Friday, October 24, 2008

This Week's Citation Classic: Human Natural Selection

R.A. Fisher, Julian Huxley, and E.B Ford were members of a small clique British and American scholars who were the driving forces behind the "New Synthesis", the refinement and spread of Darwin's theory of evolution during the 1930's and 40's.

They can together also be counted as publishing the first ever test of the effects of natural selection on humans.

This week's citation classic is FISHER, R. A., E. B. FORD and J. HUXLEY, 1939 Taste-testing the anthropoid apes. Nature 144: 750.

You probably remember phenylthiocarbamide or PTC from Intro Biology or Genetics class. Those little strips of paper which, depending on your genotype, was either bitter or tasteless. Bitter for me.

PTC's unique attributes was first discovered by Arthur Fox in 1932 when he was pouring some of the powder and it flew into the air (aahh the days before the Lab Safety Officers). His co-worker C.A. Noller complained that the powder was bitter, yet Fox could taste nothing. Fox set about testing a large group of people and found that indeed they could be divided into tasters and non-tasters.

Fisher, Ford and Huxley realized that this could be a great opportunity to test theories regarding the origins of balanced polymorphisms and whether natural selection has acted upon human genes.

Fisher et al. wrote "in the course of discussions on the possibility that the blood-group frequencies found in man were determined by a balance of selective influences, it occurred to one of the authors that evidence on the parallel possibility for taste could be obtained by testing the anthropoid apes."

In what must have been an almost comic series of experiments, the three tested whether apes could taste PTC. One of the apes took a strong dislike to Fisher and "and spat at him and even tried to grab him". But the trio succeeded in measuring PTC sensitivity for all apes, "excepting one chimpanzee, which was too shy".

The results were remarkable. Mendelian expectation for dominant and recessive genes suggests tasters should represent 3/4ths of the population and nontasters 1/4th. Of the 27 individuals tested, 20 were tasters and 7 were nontasters, implying allele frequencies of 49 and 51% for the taster and nontaster alleles, almost precisely as expected.

Fisher et al. write "Without the conditions of stable equilibrium it is scarcely conceivable that the gene - ratio should have remained the same over the million or more generations which have elapsed since the separation of the anthropoid and hominid stocks. The remarkable inference follows that over this period the heterozygotes for this apparently valueless character have enjoyed a selective advantage over both the homozygotes, and this, both in the lineage of the evolving chimpanzees and in that of evolving man. Wherein the selective advantages lie, it would at present be useless to conjecture, but of the existence of a stably balanced and enduring dimorphism determined by this gene there can be no room for doubt."

Fig. Hypotheses for the origin of PTC taster and nontaster alleles. (Left) FISHER et al.'s (1939) "Single Origin" hypothesis. Under this hypothesis, the taster (T) and nontaster (t) alleles diverged prior to the human–chimpanzee species divergence. Then both alleles were maintained separately in each species up to the present time. The maintenance of both alleles for such an extended period [FISHER (1939b) thought that it must be ~1 million generations, or 20–30 million years] is unlikely if balancing selection has not been active because one allele or the other would be expected to go to fixation. (Right) WOODING et al.'s (2006) "Separate Origin" hypothesis. Under this hypothesis, nontaster alleles were derived from taster alleles twice—once in each species—after the human–chimpanzee species divergence. Arrows indicate divergence events.

The biological significance of the polymorphism was not clear to Fisher et al. nor was it identified until quite recently. Long story short is that the non-taster allele is not non-functional. On the contrary it appears to provide the non-PTC taster with the ability to taste other compounds that the PTC taster cannot taste.

Evidence that the TAS2R38 nontaster allele is functional suggests an immediate mechanism through which heterozygote advantage might arise at this locus. If the taster allele confers sensitivity to PTC and its chemical relatives, and the nontaster allele confers sensitivity to some other set of compounds, then heterozygotes should be able to taste both sets of compounds. Thus, they might garner a fitness advantage by being able to regulate the intake of a greater diversity of bitter compounds than can homozygotes. Wooding 2006.

A final point is that the parsimonious hypothesis that the PTC allele arose once has been refuted.

Taken together, the findings of WOODING et al. (2006) support FISHER et al.'s (1939) finding that both humans and chimpanzees harbor taster and nontaster alleles and that these alleles are found at similar frequencies in each species; however, they reject the hypothesis that these alleles were derived once, prior to the human–chimpanzee divergence. Rather, the nontaster alleles, which confer their phenotypic effects through entirely different molecular mechanisms, appear to have twice evolved independently. The details of the selective pressures underlying this more complex process remain a matter of conjecture. Wooding 2006.

This post was largely derived from Wooding 2006.

Photo: (Left to right) R. A. Fisher, E. B. Ford, and Julian Huxley. Portraits are from YATES and MATHER (1963), CLARKE (1995), and BAKER (1976).

Thursday, October 23, 2008

Small World Winners Announced.

The Small World Photomicrography contest winners have been announced. This year's top prize went to Michael Stringer for the above image.

Though Mr. Stringer is not a microscopist by trade, he has been interested in diatoms for over 60 years. When he retired from his work as an Ophthalmic Nurse Practitioner, he decided to emulate English Botanist and Diatomist Dr. C. L. Odam and collect diatoms from tributaries. Stringer now works on Two Tree Island amassing information and collecting diatoms.

This image was one of a series Mr. Stringer created to illustrate a talk to a camera club on “Photography through the microscope.” His objective was to display diatoms in a modern way using super contrast and careful application of color. Rather than showing all the details, or warts and wrinkles as Mr. Stringer likes to call them, he dressed up the diatoms by manipulating the image and creating this beautiful photomicrograph.

Wednesday, October 22, 2008

Book Review: Myth of the Oil Crisis

I was pretty skeptical when I received Robin Mills Myth of the Oil Crisis because Peak Oil makes intuitive sense. Oil is a finite resource, demand is skyrocketing and there is no doubt that, at some point, demand will outstrip supply. However, Mills, a geologist and economist, makes a convincing case that Peak Oil is not imminent. If true, this finding has important implications for the global economy and environment.

In brief, Mills argues:

  1. supply is greater than we think
  2. supply and demand responsive to prices
  3. current high prices result of underinvestment due to oil glut of 80s-90s
  4. gas, unconventional, and alternative fuels can make up balance
  5. peak oil reasoning will lead us into bad decisions
I agree with many of Mills' claims. Peak oil scenarios of economic chaos and the collapse of civilization are overly dramatic. There probably is more oil (conventional and unconventional) than peak oil proponents believe. Economics will drive the switch to alternative fuels and products, and make no mistake, alternatives are available. The transition will not occur overnight but rather over many decades.

If Mills is correct, then some of the assumptions regarding global climate change need to be reconsidered. Many carbon scenarios suggest that a major decline in hydrocarbon availability will force carbon reductions by default. Governments will not need to make painful choices now because "the invisible hand" will make those choices for them. If hydrocarbon supply is not at risk, then we will need government manipulations of oil supply and demand to alleviate human induced climate change.

Some of Mills' arguments, however, ring false. The contention that supply is underestimated because large unconventional reserves (off-limits oil, coal, oil sands, gas) will seamlessly replace conventional oil is demonstratively false. Some unconventional reserves will have a much greater negative environmental impact and should be taken "off the table". For example, a recent report by David Israelson of the University of Toronto claims that developing the Alberta Oil Sands will devastate the Great Lakes basin.

"Difficult to extract and dirty to process, tar sands oil is coming to the Great Lakes via a planned network of pipelines and refinery expansions. Currently disclosed project costs show that pipeline companies and U.S. refiners plan to invest more than U.S. $31 billion between now and 2015 to upgrade, export, and refine tar sands oil. This expansion promises to bring with it an exponential increase in pollution – discharges into waterways including the Great Lakes, destruction of wetlands, toxic air emissions, acid rain, and huge increases in greenhouse gas emissions. All of this comes before anyone even uses a drop of this oil in their cars and trucks and factories, before the oil is even processed in these expanded refineries. If the great challenge of the 21st century is to figure out how to wean society off oil, this is the diametric opposite of the way to go about it."

The one thing we must not do is sacrifice our ecological future for our present comfort. Mills does make some concessions to this need in his final chapter on "Green Oil". However his willingness to advocate environmentally disastrous sources of energy make me queasy. Ultimately, while I subscribe to much of what Mills says, I think Peak Oil is probably closer than Mills believes, not because oil is running out, but rather the consequences of oil use is making it unsustainable. Despite these failings, I thought Mills' book was eminently readable, thought provoking and a worthy contribution to the Energy Debate.

In research for this post, I came across this great poster.

Saturday, October 11, 2008

This Week's Citation Classic: GFP

This week's citation classic is M Chalfie, Y Tu, G Euskirchen, WW Ward, and DC Prasher.
Green fluorescent protein as a marker for gene expression. Science 11 February 1994:
Vol. 263. no. 5148, pp. 802 - 805. DOI: 10.1126/science.8303295.

Martin Chalfie has just been awarded a Nobel Prize for his work relating to the development of one biology's most ubiquitous tools: green fluorescent protein. In one of Chalfie's first experiments, he marked six individual C. elegans cells in the with the aid of GFP.

GFP allows "the monitoring in time and space of an ever-increasing number
of phenomena in living cells and organisms like gene expression, protein localization and
dynamics, protein-protein interactions, cell division, chromosome replication and organization,intracellular transport pathways, organelle inheritance and biogenesis, to name but a few" [].

Chalfie first found out about GFP in 1988 during a seminar on bioluminescent organisms by Paul Brehm. Brehm's seminar reported that GFP, a protein found in the jellyfish, Aequoria victoria, fluoresces green in the presence of blue light.

Chalfie thought to himself, "What an absolutely wonderful, wonderful compound this would be. I would love to put it into C. elegans and look at gene expression. In fact I imagined a really large number of things I would like to do if I had such a way of marking gene expression and protein localization in living cells. I got very excited and didn’t listen to another word of the seminar."

Chalfie contacted Doug Prasher at Woods Hole who was attempting to clone the GFP cDNA. Chalfie and Prasher agreed to get in touch when Prasher succeeded with the cloning, but due to missed connections, four years passed before Chalfie saw the published sequence in Gene.

Chalfie contacted Prasher and asked "What happened to our collaboration? Do you still want to do this?". Prasher was unable to get the GFP to fluoresce but sent the protein to Chalfie anyway. Chalfie then gave it to his grad student Ghia Euschirken. Two weeks later, Euschirken had something to show Chalfie: green fluorescent E. coli.

Chalfie describes why he was able to get GFP to fluoresce while others failed:

I was very concerned that we only use the coding sequence and no flanking DNA in our construct. We used PCR to obtain just the coding sequence and that worked terrifically. But the others who tried to use GFP simply cut the original lambda cDNA clone with restriction enzymes, and got additional bases associated with each end. These extra sequences turned out to be quite detrimental; expression wouldn’t occur. So we were fortunate in the way we designed the experiment.

Chalfie and Euschirken eventually cloned GFP into worms as a promoter driven construct, and the rest is history.

On a sad note, Prasher no longer works in science. He is now driving a courtesy shuttle for a car dealership in Huntsville, Ala.

An interview with Chalfie is available here.

Friday, October 3, 2008

Noble Foundation

Today I am blogging from the 5th Virus Evolution workshop at the Samuel Roberts Noble Foundation in Ardmore OK. Also present is fellow blogger Abbie Smith of ERV. The talks have been excellent, the accommodations sumptuous and the grounds striking. This is clearly a high class outfit. In fact the Noble Foundation is Oklahoma's largest foundation and one of the 60 largest private charitable foundations in the United States. Apparently the Noble Foundation has an almost 1 billion dollar endowment . Where did this money come from? I've heard an interesting story. Apparently the Noble Family owned farm implements company. They sold farming tools to farmers on credit. Unfortunately for the farmers, disaster struck in the 1930s. The region was stricken by the catastrophic drought later known as the Dust Bowl. Unable to grow crops, many of the farmers defaulted on their debt and the Noble's came into possession of a large amount of Oklahoma's land. Lloyd Noble, who was a major player in the oil business, later started the foundation in honor of his father and dedicated the foundation to the betterment of the lives of Oklahomans. Today, the foundation provides ~60 million a year in grants for scientific research as well as hosting a campus devoted to the study of forage improvement, plant biology and agriculture. I'm not sure how true the story is since I've been unable to find corroboratory evidence but it is pretty interesting nonetheless.

Wednesday, October 1, 2008

Science Blogs Book Club: Autism's False Prophets

The latest edition of Science Blogs Book Club is up. This time the selected book is "Autism's False Prophets" by Dr. Paul Offit. The discussion panel includes Paul Offit, Kristina Chew, Kev Leitch, Orac and Bob Park.

I posed some questions for the panel:

In my microbiology class, I've fended questions from students regarding whether vaccines were "safe". Most students, although educated and worldly, were unaware of the studies showing no relationship between vaccines and autism for example.

The most disturbing issues for me (highlighted in Ch. 9 of the book) is the tendency of the media 1) to report only "sexy" stories 2) seek unwarranted "balance".

It is clear that the media attention given to reports that vaccines were unsafe far outweighed reports that vaccines are safe.

Moreover, reports of the safety of vaccines were often accompanied by contradictory opinions in the interests of "balance". I liken this to the Intelligent Design controversy where some believe educators should present "all sides" of the evolution "controversy".

So, my questions to the panel are "What do we do about it?" Can we create a media whose primary objective is to inform rather than to entertain, and, if so, how can we get people to pay attention to it?

I look forward to exciting discussions.