection and quantitative genetics, Wilson and Rambaut, "test whether there is genetic variation for success on the racecourse by analysing data on lifetime prize money earnings [and] ask whether stud fees are a useful indicator of a stallion’s genetic quality and hence its offspring’s prize-winning potential."

Unfortunately for breeders, parentage only accounts for 10% of the variation in lifetime earnings.

Dr. Wilson says, "The offspring of expensive stallions might tend to win more money, but not necessarily because they have inherited the best genes.

"It is likely that those breeders best able to pay high stud fees are also those who are able to spend more on care of the horse, how it is trained, and who rides it -- all of which will contribute more to how much it will win.''

Of course, given the competitiveness of horse racing, this probably will not deter studs from commanding high fees because people with money will spend it for any advantage no matter how small.

Photo: Secretariat winning the Preakness.

This Week's Citation Classic

I am a little late with the post, but there's been a perfect storm of conflicting obligations. Without further ado, here is this week's citation classic:

Lenski, R. E., M. R. Rose, S. C. Simpson, and S. C. Tadler. 1991. Long-term experimental evolution in Escherichia coli. I. Adaptation and divergence during 2,000 generations. American Naturalist138:1315-1341.

The field of experimental evolution is a surging one; many scientists have seen that they can observe the process of evolution in real time using microbes and other model organisms. Jacques Monod's aphorism, "anything that is true of E. coli must be true of elephants, except more so", can be extended to say that evolutionary processes are the same for E. coli as they are for elephants.

Lenski et al. recognised this and initiated one of the longest experiments in evolutionary biology history. At the time of publication, 12 populations initiated from a single E. coli ancestral strain had undergone 2,000 generations of evolution and adaptation. ~20 years later, the group is up to 40,000+ generations. The initial environment was a poor one, a restricted diet of glucose, but the beasties have responded to this challenge vigorously, and because Lenski and team have saved individuals from various times during the experiment, the process of adaptive evolution can be traced via this "frozen fossil record".

Lenski et al.'s experiments have proved to be enormously informative, have generated 40+ publications and have launched the careers of numberous graduate students and postdocs. Indeed an entire Gordon Conference is devoted to the subspecialty, Microbial Population Biology, and a substantial number of attendees are Lenski's intellectual descendants.

On a personal note, when I was in graduate school, my mentor suggested that I model my career after a successful scientist. "Who?", I asked. "How about Rich Lenski?" I then downloaded all of Lenski's papers and read, for the first time, about the fascinating series of experiments that began with the present classic. Inspired, I soon dropped my researches into the population biology of mosquitoes (well I was looking for justification to do so anyway ;) and dived into the field of experimental evolution. When it came time to seek out postdoctoral mentors, I queried Dr. Lenski, but unfortunately his lab lacked funding for a postdoc. He did, however, suggest his former grad student, Dr. Paul Turner, whom I began working for in 2003. And the rest is history...

Carl Zimmer wrote about the experiments for the Science Times here. Another interesting article is available from Science. A website dedicated the the long-term evolution experiment is available here. And Rich Lenski's lab page is here.

Photo of Rich Lenski courtesy of Bruce Fox, MSU.

Nobel Week

Nobel Week is coming to a close. This year's highlight was Al Gore's Nobel Lecture on the dangers of global climate change. Gore says, "We are what is wrong, and we must make it right."

Gore states unequivocally that CO2 is pollution, and the consequences of its accumulation are devastating.

"Last September 21, as the Northern Hemisphere tilted away from the sun, scientists reported with unprecedented distress that the North Polar ice cap is "falling off a cliff." One study estimated that it could be completely gone during summer in less than 22 years. Another new study, to be presented by U.S. Navy researchers later this week, warns it could happen in as little as 7 years.

Seven years from now.

In the last few months, it has been harder and harder to misinterpret the signs that our world is spinning out of kilter. Major cities in North and South America, Asia and Australia are nearly out of water due to massive droughts and melting glaciers. Desperate farmers are losing their livelihoods. Peoples in the frozen Arctic and on low-lying Pacific islands are planning evacuations of places they have long called home. Unprecedented wildfires have forced a half million people from their homes in one country and caused a national emergency that almost brought down the government in another. Climate refugees have migrated into areas already inhabited by people with different cultures, religions, and traditions, increasing the potential for conflict. Stronger storms in the Pacific and Atlantic have threatened whole cities. Millions have been displaced by massive flooding in South Asia, Mexico, and 18 countries in Africa. As temperature extremes have increased, tens of thousands have lost their lives. We are recklessly burning and clearing our forests and driving more and more species into extinction. The very web of life on which we depend is being ripped and frayed."

He singles out, USA and China for action: "But the outcome will be decisively influenced by two nations that are now failing to do enough: the United States and China. [I]t should be absolutely clear that it is the two largest CO2 emitters – most of all, my own country – that will need to make the boldest moves, or stand accountable before history for their failure to act."

Quoting Henrik Isben, Gore says, ""One of these days, the younger generation will come knocking at my door."

They will ask either, ""What were you thinking; why didn't you act? "Or they will ask instead: "How did you find the moral courage to rise and successfully resolve a crisis that so many said was impossible to solve?"

When the next generation knocks on your door, what are you going to say?

The full text is available here.

Photo: Scanpix/Tom Hevezi

Venter Interview in SD Union Tribune

There's an interesting interview with Craig Venter in the San Diego Union Tribune. In the interview, the sequencing maven reflects on being a scientist. There's a lot of things about Venter that I didn't know, such as his having served as a medic in Vietnam.

Venter writes, "I was feeling lucky, that I had escaped with my life. I had seen so much death, 19-and 20-year-old boys maimed and killed, that I felt I had been given a second chance to do something with my life."

Perhaps this is why he has little patience for roadblocks and is often described as a "maverick".

Venter is, of course, one of two humans to have their entire genome sequenced (Jim Watson is the other). Celera Genomic's race with the National Human Genome Research Institute is the stuff of legend. Venter's company sequenced the genome for far less money than the government, and accomplished it in approximately the same amount of time.

However, Venter seems disappointed with the progress made since the human genome was published.

"I think it's because we're dealing with humans, and that paralyzes things. The government, which has the deepest resources, is increasingly unwilling to fund research if it involves human genetics. Government research is becoming irrelevant. Instead, the work is being left to private groups who have less money and maybe conflicting agendas."

Venter also expressed disappointment with the state of science in America when questioned about the anti-evolution stances of some presidential candidates (Brownback, Huckabee, Tancredo) and reports of another (Kucinich) to have seen a UFO.

"I saw those debates. It's a disturbing phenomenon. People simply aren't making decisions based on evidence. I don't object to people believing in God, but our thinking has to adjust to new facts and discoveries about the universe. We're past the age of Galileo. As a modern society, we are now 100 percent dependent upon science. It's not optional."

It's a sobering interview. Venter sees that "We're at a critical juncture in human existence. I just hope we haven't screwed things up so much that there's no real chance for the future."

I agree. The evidence is out there. Do we have the courage to take off the blinders and see the world as it really is?

Hat tip to Moselio Schaechter.

This Week's Citation Classic

Brenner S. 1974. The genetics of Caenorhabditis elegans. Genetics 77: 71-94.

Sidney Brenner is one of the founding fathers of molecular biology, having identified mRNA and the nature of the triplet code. Brenner, like other far-sighted scientists, felt that mo-bio was pretty played out by the late '60s and early '70s. Benzer switched to fruit fly behavior. Crick decided to study consciousness. Brenner decided to focus on behavior and development. In his Nobel speech, Brenner stated, "choosing the right organism for one’s research is as important as finding the right problems to work on."

Brenner certainly benefited from bacteriophage, the organism of choice for many molecular biologists, but he was drawn in that direction by Delbruck and the Phage Group. This time, now a mature scientist in his own right, Brenner had a chance to select an organism of his own. He chose wisely: Caenorhbabditis elegans. C. elegans is an ~1mm long bacteriophagous soil nematode. Large populations can be maintained in the laboratory on bacteria cultured on agar, and they have the added advantage of being almost entirely transparent (a huge benefit for neuronal studies).

Brenner's classic 1974 paper asked “How genes might specify the complex structures found in higher organisms?", a major problem in biology today as well as then. Brenner's approach was to link genetics with detailed studies at the cellular level, and introduced C. elegans as the worm of choice for this work.

As Brenner wrote, “Behaviour is the result of a complex ill-understood set of computations performed by nervous systems and it seems essential to decompose the question into two: one concerned with the question of the genetic specification of nervous systems and the other with the way nervous systems work to produce behaviour.”

Thus Brenner launched a two-pronged effort to map the genetics and complete structure of the worm. This effort succeeded marvelously. Today we have unprecedented knowledge of this humble beastie. The developmental fate of each of the worm's 959 cells has been determined. The patterns of connectivity for each of its 302 neurons has been completely mapped. Its entire genome has been sequenced (the first multicellular eukaryote to be sequenced).

Brenner's choice of study organism was enormously influential. I don't think there are many full-fledged biology departments around the country that don't have at least one "worm person". Brenner has produced an amazing legacy.

Some last thoughts...
I am still, at the age of 76, excited by scientific research and the prospect of what can be done in biology. Science is something one is tied to for life and one should never retire from anything until one has secured one's next job. The endless quest for knowledge will continue as long as humans exist.

Brenner won the Nobel Prize in 2002 for his contributions; his speech was wonderful and can be accessed here (video and text). Brenner wrote an autobiography here. Visit the Brenner lab here. The Worm Nation maintains a web presence here.

Image: C. elegans neurons expressing green fluorescent protein.

Book Review: The Body Has a Mind of Its Own

Body maps are areas of the brain that represent all areas of your body inside and out. Most of us recall the goofy pictures of homunculi, the distorted figures that represent the relative space our body parts occupy in the somatosensory cortex. Because sensory schemata of the hands and face occupy relatively large areas of our cortex, they are overrepresented in the physical map.

In The Body Has a Mind of Its Own mother-son science writing team Sandra and Matthew Blakeslee write about these and other body maps as revealed by cutting edge neuroscience. My first impression on reading was that neuroscience and, by extension, the authors were overselling body maps and their implications. But after reading a few chapters, I was impressed.
While the authors freely admit, "certain details and caveats that a specialist would consider vital have been condensed, glossed over, or shoehorned into metaphors", their ability to summarize the complex and confusing field of neuroscience is admirable. Granted much of the information is highly speculative, but as an introduction to the field of body maps, I found the book highly informative and entertaining. The take home message is that body maps and the brain are far more plastic than most of us are aware of.

Some of the best topics include:

Can sports players improve their "games" by mental means alone?
How do body maps figure into eating disorders?
What causes phantom limbs?
Can you fool your body into regaining body areas lost to strokes?
What are the "yips"?
Why do video game players move their bodies to the action on the screen?
What happens when you have an "out of body" experience?
Can inanimate objects become part of your "body"?

The book contains many interesting anecdotes, such as:

“Carter” was a master chef at a well-known New York restaurant when, in late 1994, a blood clot in his brain almost cost him his livelihood. Rushed to the hospital in time to receive state-of-the-art clot dissolving care, Carter was left with a potentially devastating problem: He could no longer recognize fruits and vegetables. He couldn’t tell a banana from a leek, though he could still tell a bread knife from a butcher knife and a hawk from a handsaw. He could use English fluently, and his senses were all intact. He had no discernible problems naming or thinking about any other categories of object—just fruits and veggies.

It sounds like a career killer for a chef, but Carter managed to get by. You see, his brain's network body maps still knew what to do with each item. There was nothing wrong with the body maps containing his visual-motor templates for how to manipulate objects. And there was nothing wrong with the body maps that storehoused his library of well-practiced motor sequences involved in food prep. He could still peel a carrot, slice a tomato, or dice an onion—but first he had to be told what each thing was. He would simply query the kitchen staff: “Hey, Jane, is this a cucumber?

"Yeah? Thanks.” Chop chop chop.

On the whole, this book is an excellent introduction to a complex and important topic of science. The prose is lively and easy to read, and once I got going, I was able to finish it in a matter of days. The book is intended for a wide audience, and other than the occasional jargony neuroanatomy term, it is accessible to anyone with a high school education. The only notable failure of this book is to make clearer distinctions on the science that is well-established and the science that is pure speculation. I'm no specialist, yet I would have liked to have seen more pointers to primary sources; an appendix containing citations and/or pointers for further reading would have been highly appropriate and useful.

Clay model on display at the Natural History Museum in London.

This Week's Citation Classic

This week's citation classic honors Seymour Benzer who passed away yesterday.

Benzer S. 1955. Fine structure of a genetic region in bacteriophage. PNAS 41(6):344-54.

Benzer began his career as a physicist, but was inspired to switch to molecular biology by Schrodinger's book What is Life and by Max Delbruck. He took a leave of absence from his position at Purdue to pursue research on the structure of the gene, and he never looked back. Biology, bacteriophages in particular, captivated him.

In his classic 1955 PNAS paper, Benzer used the bacteriophage T4 to map the r gene.

Benzer describes his experiments:

I plated some of these r mutants on two different strains of E. coli bacteria. And I had two different strains of K-12 phage, one that was lysogenic and had Lwoff’s lambda phage in it, and one that didn’t. What happened first was that when I plated these r mutants on the plain K-12 strain, instead of making the big plaques they made the little plaques. So they were showing lysis inhibition on that strain. Then, when I plated them on the strain that had the lambda, I got zero plaques. And having been alerted by reading Pontecorvo’s article, I immediately, really instantly, realized…. Well, at first I thought I made a mistake. I thought I had forgot to put the phage on there. Dummkopf, do it again! I did it again and saw the same phenomenon.

Benzer's key insight was that he had stumbled upon a system where he could do genetic mapping by using recombination between r mutants to map the r gene much in the way that Alfred Sturtevant used recombination to map Drosophila. The trouble with using recombination to map genes is that the closer two genes are together, the less likely they will recombine. Thus mapping a single gene was thought to be impossible.

But not so for phage. So many offspring (~100 million) are produced that the odds are that recombination can occur even among two adjacent nucleotides.

Benzer describes the moment:

So I immediately realized—a eureka moment, and they’re all too rare—that this was a system in which I could do very fine genetic mapping. I could take two r mutants, cross them with each other, and take the progeny and put them on this K-12 lambda strain. The r mutants themselves would produce no plaque, but if in any of the progeny there was a crossing-over between these two different mutations, such as to produce a wild-type recombinant that had neither mutation, that would produce a plaque. And that you could put 100 million plaques on one plate. So a quick calculation told me that that was enough, knowing the number of nucleotides in the DNA of the bacteriophage. This was about 1954 or ’55—after the Watson-Crick discovery. So, based on the number of nucleotides in the DNA and the phage, I would have enough resolving power to separate the rII mutations, even if they were just one nucleotide apart.

When r mutants are plated on lysogenic K-12 E. coli, only those that have undergone recombination within the r gene to form wild-type phage will form plaques. The number of plaques on the bacterial lawn indicates how far apart the two nucleotide mutations were on the gene. Thus, Benzer had the tool of exceptionally high resolution; he could to map the r gene down to the nucleotide.

Benzer's results showed conclusively that genes were not indivisible as commonly thought.

Benzer later went on to dissect the nervous system of Drosophila in a third highly productive career.

Even at 86 years of age, Benzer still ran a laboratory at CalTech. A very entertaining oral history interview series with Benzer is available here. Benzer's CV should give us all pause; he was a tremendously accomplished man.

Updates: Larry Moran points out this paper: Adventures in the rII Region and other tributes to Benzer in the blogosphere.