Nobel Laureate: Susumu Tonegawa

 

The Nobel Prize in Physiology or Medicine 1987.

"for his discovery of the genetic principle for generation of antibody diversity"

Susumu Tonegawa (1939 - ) received the Nobel Prize in Physiology or Medicine for working out the mechanism of generating antibody diversity. This was one of the fundamental problems in immunology—and, indeed, all of biology. How do antibodies recognize so many different antigens?

We now know the answer thanks to Tonegawa and his coworkers. The genes for antibody proteins are constructed in antibody-producing cells by recombining bits of DNA from several different locations. Millions of different permutations can be constructed to create a random library of antibody molecules. The chance that one of these randomly constructed antibody molecules will recognize a new antigen, such as virus, is very high.

This is one of the most significant Nobel Prizes of the 2oth century. Tonegawa's discovery deserves a lot more attention that it normally gets.

The presentation speech was delivered (in Swedish) by Professor Hans Wigzell of the Karolinska Institute.

THEME:
Nobel Laureates

Your Majesties, Your Royal Highnesses, Ladies and Gentlemen,

The defence of our body against infections is carried out by the immune system, a talented cellular society with a capacity to distinguish between self and non-self and with a memory capable of remembering a previous contact for decades. The system is managing this through the inbuilt capacity in a single human being to produce billions of different forms of protective molecules, antibodies. The Nobel Prize of this year is given for the elucidation of the unique capacity of the immune system to produce this enormous diversity of specific antibodies.

Susumu Tonegawa is the great molecular biologist in immunology. In a series of ingenious experiments carried out in the middle of the 1970's he solved the problem how our limited genetic material is capable of generating the diversity required to create protection against established as well as future disease provoking microorganisms. When Tonegawa did his experiments at the Basel Institute of Immunology in Switzerland other scientists had already generated a-considerable amount of knowledge regarding the features and functions of antibodies. But this knowledge had also led to uncertainty and even confusion. Antibodies are proteins and their structure is strictly ruled by genes, by the DNA in our chromosomes. When Tonegawa carried out his experiments it was commonly believed that each protein, each polypetide chain, was governed by its gene in a relation one to one. But at the same time calculations on the number of genes in the chromosomes in man determining proteins gave a number probably below one hundred thousand genes. They should suffice to all the proteins in the body, to the hemoglobin in the red blood cells, to the pigment in our eyes and so on. Only a minor part, maybe one percent, could probably be used for the creation of antibodies. Around one thousand genes being able to create billions of different forms of antibodies? The equation seemed impossible to solve.

Our antibodies are made up of two sorts of polypeptide chains, short and long ones. Tonegawa did first acquire a toolbox, filling it with the best precision tools there were of hybrid-DNA nature, developed new methods and started to study the actual construction of the genes determining the short chains of antibody molecules. He discovered something entirely new and revolutionary in genetics. On the chromosome where the gene for the short chain was expected to be located, there was not one single, but a string, of pearls of genes. One special gene resided at one position whereas two other sets of variable genes create two gene families, in all maybe around one hundred genes. When a cell should start to make antibodies - this was preceded by a gene-lottery.

One member of the largest gene family selected at random was cut out from the chromosome and moved close to a member of the second gene family, whereafter they created a functional gene for the short chain together with the solitary gene. Three and not one gene participate in the creation of the short chain of antibody molecules. Each member in one family can probably be linked to any one of the members of the second gene family, increasing variability by multiplication. The results showed beyond doubt that our body has the capacity to carry out advanced recombinant DNA processes. The intelligence of Nature can also be seen as the studies went on. The recombination of genes and their coupling together do not occur in exactly the correct manner. While such relative misfits should in other systems be bad, here they constituted yet another mechanism of increasing the diversity of antibodies. Experiments by Tonegawa as well as other scientists also revealed that the same genetic lottery principle did apply to the generation of the long chain although here the number of variants were even larger. Four different genes could be shown to create these chains together. The number of variant short chains should then be multiplied by the combinatorial possibilities of the heavy chain to give the variation at the antibody level, a fact which will also drastically enhance the diversity of antibodies.

The equation was in essence solved. A few hundred genes are used by the body in a new, revolutionary way and can thus generate billions of different antibodies. Through this genetic lottery the immune system is always prepared to react against known as well as unknown microorganisms. The economic usage of precious DNA is compensated by wasting more dispensable material. Every minute our body produces several millions of white blood cells - lymphocytes. Each one of these has undergone the hybrid-DNA procedure and is prepared with its own, unique antibodies. If not called upon to react they will rapidly die. If, however, they make contact with the fitting foreign structures they receive a reward, i.e., they are allowed to proliferate and live longer. After the great randomized gene lottery natural selection will pick the winners, thereby generating specific immunity, the cheapest and most efficient protection there is against infections.

Dr. Tonegawa,

On behalf of the Nobel Assembly of the Karolinska Institute I would like to congratulate you on your outstanding accomplishments and ask you to receive the Nobel Prize in Physiology or Medicine from the hands of His Majesty the King.

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[Photo Credit: Nature]

[Figure credit: The figure showing immunoglobulin gene rearrangment is from carthage.org]

Tangled Bank #108

 
The latest issue of Tangled Bank is #108. It's hosted at Wheat-dogg's world [The Tangled Bank #108].

Welcome to The Tangled Bank 108 and to the little-known but still fascinating Wheat-dogg’s World. I hope that after you peruse the fine entries in this edition of The Tangled Bank you’ll stroll around and check out things here in my neck of the Worldwide Woods.

Today we have science bloggers musing on some of the greater profundities of the universe as well on more concrete issues closer to home. Some of these posts ask more questions than they answer, but heck that’s what science is all about, hey?

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If you want to submit an article to Tangled Bank send an email message to host@tangledbank.net. Be sure to include the words "Tangled Bank" in the subject line. Remember that this carnival only accepts one submission per week from each blogger. For some of you that's going to be a serious problem. You have to pick your best article on biology.

Get a Job at CFI

 
The Center for Inquiry (Toronto) is looking for someone to help out with their various activities. This is a part-time job. It's a wonderful opportunity for a student.

CFI ONTARIO IS HIRING A LONG-TERM PART-TIME
CENTRE & FIELD ORGANIZER!

Please spread the word to anyone interested in taking on a decisive leadership position in the expanding freethought movement in Canada. Position starts mid July.

Deadline to apply: Monday, July 7.
Full info and updates will be provided online.
Visit Center for Inquiry.

The Centre for Inquiry is an international education and outreach organization dedicated to promoting and advancing reason, science, secular ethics and freedom of inquiry in all areas of human endeavour. We engage in educational lectures, debates and conferences, coordinate 30 campus freethought groups across Canada, run a robust series of secular humanist social and community services, and undertake advocacy defending church-state separation, the integrity of science and equality rights for non-believers. The new CFI Ontario is CFI's first location in Canada and our nation’s premiere venue for secular humanists, skeptics and freethinkers.

RESPONSIBILITIES:

This position is two-fold:

1. The successful candidate will act as an assistant director at CFI Canada headquarters in Toronto. He/she will lead CFI Ontario’s in-house and ongoing programming, event planning and hosting, promotions, newsletter publishing, social services, campus outreach and membership committees. There will be numerous leadership opportunities through support staff and volunteer recruitment, training, supervision and delegation.
2. CFI's Canadian operations have recently expanded with the launching of new Communities in Montreal and Calgary and the anticipated launch of a Community of Vancouver in the next few months. The successful candidate will provide organizing assistance to our new CFI Communities in Canada.

HOW TO APPLY

If you are interested in applying, please email a cover letter, resume/CV and writing sample as a text, Word or PDF attachment, to Justin Trottier at jtrottier@centerforinquiry.net. Include a brief statement of your academic background, interests, your activities with the skeptic or humanist movements and/or other extracurricular, community, work or voluntary experience of relevance, and why interning at CFI is something you want to do. You are also encouraged to include any documentation or samples of your relevant experiences (eg. media coverage of your event, political policy statement you wrote, poster you created, etc).

This is an exciting opportunity to contribute to the overall growth of the secular community in Canada and to strengthen your relationship with CFI. We hope you will consider joining us.

Position starts mid July. Deadline to apply: Monday, July 7

TIMING/DURATION:

This position will last one year with the possibility of renewal. The daily and weekly time commitment are flexible but would work out to ~ 15-20 hours/week. Please indicate your daily and weekly availability as well as the duration of your commitment.

JOB REQUIREMENTS:

An understanding of the freethought/humanist/skeptic community and/or some demonstration of commitment to the values of free and critical inquiry is essential.

To perform this job successfully an individual must possess excellent skills in organization, promoting and leading. The individual must also have the ability to exercise independent judgment and manage multiple priorities, the ability to organize and lead volunteers, strong verbal and written communication skills, and the ability to represent CFI via public speaking and media appearances. The job frequently involves speaking in front of crowds and other PR activities for which the successful candidate must be comfortable, experienced and proficient. Knowledge of the non-profit sector and community development strategies is ideal.

Since there is some travel access to own car is very helpful. In addition, because the computer resources at CFI Ontario are limited, access to own laptop is also ideal.

Since the successful candidate will be involved in setting up our Community of Montreal, he/she must be very comfortable conversing and writing in the French language. In addition, some knowledge of Montreal and Quebec culture is ideal.

ADDITIONAL TECHNICAL KNOWLEDGE

To assist in specific projects, the following technical background is helpful, though not completely required. Candidates without such background should still apply. Candidates with such technical knowledge should highlight it in application:

• Web development experience
• Basic image editing skills in Adobe Photoshop or similar program
• Experience using and maintaining SQL databases (eg. MySQL) or similar technology
• Basic understanding of video technology and video editing, uploading and embedding (e.g. through youtube or google video)
• Proficiency in Adobe Illustrator, Photoshop, Microsoft Publisher or similar program for poster and ad creation

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Selfish Genes

 
In honey bee colonies the queen is the only fertile female. She lays all the eggs. The worker bees are female but sterile. The process of ovulation in worker bees is suppressed in response to phermomes. This is an example of genetic altruism where the reproductive benefit of worker bees is suppressed in favor of the good of the hive. There are good theories about why this would ultimately benefit the workers.

In some hives, a few worker bees can lay eggs and these eggs will hatch. The presence of "cheaters" in an altruistic society is expected and normal. Oxley et al. (2008) looked at the DNA from these "cheater" hives and compared it to the DNA from bees that were sterile. The idea was to identify the gene responsible for suppressing ovulation in workers; presumably that gene was somehow different in the hives with "cheaters."

Here's the abstract of the paper.

The all-female worker caste of the honey bee (Apis mellifera) is effectively barren in that workers refrain from laying eggs in the presence of a fecund queen. The mechanism by which workers switch off their ovaries in queenright colonies is pheromonally cued, but there is genetically-based variation among individuals: some workers have high thresholds for ovary activation, while for others the response threshold is lower. Genetic variation for threshold response by workers to ovary-suppressing cues is most evident in "anarchist" colonies in which mutant patrilines have a proportion of workers that activate their ovaries and lay eggs, despite the presence of a queen. In this study we use a selected anarchist line to create a backcross queenright colony that segregated for high and low levels of ovary activation. We used 191 informative microsatellite loci, covering all 16 linkage groups to identify QTLs for ovary activation and test the hypothesis that anarchy is recessively inherited. We reject this hypothesis, but identify four QTLs that together explain approximately 25% of the phenotypic variance for ovary activation in our mapping population. They provide the first molecular evidence for the existence of quantitative loci that influence selfish cheating behavior in a social animal.

This is an interesting paper but that's not the reason for this posting. The real reason is to contrast the actual paper with the press release from the University of Western Ontario (Canada) [Discovery proves 'selfish gene' exists]. Here's the complete press release.

A new discovery by a scientist from The University of Western Ontario provides conclusive evidence to support decades-old evolutionary beliefs about the existence of a so-called selfish gene.

Since renowned British biologist Richard Dawkins ("The God Delusion") introduced the concept of the ‘selfish gene’ in 1976, scientists the world over have hailed the theory as a natural extension to the work of Charles Darwin.

In studying genomes, the word ‘selfish’ does not refer to self-centred behaviour but rather to the blind tendency of genes wanting to continue their existence into the next generation. Ironically, this ‘selfish’ tendency can appear anything but selfish when the gene does move ahead for selfless and even self-sacrificing reasons.

For instance, in the honey bee colony, a complex social breeding system described as a ‘super-organism,’ female worker bees are sterile. The adult queen bee, selected and developed by worker bees, is left to mate with male drones.

Because the ‘selfish’ gene controlling worker sterility has never been isolated by scientists, the understanding of how reproductive altruism can evolve has been entirely theoretical – until now.

Working with Peter Oxley of the University of Sydney in Australia, Western biology professor Graham Thompson has, for the first time, isolated a region on the honey bee genome that houses this ‘selfish’ gene in female workers bees.

“We don’t know exactly which gene it is, but we’re getting close.”

“This basically provides a validation for a huge body of socio-biology,” says Thompson, who adds the completion of Honey Bee Genome Project in 2006 was crucial to this discovery.

So, what's the beef? The problem is that the press release is horribly confusing. In The Selfish Gene Dawkins argues that one can look at evolution from the perspective of the gene and not the organism. The goal of each and every gene, according to Dawkins, is to replicate itself and pass on copies to future generations. Every gene (allele) is selfish in his view. The selfish gene of The Selfish Gene has nothing to do with altruism. At least not directly.

Now, according to the Dawkins' view of evolution, worker sterility is not a violation of the selfish gene principle. Dawkins believes that Hamilton is correct and that altruistic behavior can be explained as an indirect way of propagating one's genes to future generations. Thus, the bee gene is a selfish gene in the Dawkins sense, but so is every other gene (allele) in the bee genome.

This study is not "conclusive evidence" of selfish genes. We've had that kind of conclusive evidence ever since the discovery of alleles that confer fitness advantage—alleles such as those for antibiotic resistance gene in bacteria. This study is interesting because it points to the discovery of altruistic genes (alleles) but that something quite different from what it says in the press release. The "cheater" allele represents selfishness of a different kind.

Incidentally, there's nothing in paper itself about "selfish genes" or Richard Dawkins.

If you want to follow up on this topic you should read the comments on Richard Dawkins.net [New discovery proves 'selfish gene' exists]. As you might imagine, the readers over there are split between those who hail this as confirmation that Dawkins is vindicated and those who have actually read The Selfish Gene. Many are calling for clarification from Richard Dawkins himself. I hope he responds because this is a perfect opportunity for him to set the record straight.

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[Photo Credit: The Telegraph (UK)]

Oxley, P.R., Thompson, G.J., Oldroyd, B.P. (2008) Four QTLs that Influence Worker Sterility in the Honey Bee (Apis Mellifera). Genetics. 2008 Jun 18. [Epub ahead of print]Click here to read [PubMed] [DOI: 10.1534/genetics.108.087270]

Monday's Molecule #77

 
Today's molecule is related to a previous Monday's Molecule. This time you have to name the molecule and identify the various symbols on the cartoon. Be as specific as possible.

There's a direct connection between today's molecule and a Nobel Prize. The prize was awarded for figuring out how this molecule was made. It was one of the most brilliant discoveries of the 20th century.

The first person to correctly identify the molecule (and its parts) and name the Nobel Laureate(s), wins a free lunch at the Faculty Club. Previous winners are ineligible for one month from the time they first collected the prize. There are five ineligible candidates for this week's reward. You know who you are.

THEME:

Nobel Laureates
Send your guess to Sandwalk (sandwalk (at) bioinfo.med.utoronto.ca) and I'll pick the first email message that correctly identifies the molecule and names the Nobel Laureate(s). Note that I'm not going to repeat Nobel Laureate(s) so you might want to check the list of previous Sandwalk postings by clicking on the link in the theme box.

Correct responses will be posted tomorrow. I may select multiple winners if several people get it right.

Comments will be blocked for 24 hours. Comments are now open.

UPDATE: The molecule is immunoglobulin G (IgG)—same as last week. The V, D, and J symbols stand for variable, diversity, and joining regions of the protein. The antigen binding site is formed from the combination of these regions on the heavy (H) chain and the light (L) chain of the molecule. The ability of antibodies to recognize a huge number of different antigens is due to formation of a huge number of different antigen-binding sites. This is achieved by rearranging the genome in order to bring together one of hundreds of V regions with 20 or so D regions and 5-6 J regions. The recombination events are associated with mutations that serve to create even more diversity.

The generation of antibody diversity by genomic rearrangement was discovered by Susumu Tonegawa who received the Nobel PRize in 1987. Today's winner is Alex Ling or the University of Toronto.

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Peter McKnight Reviews Expelled

 
The movie is called Expelled: No Intelligence Allowed. Perhaps you've heard of it? After flopping in the USA it's about to open in Canada on June 27th. I heard an ad on the radio today as I was driving to work.

The movie is full of errors and lies. For a complete list, check out Expelled Exposed.

Peter McKnight of The Vancouver Sun reviewed the movie last Saturday [No intelligence allowed in Stein's film]. It's an excellent review. I recommend you read the whole thing. Here are the opening paragraphs ...

Although you're probably not aware of it, scientists, lobby groups, the media and the courts are all united in a massive conspiracy to destroy your freedom. But have no fear, freedom fighter Ben Stein is here.

That, in effect, is the thesis of Expelled: No Intelligence Allowed, the new anti-science "documentary" which opens across Canada on June 27, was produced by Vancouver's Premise Media, and stars Stein, the lawyer, actor, game show host and speechwriter for former U.S. president Richard Nixon.

The subtitle of the film is wholly appropriate as there is precious little intelligence displayed in its more than 90 minutes. But the subtitle's reference to the content of the film was unwitting -- it was meant to refer to a giant conspiracy to banish intelligent design theory from the halls of academe and the culture as a whole.

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[Hat Tip: John Pieret]

Darwin Symposium at the ROM

 
Come to the Darwin Symposium at the Royal Ontario Museum (Toronto) this Friday.

Darwin Symposium

Friday, June 27, 10:30 am - 3:30 pm
Status: Available

Join these leading thinkers in Evolution and Darwinism for a day of fascinating presentations.

10:30 am - 11:30 am
Michael Ruse: Has Darwinism Expired?

11:30 am - 12:30 pm
Spencer Barrett: A Darwinian Perspective on the Evolution of Plant Sexual Diversity

12:30 - 1:30 pm, LUNCH BREAK

1:30 - 2:30 pm
Rosemary and Peter Grant: Darwin's Finches

2:30 - 3:30 pm
Alan Baker: Modern Darwinism: Natural Selection and Molecular Evolution

Talks will be approximately 40-45 minutes long with a question and answer period after each talk. Lunch is not included.

Location: Royal Ontario Museum, Level 1B
Signy and Cléophée Eaton Theatre; Please enter through the South Entrance.

Cost: Free Lecture. Museum admission not included.

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Come and Meet the Friendly Atheist!

 

Hemant Mehya (Friendly Atheist) is giving a talk in Toronto this Friday. The talk is sponsored by the University of Toronto Secular Alliance.

When? Friday, June 27th, 2008 (Meet & Greet: 6-7pm, Lecture: 7pm-9pm)

Where? U of T's Multi-Faith Centre, 569 Spadina Ave, Multi-Purpose Room (2nd Floor)

How Much? Free!

RSVP (if possible): Facebook

Hemant Mehta comes to Toronto to talk about faith and his experience with "selling his soul".

Hemant Mehta was born into the Jain faith, and became an atheist at age 14. In 2006, he created an auction on eBay offering up his atheist mind and body to attend a worship service of the winning bidder's choice. Every $10 would equal one hour in that particular place of worship.

The bidding ended on February 3, 2006 with the final bid sitting at $504 from Jim Henderson, a minister from Seattle, Washington. The money was later donated by Hemant to the Secular Student Alliance, a non-profit organization. The agreement was for Hemant to visit a variety of churches and to write about his experiences at them at the web-site off-the-map.org.

Hemant later developed these experiences into his book "I Sold My Soul On eBay". He continues to open up dialogue at his personal blog friendlyatheist.com.

Co-hosted by the University of Guelph Skeptics, sponsored by the Secular Students Alliance.

Even though the meeting notice and the RSVP are on Facebook, I'm told that the meeting is not exclusively for university students. If you don't have a Facebook account (I don't) then you can just show up at the meeting (I think).

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Professor Sues Students for "Anti-intellectualism"

Priya Venkatesan earned an Master's degree in genetics then went on to a Ph.D. in literature. She was a Professor at Dartmouth last year and now has a postion at Northwestern.

Here's an except from an article she wrote in Dartmouth Medicine last summer [Yin, meet yang].

In graduate school, I was inculcated in the tenets of a field known as science studies, which teaches that scientific knowledge has suspect access to truth and that science is motivated by politics and human interest. This is known as social constructivism and is the reigning mantra in science studies, which considers historical and sociological understandings of science. From the vantage point of social constructivism, scientific facts are not discovered but rather created within a social framework. In other words, scientific facts do not correspond to a natural reality but conform to a social construct.

...

In many ways, social constructivism has been reframed as postmodernism, since both movements question the scientific realm's theory of truth—that is, that scientific facts mirror an external reality which does indeed exist. However, this reframing is unnecessary, since clear distinctions exist between social constructivism and postmodernism. Through my experience in the laboratory, I have found that postmodernism offers a constructive critique of science in ways that social constructivism cannot, due to postmodernism's emphasis on openly addressing the presupposed moral aims of science. In other words, I find that while an individual ethic of motivation exists, and indeed guides the conduct of laboratory routine, I have also observed that a moral framework—one in which the social implications of science and technology are addressed—is clearly absent in scientific settings. Yet I believe such a framework is necessary. Postmodernism maintains that it is within the rhetorical apparatus of science—how scientists talk about their work—that these moral aims of science may be accomplished.

By all accounts, Priya Venkatesan is one of those post-modernist thinkers who are much more impressed with their words than with their ideas. They are the ones spoofed by the Sokal hoax back in 1996. Venkatesan is the author of a book called Molecular biology in Narrative form., which is also the title of her Ph.D. thesis. At least one reviewer thought the book was a joke [ReviewScout.com].

Following all the forms of both Literary deconstructionist criticism as well as Scientific Peer-reviewed journals, one might actually think this was a serious work -- and indeed, the sheer volume of dense text only adds to the realism. Happily, the content of the text seems to be some remarkably well-disguised trippy-hippy post-modernist anti-establishment pseudo-feminist rant taken directly from protest speeches from the sixties.

Well Done! This deserves a place on your shelf alongside your bound volumes of The Journal of Improbable Research and other 'Mad Scientist' Jokebooks!

Professor Venkatesan taught a freshman course on "Science, Technology and Society" at Dartmouth where she expounded at length on various post-modern ideas and the concept that, "scientific facts do not correspond to a natural reality but conform to a social construct." During one of those lectures some of her students challenged her and attempted to refute her post-modernist views. Some students applauded the dissidents.

The result was traumatic for Professor Venkatesan and she ended up quitting her job at Dartmouth. She also launched a lawsuit against her students for violating her civil rights. You can read about it in the Wall Street Journal [Dartmouth's 'Hostile' Environment].

After a winter of discontent, the snapping point came while Ms. Venkatesan was lecturing on "ecofeminism," which holds, in part, that scientific advancements benefit the patriarchy but leave women out. One student took issue, and reasonably so – actually, empirically so. But "these weren't thoughtful statements," Ms. Venkatesan protests. "They were irrational." The class thought otherwise. Following what she calls the student's "diatribe," several of his classmates applauded.

Ms. Venkatesan informed her pupils that their behavior was "fascist demagoguery." Then, after consulting a physician about "intellectual distress," she cancelled classes for a week. Thus the pending litigation.

Her lawsuit has been dropped but the fact that she initiated it in the first place is deeply troubling.

Here's the text of the email message she sent to her students.

Date: Sat, 26 Apr 2008 20:56:35 -0400 (EDT)
From: Priya.Venkatesan@Dartmouth.EDU
To: "WRIT.005.17.18-WI08":;, Priya.Venkatesan@Dartmouth.EDU
Subject: WRIT.005.17.18-WI08: Possible lawsuit

Dear former class members of Science, Technology and Society:

I tried to send an email through my server but got undelivered messages. I regret to inform you that I am pursuing a lawsuit in which I am accusing some of you (whom shall go unmentioned in this email) of violating Title VII of anti-federal [SIC] discrimination laws.
The feeling that I am getting from the outside world is that Dartmouth is considered a bigoted place, so this may not be news and I may be successful in this lawsuit.
I am also writing a book detailing my experiences as your instructor, which will "name names" so to speak. I have all of your evaluations and these will be reproduced in the book.

Have a nice day.
Priya

In most of my classes I'd be delighted if students challenged what I was saying and engaged in debate. That's what university is supposed to be all about. The troubling aspect of this case is not only that students were dissatisfied with what Professor Venkatesan was saying in class but, more importantly, that Dartmouth gave her the opportunity to spout such nonsense to freshman students in the first place. What was Dartmouth thinking?

The sad thing is that we know the answer to the last question. There are too many universities these days whose faculties subscribe to the gibberish of these post-modernist pseudo-intellectuals. This may be a bigger threat to university students than creationism.

There's lots of stuff about this on the internet. I wish I could have included a link to some of Venkatesan's supporters but I couldn't find any.

The Dartmouth Review: TDR Interview: Priya Venkatesan '90

Sepiamutiny: The Strange, Twisted Tale of Priya Venkatesan, PhD

The Reference Frame: Priya Venkatesan: a mad scholar sues her students

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[Hat Tip: John Hawks Anthropology Weblog]

Sequence Alignment

Sequence alignment is one of the crucial steps in deciding whether two genes/proteins are homologous. The two sequences are aligned from one end to the other and the number of identical, or similar, residues is counted. If this number reaches a significant percentage of the total length (usually >25%) then the two sequences are homologous—they descend from a common ancestor.

Sequence alignment is not straightforward, even for two sequences, because in addition to substitutions the genes might have undergone insertions or deletions (indels). In order to identify conserved residues, one needs to insert gaps in one sequence or the other to compensate for these indel events.

You can't just willy-nilly stick in gaps to maximize the number of aligned residues because the gaps represent true historical events (insertions and deletions). In theory, you can get high identity scores with any two sequences as long as you insert enough gaps but that isn't allowed. When the alignment is done by computer algorithm, each gap is associated with a gap penalty.

The determination of proper gap penalties is a major challenge in multiple sequence alignment. A crude estimate is that each gap comes with a penalty of 3—that is you have to generate at least three identities in order to make the gap worthwhile. The number of gaps and gap penalties have to be subtracted from the identity/similarity scores when deciding about homology. (This isn't always done.)

Here's an example of a multiple sequence alignment from a region of bacterial HSP70 genes. The letters represent the amino acid residues and the dashes are gaps due to insertions and deletions.


The HSP70 genes are the most highly conserved genes in biology so, in principle, it should be easy to align them. In fact, it is easy in most regions but the one shown above is the most difficult. This is a manual alignment that takes into account the similarities of groups of sequences. Those that are most similar are clustered together and whenever possible the alignment is adjusted so that the positions of the gaps in the most closely related sequences are identical.

This is a procedure known as phylogenetic alignment but it would be better to call it similarity alignment because what we're actually doing is clustering sequences by their overall similarity and not their phylogeny. (The fact that their phylogenetic relatedness closely corresponds to their similarity is a consequence of the the analysis and not a cause.)^1.

The placing of gaps in this region of HSP70 sequences is very difficult. No computer program can come close to achieving the quality of alignments that well trained humans can achieve. That's because the overall alignment has to take into account a number of variables simultaneously and the progressive alignment takes many trial-and-error steps. As a general rule of thumb, if you see a paper where phylogenetic trees are constructed using computer-generated multiple sequence alignments only, then you should assign a low confidence value to that work.

Is this important? Indeed it is. The exact nature and position of the large gap in the above sequences, for example, plays an important role in testing the Three Domain Hypothesis. Different alignments give different trees and the most important variable is the position of gaps.

This brings me to an important paper just published in this week's issue of Science. Löytynoja and Goldman (2008) have developed a new algorithm for multiple sequence alignment. The abstract of their paper describes the problem, and their solution.

Genetic sequence alignment is the basis of many evolutionary and comparative studies, and errors in alignments lead to errors in the interpretation of evolutionary information in genomes. Traditional multiple sequence alignment methods disregard the phylogenetic implications of gap patterns that they create and infer systematically biased alignments with excess deletions and substitutions, too few insertions, and implausible insertion-deletion–event histories. We present a method that prevents these systematic errors by recognizing insertions and deletions as distinct evolutionary events. We show theoretically and practically that this improves the quality of sequence alignments and downstream analyses over a wide range of realistic alignment problems. These results suggest that insertions and sequence turnover are more common than is currently thought and challenge the conventional picture of sequence evolution and mechanisms of functional and structural changes.

The authors test their phylogeny-aware program (PRANK) against several other multiple sequence alignment programs (ClustalW, MAFFT, MUSCLE, and T-COFFEE) using a set of sequences that were "evolved" using a computer program that created substitutions and insertions/deletions. Since the true phylogeny of this artificial set is known, they were able to evaluate the performance of the various programs.

As you might expect, PRANK came out best in this test. I'm not sure that it would work best with real data but that's not really my point. My point is that this is an ongoing problem that has not been fully solved. It is still best to avoid multiple sequence alignments that have not been manually improved by humans with considerable experience in sequence alignment.

I'll close by quoting from the discussion in Löytynoja and Goldman (2008) just to remind everyone how important this is. They argue that even post-alignment human "refinement" of computer generated sequence alignments suffers from systemic bias.

Our analyses show that sequence alignment remains a challenging task, and alignments generated with methods based on the traditional progressive algorithm may lead to seriously incorrect conclusions in evolutionary and comparative studies. The main reason for their systematic error is disregard of the phylogenetic implications of gap patterns created—which is not corrected by considering alignment consistency (13) or using post alignment refinement (14, 15)—and this error is intensified by methods that intentionally force gaps into tight blocks. Affected methods can be positively misleading and become increasingly confident of erroneous solutions as more sequences are included. It is not the progressive algorithm as such that is defective, rather, correct alignment requires that we take account of sequences' phylogeny, irrespective of alignment method used or data type, but the original implementations of the progressive algorithm have a flaw that has gone unnoticed as long as different methods have been consistent in the error they create.

That such a significant error has passed undetected may be explained by the alignment field's historical focus on proteins, where these biases tend to be manifested in less-constrained regions such as loops (compare Fig. 1). Alignments with insertions and deletions squeezed compactly between conserved blocks may suffice for, and even be preferred by, some molecular biologists working with proteins. We have shown, however, that these patterns are, in fact, imposed by systematic biases in alignment algorithms, even in cases where they are incorrect and, indeed, phylogenetically unreasonable. We contend that algorithms that impose gap patterns like those found in structural alignments of proteins are inappropriate for the increasingly widespread analysis of genomic DNA and are likely to cause error when the resulting alignments are used for evolutionary inferences.

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1. In a sense, phylogenetic alignment creates a circular argument. What we're trying to do is to build a phylogenetic tree from the multiple sequence alignments. If we use the presumed phylogeny to generate the alignments then we have a problem. Part of the problem goes away once we recognize that the alignment is driven by clustering similar sequences rather than phylogenetically related sequence.

Löytynoja, A. and Goldman, N. (2008) Phylogeny-Aware Gap Placement Prevents Errors in Sequence Alignment and Evolutionary Analysis. Science 320:1632-1635. [DOI: 10.1126/science.1158395]

A Graduate Student Oath

 
The Institute of Medical Studies (IMS) at the University of Toronto is a large department with many graduate students. Many of them are M.D.s doing clinical research.

The department has instituted a graduate student oath that beginning graduate students recite at their first meeting. The idea is to teach students the value of social and moral responsibilities. Beginning graduate students also have to take a mandatory seminar course on ethics.

The oath is explained and reproduced in this week's issue of science magazine in an article by Davis et al. (2008). Here it is.

"I, [NAME], have entered the serious pursuit of new knowledge as a member of the community of graduate students at the University of Toronto.

"I declare the following:

"Pride: I solemnly declare my pride in belonging to the international community of research scholars.

"Integrity: I promise never to allow financial gain, competitiveness, or ambition cloud my judgment in the conduct of ethical research and scholarship.

"Pursuit: I will pursue knowledge and create knowledge for the greater good, but never to the detriment of colleagues, supervisors, research subjects or the international community of scholars of which I am now a member.

"By pronouncing this Graduate Student Oath, I affirm my commitment to professional conduct and to abide by the principles of ethical conduct and research policies as set out by the University of Toronto."

What do you think? Is this something that all departments should consider?

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Davis, K.D., Seeman, M.V., Chapman, J. and Rotstein, O.D. (2008) A Graduate Student Oath. Science 320:1587-1588. [DOI: 10.1126/science.320.5883.1587b]

Errors in Sequence Databases

Sandra Porter at Discovering Biology in a Digital World brings up an issue that has been bugging me for two decades [Biologists vs. the Age of Information]. The issue is the accuracy of information in biological databases.

Let's begin with GenBank - GenBank is the main database of nucleotide sequences at the NCBI. Sequence data are submitted to GenBank by researchers or sequencing centers. If mistakes are found, the information in the records can be updated by the submitters or by third parties if the corrected versions are published. This correction activity doesn't always happen though, and the requirement for third party annotations to be published makes it pretty unlikely that anyone will submit small corrections to a sequence.

This is why we see these kinds of quotes from Steven Salzberg (3):

So you think that gene you just retrieved from GenBank [1] is correct? Are you certain? If it is a eukaryotic gene, and especially if it is from an unfinished genome, there is a pretty good chance that the amino acid sequence is wrong. And depending on when the genome was sequenced and annotated, there is a chance that the description of its function is wrong too.

This is a serious problem. Most people don't realize that GenBank is full of sequences that are known to be incorrect and/or poorly annotated. In most cases, the errors are relatively minor such as one or two incorrect codons or deletion of a single codon. In other cases, the errors are more important, such as a pseudogene being represented as a real gene, or missing exons. Sometimes the identity of a gene is completely wrong. I've even seen examples where the species is incorrectly identified.

Sandra asks,

So what do we do? Do we care if the database information is up-to-date? If so, who should be responsible for the updates?

I'm sure some people would like the NCBI to be the final authority and just fix everything but I don't think that's very realistic.

Other people have proposed that wikis are the answer. Maybe they're right, but I really wonder if researchers would be any better at updating wikis than they are at updating information in places like the NCBI.

Well, dear readers, what do you think? Does GenBank need to be fixed? Do we just need more alternatives? Does it even matter?

Back in 1992, I spent part of a summer at the GenBank site in Los Alamos (New Mexico, USA). That was before GenBank moved to NCBI in Bethesda. My task was to explore the possibility of curating GenBank to fix all the errors. I worked with the HSP70 sequences since I had already documented most of the errors in those sequences (The HSP70 Sequence Database).

We decided that I could make corrections to any HSP70 sequence as long as I annotated the changes and got permission from the authors by 'phone.¹ This didn't work. Most of the authors were unwilling to allow changes 'cause they weren't aware of the fact that there was a conflict between their sequences and the aligned sequence database. They didn't even know that others had sequenced the same gene and gotten a different sequence.

We discussed this problem. At the time, everyone was aware of the fact that the SwissProt database was curated and that the curators were making decisions on their own about which sequences were correct and which ones were errors. Here's an example of the entry for human HSPA1A showing the conflicts and variations.

Sometimes the SwissProt curators get it wrong and identify the correct sequence as an error and vice versa. Sometimes they really screw up. Here's an example of that mistake [P23931].

Curating a sequence database is incredibly expensive. You need to hire hundreds of competent workers who can analyze every sequence as it comes in. There are some tools that will help identify errors but in order to reach an acceptable level of accuracy you need to build aligned sequence databases for every gene. That can't be done automatically; you need to have real people look at the data and make the best alignment if you are going to use it to make judgements on the accuracy of a submitted sequence.

The final decision at GenBank was to forget about correcting errors and treat the database as an archive of submitted sequences. It would be up to every researcher to become aware of the error-prone nature of the database before drawing any conclusions. I think this was the correct decision—it was the only realistic decision. Unfortunately, the average researcher doesn't realize how may errors are being propagated in the sequence databases.

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1. It was a huge ego-trip to have the power to change records in GenBank. All of the changes I made to other people's sequences have been removed but the ones I made to my own sequences are still there. You can check out [M76613] to see an example of what an annotated sequence could have looked like. Note the references to "old-sequence," "conflict," "variation," and "unsure." These represent differences between the genomic sequence and our older error-prone cDNA sequences.

Kristin Roovers Punished for Falsifying Data

 
Kristin Roovers was a post-doc at the Ottawa Health Research Institute in Ottawa (Canada) until last week. Her job was abruptly terminated when OHRI learned that she had been convicted and punished for falsifying data while she was a graduate student and a post-doc at the University of Pennsylvania. Apparently they first heard that something was wrong from an article in The Chronicles of Higher Education [Journals Find Fakery in Many Images Submitted to Support Research].

Read about it in yesterday's Ottawa Citizen [Researcher's tainted past leads Ottawa health facility to sever ties]. See the fraudulent data on baylab [Kristin-gate at the OHRI].

You can read the July 2007 report from the Office of Research Integrity (USA) at Case Summary - Kristin Roovers.

Here's the question. Why was she hired at OHRI? They probably didn't ask for letters of reference and they certainly didn't Google her name.

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An Unusual Science Conference

 

An unusual science conference was held recently in Azeroth. Many of you, like me, who know where Azeroth is. It's the virtual world of World of Warcraft. There were more than 200 people in attendance.

The three days of meetings were packed full of interesting discussion about science, or so I'm told. What was most exciting were the social events, culminating on the last day when all of the participants died in a mass attack on an enemy fortress. I've never been to a science conference that was quite like that.

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Gunther Stent (1924 - 2008)

 
Gunther Stent was one of the leading figures in the 'phage group, a group of molecular biologists who transformed the science of biology back in the 1940's, '50's, and 60's. He died on June 12th [Gunther Stent, an Early Researcher in Molecular Biology, Is Dead at 84].

Today's Citation Classic from John Dennehy is the book The Molecular Biology of Bacterial Viruses by Gunther Stent. In keeping with his main theme, John often uses the citation classic to highlight the influence of past scientists and not necessarily the significance of a single paper. Stent's name is not associated with any one experiment, or even a series of experiments. His influence extended well beyond his ability to do important experiments.

I first encountered Gunther Stent at the annual 'phage meeting held at Cold Spring Harbor every summer. I learned pretty quickly that he thought on a different plane than the rest of us. I also observed first hand the respect he earned from other famous biologists. At the time I was just a graduate student, I'm certain that Gunther Stent was unaware of my existence.

Later on I began to read Stent's articles on the history and philosophy of biology and I was greatly influenced by his writing.¹ Stent had an amazing ability to sift through the garbage and get to the heart of an argument; especially if that meant going against the perceived wisdom of his intellectual peers. Here are two examples from THE DILEMMA OF SCIENCE AND MORALS published in Zygon in March 1975. Stent is discussing contradictions between modern science and Western moral traditions.

The first example we might consider concerns the teaching of evolution in the public schools, which evidently has come a long way from the days of the Scopes Monkey Trial in Tennessee half a century ago. In 1972 the Curriculum Commission of the California State Board of Education held hearings in response to the demand of some Christian fundamentalist groups that in the officially approved biology textbooks the biblical account of Creation ought to be presented on an equal footing with the Darwinian view as an explanation of the origin of’ life and of the species. Although much of the argument before the Commission pertained to the question of whether the theory of evolution is merely an unproven speculation, as alleged by the fundamentalists, or a solidly documented scientific proposition, as claimed by the biologists, the deeper point at issue was religious freedom.

For the fundamentalists held that a Christian child in a tax supported school has as much right to be protected from the dogmas of atheism as an atheist child has to be protected from prayer. Hence, it would follow that the classroom teaching of Darwinism as the only explanation of biocosmogony is an infringement of the religious freedom of Christian parents to raise their children in the faith of their choice. This argument seems completely justified, whether or not it is true as claimed in pro-Darwinian testimony at the hearings by liberal, apologist clergymen that one can be a good Christian without taking the biblical account of Genesis all that literally. After all, the fundamentalist faith is to take the Bible literally. But the inference that follows from admitting the justice of the fundamentalist claim is not that biology texts should give Genesis equal time with evolution. Rather, it is to be concluded that no public school system can operate effectively in a heterogeneous social setting without having its curriculum prejudice the minds of the pupils against the cherished beliefs of some of the citizens. In other words, in this case the ultimate Christian ethical aim of freedom and individual rights has to give way to the pagan aim of mounting a pedagogically effective society.

The second example is much more controversial, yet the logic is impeccable. This is not the sort of thing that modern liberals (I am one) want to hear, but the very fact that they cover their ears and chant nonsense verses at the top of their lungs is the problem that Stent addresses. Most of us don't realize that the conflict between science and culture is much deeper than the fight between scientist and Biblical literalists would suggest. If you are going to adopt the positions of science and rationalism then there are some implications that may be hard to confront. Sweeping them under the rug, as many try to do, is hypocritical.

We may now consider the ethical conflicts surrounding two applications of human genetics. One of these is the very troublesome matter, at least for present-day American society, of the heritability of intelligence and in particular of the problem whether there exist significant racial differences in intelligence genotype. On the one hand, it seems reasonable to think that if there is a significant variation in the genetic contribution to intelligence between individuals, or between racial groups, then this factor ought to be taken into account in the organization of society. But, on the other hand, the mere acknowledgment of the existence of this factor, let alone taking it into account in social action, seems morally inadmissible, a scientistic underpinning of racist ideology. An excellent exposition of this problem was recently provided by W. Bodmer and L. L. Cavalli-Sforza, who show that the heritability of intelligence, unlike extrasensory perception and telepathy, is a genuine scientific proposition.

First, it is possible to obtain a meaningful measure of intelligence through IQ tests, at least insofar as the concept of intelligence applies to the capacity to succeed in the society in whose contextual setting the tests are given. Second, there do exist significant differences in IQ between individuals and between social and racial subgroups. Third, it is possible, at least in principle, to perform studies that can ascertain the relative contribution of genetic and environmental factors to the observed differences in IQ. Bodmer and Cavalli-Sforza find that there is sufficient evidence at present to make it very likely that within a socioeconomically homogeneous group heredity does make a significant contribution to extant differences in IQ. When it comes to the considerably lower mean IQ of American blacks, however, they conclude not only that the currently available data are inadequate to ascertain whether this fact is attributable mainly to hereditary or mainly to environmental differences, but “that the question of a possible genetic basis for the race IQ differences will be almost impossible to answer satisfactorily before the environmental differences between U.S. blacks and whites have been substantially reduced. . . .” Finally, “[since] for the present at least, no good case can be made for [studies on racial IQ differences], either on scientific or practical grounds, we do not see any point in particularly encouraging the use of public funds for their support. There are many more useful biological problems for the scientist to attack.”

In my opinion, this recommendation, which trivializes the problem scientifically, amounts to taking the easy way out from a serious dilemma. What if, as Bodmer and Cavalli-Sforza admit could be true, there does exist a significant genetic contribution to the mean IQ differences found between blacks and whites? They think that this “should not, in a genuinely democratic society free of race prejudice, make any differene.”’~ But if the races really differed hereditarily in intelligence, then racism would not be a “prejudice” but a true perception ofthe world and one of which a rational society ought to take account. For instance, in this case, the black-white disparities in socioeconomic levels would not reflect discrimination at all but merely an underlying biological reality. And hence the aim of an egalitarian, multiracial society would be just another unattainable, utopian dream. We thus encounter another Machiavellian contradiction between the two incompatible ethical systems of our heritage. The pagan ethics of communal purpose, which science serves, would demand that every effort be made to ascertain whether the member races of a multiracial society do in fact differ hereditarily in their intelligence. But the Christian ethics of ultimate values, which inspire science, holds racism to be an absolute evil in that it is subversive of the fundamental concept of the freedom and responsibility of the human soul. Hence, these ethics demand an uncompromisingly hard line against research on race intelligence. Since there must not be any hereditarily determined racial differences in intelligence, research that entertains the possibility of such differences is a priori evil.

In today's world we need more Gunther Stent's, not fewer.

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1. Incidentally, I'm currently reading Richard Dawkin's anthology of Modern Science Writing. Stent is not in that book but, then again, neither are many other scientists who should be there. It's probably no coincidence that most of those scientists express opinions that differ from those of Richard Dawkins.

[Photo Credit: Left-to-right: Esther Lederberg, Gunther Stent, Sydney Brenner and Joshua Lederberg. From Wikipedia : "The original photo is owned by the Esther M. Zimmer Lederberg Estate. With the permission of that Estate's Trustee, Matthew Simon, I have adapted the photo for free use."