Sleepy Hollow

This is a view of the cemetery of the Old Dutch Church of Sleepy Hollow. It was taken by a visitor who posted it on the Friends of the Old Dutch Burying Gorund website.

The church, which you can see in the background of the photo, was built in 1697 in what was then called Phillips Burgh. It is now located in Tarrytown, New York, north of New York City on the east bank of the Hudson river. Sleepy hollow was made famous by Washington Irving, who is buried in this cemetery [The Legend of Sleepy Hollow].

From the listless repose of the place, and the peculiar character of its inhabitants, who are descendants from the original Dutch settlers, this sequestered glen has long been known by the name of SLEEPY HOLLOW, and its rustic lads are called the Sleepy Hollow Boys throughout all the neighboring country. A drowsy, dreamy influence seems to hang over the land, and to pervade the very atmosphere. Some say that the place was bewitched by a high German doctor, during the early days of the settlement; others, that an old Indian chief, the prophet or wizard of his tribe, held his pow-wows there before the country was discovered by Master Hendrick Hudson. Certain it is, the place still continues under the sway of some witching power, that holds a spell over the minds of the good people, causing them to walk in a continual reverie. They are given to all kinds of marvellous beliefs; are subject to trances and visions; and frequently see strange sights, and hear music and voices in the air. The whole neighborhood abounds with local tales, haunted spots, and twilight superstitions; stars shoot and meteors glare oftener across the valley than in any other part of the country, and the nightmare, with her whole nine fold, seems to make it the favorite scene of her gambols.

The dominant spirit, however, that haunts this enchanted region, and seems to be commander-in-chief of all the powers of the air, is the apparition of a figure on horseback without a head.

Phillips Burgh was settled in the late 1600s, mostly by Dutch settlers from New York (New Amsterdam). The original Dutch colony was lost to the English in the Second Anglo-Dutch war, which ended in 1667 and the Dutch territory was permanently ceded to England after the Third Anglo-Dutch war ending in 1674.

One group of settlers were not Dutch but Canadian. The David sibship consisted of Carel David, David David, Angelica David, Mathys David, Margaret David, and Daniel David. They were born in Laval, Quebec (Canada) and moved to New York with their parents Guillaume David and Marie (Armand)¹ David. As the children reached adulthood they migrated north to become farmers in Phillips Burgh and they joined the Dutch Church of Sleepy Hollow.

The David family was originally from France and their ancestors can be traced back to Julien David of St. Etienne who was born about 1200. By the time they emigrated to Canada they were Hugenots.²

I am directly descended from Margaret David who married a French soldier named Pierre Montras (Montrose). They moved to Kingston, New York, just up the river from Phillips Burgh. That's where their daughter Margaret Montras was born in 1691. Pierre died in 1703 leaving Margaret with several children who she farmed out to her brothers and sisters in Phillips Burgh. Many of the Montras (Montrose) children also joined the Dutch Church of Sleepy Hollow.

Margaret Montras was probably living with her uncle Carel Davids (name change) when she met and married Harmen Harmse, the son of the Dutch settler Capt. Jan Harmse and his wife Aeltje (Abrahams) Harmse. Jan Harmse was an elder in the Dutch Church of Sleepy Hollow. We can trace Aeltje Abrahams' ancestors (and mine) back to 1555 in Holland.

When Harman married Margaret Montras he took her name as his surname and became known as Harmen Montras. Their fourth child, Peter (Petrus) Montras, was baptized on March 6, 1715 in the Dutch Church of Sleepy Hollow. He is my great- great- great- great- great- great-grandfather. Peter's descendants changed their last name to Montrose or Montross.

Harmen Montras and his wife Margaret Montras are almost certainly buried in the Old Dutch Church of Sleepy Hollow cemetery in unmarked graves and so are Harmen's parents Jan Harmse and Aeltje. That's four direct ancestors of mine. Part of the house built by Jan Harmse is still standing in Irvington, New York.

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1. The maiden name of Guillaume David's wife Marie is not known for certain. It was probably "Harmens" or some variant of that name. She appears to be from New Holland, possibly Manhattan. She was NOT a french "filles à marier" or a "filles du Roi."

2. There is no evidence to support a connection between Guillaume David and the David line in France. In fact, there's no evidence to support the clam that David was French.

The Oldest Non-Living Things on Earth

 
First we had a link to the oldest living thing on Earth [Botany Photo of the Day and the Oldest Living Organism] and now we link to the oldest thing on Earth [Oldest Rocks on Earth Discovered?].

These rocks are found in the Nuvvuagittuq region of Hudson Bay in Northwestern Quebec (Canada). As part of the Canadian shield they have long been known to be among the oldest rocks on Earth. Some of the rocks from this region have now been reliably dated to 4.28 billion years ago making them the oldest rocks known.

The dating technology is based on the decay of samarium to neodymium-142 and the work is published in this week's Science magazine (O'Neil et al. 2008).

These rocks are not the oldest things, however, because there are zircon inclusions from rocks in Western Australia that date back to 4.38 billion years. The zircon crystals probably formed somewhere else and were incorporated into the Australian rocks.

The Canadian rocks might also be much younger, having incorporated bits of older sediment, but for now, it looks like the Canadian shield may actually have formed over four billion years ago.

One thing is clear, Canada and Australia are the oldest countries in the world, by far.

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J. O'Neil, R. W. Carlson, D. Francis, R. K. Stevenson (2008). Neodymium-142 Evidence for Hadean Mafic Crust Science, 321 (5897), 1828-1831 DOI: 10.1126/science.1161925

Botany Photo of the Day and the Oldest Living Organism

 
The oldest known organism on the planet is about 4,800 years old. Find out what that has to do with the Botany Photo of the Day.

It is often very hard to tell the difference between various species of pine. One of the distinguishing characteristics of this species (left) is that it has five needles per cluster. Other species have one, two, or three. I don't know if there is a species with four needles per cluster, or six.

Here's a question for all the adaptationists, is number of needles per fascicle an adaptation or is it just an allele that was fixed by accident? Is it an example of a morphological characteristic that is not an adaptaion?

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One Hundred Words of Science

 
Check out Biocurious where PhilipJ has posted on One hundred words of science. I've suggested a few changes. Look over the list and see whether you agree.

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Unrealistic Expectations

 
Harold Varmus was in town recently to receive the Henry G. Friesen International Prize in Health Research. He made some interesting comments that were reported in last Thursday's issue of the Globe and Mail [Cancer expert warns of too-great expectations]. Bayman spotted it and reported on Balblab [Varmus on "The Cure" for Cancer].

Here's what Varmus said,

Nobel laureate Harold Varmus, head of New York's Memorial Sloan-Kettering Cancer Center, said one of the inherent difficulties in continuing to raise funds for cancer research is to explain to people how difficult the problems are that still lie ahead.

“These problems are really, really tough, and they're going to be knocked off more or less one by one,” he said in an interview in Toronto, where he received one of Canada's highest-profile medical awards, the Henry G. Friesen International Prize in Health Research.

Unrealistic expectations of an imminent cure for cancer have been around since former U.S. president Richard Nixon declared war on the disease in his 1971 State of the Union address, Dr. Varmus said.

They have been fuelled, he said, by a continuous stream of media articles that trumpet some initiative such as the completion of the genome project and then predict a payoff never matched by reality.

And he argued that the culture of unrealistic expectations is encouraged by the way science is taught in schools, with a focus on outcomes rather than process.

This is part of a growing backlash against hype in the media. I think most of us realize that in the past we exploited the naivety of the media in order to advance our pet projects. As we get older we realize that we were wrong to make this pact with the devil and now we want to turn the clock back and emphasize the purity of science and the search for truth.

We want the general public to understand how science is really done and not how we pretended it was done. One of the reasons for this change in attitude is that science has lost credibility for not living up to the hype. Another reason is that we see the problems with a society that doesn't understand how science really works. It makes fighting creationism and other superstitions much harder.

I hate to bring up framing again but I think these two issues are related. For those of us who want to teach the truth about science, framing sounds too much like the old ways that we are trying to put behind us.

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[Photo Credit: In addition to being a Nobel Laureate and President & Chief Executive of Memorial Sloan-Kettering Cancer Center, Varmus is also Co-founder and Chairman of the Board of PLoS: Public Library of Science.]

Nature's Evolution Question

 
The British science magazine Nature asked the following question of each US Presidential candidate [US election: Questioning the candidates].

Do you believe that evolution by means of natural selection is a sufficient explanation for the variety and complexity of life on Earth?

My answer, of course, is "no"; natural selection is not a sufficient explanation. You also need random genetic drift and a host of other things that are part of evolutionary theory.

How would you answer the question, dear readers?

Both candidates did a pretty good job of answering this question.

Obama: I believe in evolution, and I support the strong consensus of the scientific community that evolution is scientifically validated.

McCain said last year, in a Republican primary debate: "I believe in evolution. But I also believe, when I hike the Grand Canyon and see it at sunset, that the hand of God is there also."

They both avoided answering the direct question. Instead, they interpreted the question to be whether they believe in evolution. They both believe in evolution.

Since this is one of the leading science magazines in the world I'm certain that the question was not about believing in evolution. It was designed to discover whether McCain and Obama were adaptationists. There's no other reasonable explanation since it's impossible that Nature wouldn't know the difference between "evolution" and "natural selection." At least I think it's impossible ...

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Joe Who?

 
According to CBS News,

Washington - Vice presidential candidate Joe Biden says today's leaders should take a lesson from the history books and follow fellow Democrat Franklin D. Roosevelt's response to a financial crisis.

"When the stock market crashed, Franklin D. Roosevelt got on the television and didn't just talk about the, you know, the princes of greed. He said, 'Look, here's what happened,'" Barack Obama's running mate recently told the "CBS Evening News."

Except, Republican Herbert Hoover was in office when the stock market crashed in October 1929. There also was no television at the time; TV wasn't introduced to the public until a decade later, at the 1939 World's Fair.

I would have thought the bloggers would be all over this. Have I been reading the wrong blogs?

Lately I've been wondering what happened to Joe Biden. You don't see much about him on television. Now I know why. Maybe he and Sarah should take a very long trip to Afghanistan and let the big boys run for President.

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Howler Monkeys

 
Back in the olden days before blogs, we had the newsgroup talk.origins where the battle between evolution and creation was fought. The newsgroup still exists and it's still very active.

One of the most famous anti-evolutionists on talk.origins was a man named Ted Holden. He was witty and prolific, as well as being a famous internet kook. Ted didn't like the fact that he had to defend himself against attacks from scores of people so he coined the term "Howler Monkeys" to describe the chorus of evolutionists who joined in whenever a creationist appeared. (Ted wasn't exactly a creationist in the traditional sense. There was very little about Ted that was "traditional.")

Here's a posting from Ted Holden in 1995 ...

The clique which dominates talk.origins sees themselves as heroes, doing battle with the powers of darkness in an effort to prevent a return to the dark ages. I once noted that, to any outsider attempting to present anything other than the standard lock-step glop on t.o, they present what amounts to a sort of a tribal reaction, what one might expect from a tree-full of crows confronting a hawk or a tree of howler-monkeys encountering a leopard. The crew has since adopted the term "howler-monkeys" as a heraldic device, or metaphor, and refer to themselves as "howler monkeys" as a badge of honor.

Ted is right about the term "Howler Monkeys." Many people on talk.origins were proud to call themselves Howler Monkeys and meetings of talk.origins participants were called Howlerfests. We had a Toronto Howlerfest in 2005 that brought talk.origins regulars like the Canadian cousin of Prof. Steve Steve (see photo), PZ Myers, Canadian Cynic, John Wilkins, and Jeffrey Shallit who have gone on to to become bloggers. You may have heard of some of these talk.origins alumni.

Many of you don't know about Howler monkeys. Ms. Sandwalk just sent along this National Geographic video of Howler monkeys in action. I don't think she meant it as a compliment.

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How Many Genes Do Nematodes Have? - Pristionchus pacificus Genome

 

Nematodes are small wormlike creatures that live almost everywhere. Many of them are parasites but there are thousands of species that live in the soil. "... it is said that if everything on the earth were to disappear except the nematodes, the outlines of everything would still be visible: the mountains, lakes and oceans, the plants and the animals would all be outlined by the nematodes living in every habitat."¹

The free-living species Caenorhabditis elegans was chosen by Sydney Brenner as a model organism for the study of development [Nobel Laureates: Sydney Brenner, Robert Horvitz, John Sulston]. It turned out to be an excellent choice and by the mid 1990s this small metazoan (multi-cellular animal) was selected as the best metazoan candidate for genome sequencing.

The complete genome sequence was published in 1998. The genome is 100 Mb in size (= 100 million base pairs). This was smaller than the predicted size of the fruit fly genome (165 Mb) or the human genome (3,200 Mb). The first estimates of the number of genes were over 19,000 and at the time this was thought to be a reliable estimate although there were many, including me, who though that it was probably too high.

Over the years we have become more skeptical of these initial gene counts because there are many problems. The location of genes is determined by sophisticated computer programs that are trained to recognize the important characteristics of gene sequences (protein coding genes). This year marks the tenth anniversary of the publication of the C. elegans genome sequence and most people will be surprised to learn that the annotation of this sequence is just beginning to be complete.

A recent paper by James Thomas summarizes the result so far (Thomas, 2008).

Thomas points out that gene prediction suffers from the presence of false positives. One of the complications is pseudogenes, which are not easy to distinguish from real genes. Another complication is proving that a predicted gene is actually functional and not just a computational artifact. There is no better way to resolve these issues than by having real live people look at every potential gene. This is why annotation takes so long.

The latest estimate is 20,140 protein coding genes in the Caenorhabditis elegans genome. The coding regions (exons) would take up about 40 Mb of DNA or 24% of the genome. Most of the remainder is junk DNA.

The number of genes is remarkably close to the original prediction although it should be noted that estimates of the number of genes went up after the initial draft sequence was published. Nevertheless, unlike the gene count in humans, the number of genes has held pretty steady.

The number of genes can be compared to the number in the Drosohila melanoaster genome (~15,000) and the human genome (20,500). These are the only two other eukaryotic metazoan genomes² that have been extensively annotated.

There are about 23,000 distinct transcripts from these genes. What that means is that roughly 18,000 genes produce a single transcript and about 2,000 produce two or three different transcripts by alternative splicing.

The C. elegans genes can be divided into two categories. About 8,000 of them are unique and the remainder belong to gene families. A gene family consists of multiple copies of the same gene in the same genome. The copies (paralogues) may be identical or they may be quite different but still related. Some of the gene families are very large and some have only two members.

There seem to be about 3,000 genes families contributing to the 12,000 genes that are not unique. The bottom line is that there are about 11,000 (8K + 3K) different kinds of gene in C. elegans. Interestingly, only 1800 of these genes are found in both insects (Drosophila) and primates (humans). The rest are restricted to just insets and nematodes or just nematodes (10,000 are found in other nematode species).

James Thomas points out that the determination of orthology (same genes in other species) is much more difficult than one might imagine. Many of the online databases, for example, contain erroneous entries based on faulty predictions. These false predictions propagate so that it often isn't reliable to use the database to confirm that a predicted gene actually exists. That's why he restricts his comparisons to well-annotated genomes wherever possible.

Partially annotated genome sequences of Caenorhabditis brigsae and Caenorhabditis remaneri are available. Orthologous gene comparisons indicate that the three species are remarkably dissimilar for species within the same genus. They probably diverged at least 20 My ago.

A new nematode genome sequence was published this week. The species is Pristionchus pacificus, a parasite of the oriental beetle Examala orientalis (Dieteridh et al. 2008). The authors note that there is a different species of parasitic nematode associated with almost every species of beetle, which means that there are at least as many nematodes as insects.

The Pristionchus pacificus genome is 169 Mb in size, which is considerably larger than the size of the Caenorhabditis elegans genome (100 Mb). P. pacificus has 23,500 genes.

Some of the increase in genome size is due to more genes but this is only a minor difference. Some of it is due to the presence of additional copies of repetitive DNA sequences in P. pacificus but the increase doesn't account for the extra 69 Mb of DNA.

The differences in gene number are almost entirely due to increases in the members of gene families in the P. pacificus genome. Several specific examples were given, notably 250 extra copies of ribosomal protein genes compared to C. elegans.

Another remarkable difference is in the number of genes involved in detoxification, or removal of poisonous substances. There are about 250 extra copies of gene family members in this category. The authors speculate that this expansion may be selection for detoxifying enzymes in parasites as opposed to the free-living C. elegans.

In addition to the various Caenorhabditis species, we now have a complete genome of the nematode Brugia malayi the parasite responsible for filariasis in humans. Pristionchus diverged from Caenorhabditis about 350 My (million years) ago and Brugia diverged from the others about 900 My ago according to Dietrich et al. (2008). Thomas (2008) cautions that these divergence times are based on an underestimate of mutation/fixation rates and that nematodes may be evolving more rapidly than other phyla. Nevertheless, it is clear that nematodes are an ancient, diverse, and abundant group of animals.

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1. Nematoda.

2. See the discussion in the comments for examples of other well-annotated eukaryotic genomes. Yeast is obvious but what about Arabidopsis?

[Photo Credit: Christina Beck]

Christoph Dieterich, Sandra W Clifton, Lisa N Schuster, Asif Chinwalla, Kimberly Delehaunty, Iris Dinkelacker, Lucinda Fulton, Robert Fulton, Jennifer Godfrey, Pat Minx, Makedonka Mitreva, Waltraud Roeseler, Huiyu Tian, Hanh Witte, Shiaw-Pyng Yang, Richard K Wilson, Ralf J Sommer (2008). The Pristionchus pacificus genome provides a unique perspective on nematode lifestyle and parasitism Nature Genetics DOI: 10.1038/ng.227

J. H. Thomas (2008). Genome evolution in Caenorhabditis Briefings in Functional Genomics and Proteomics, 7 (3), 211-216 DOI: 10.1093/bfgp/eln022

In the Words of Sydney Brenner

 
Sydney Brenner says,

Actually, the orgy of fact extraction in which everybody is currently engaged has, like most consumer economies, accumulated a vast debt. This is a debt of theory, and some of us are soon going to have an exciting time paying it back - with interest, I hope.

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I spent 20 years sharing an office with Francis Crick and many new and exciting ideas (both right and wrong) were generated from our conversations.

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I was asked by a student what ethical standards should be adopted by life scientists. I could immediately think of two prescriptions. The first, common to all scientists, is to tell the truth. The second is to stand up for all humanity.

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The attitude of my generation that all problems can be solved in the next decade, and should be solved in the next decade—these expectations are changed. Maybe science should be done better, but more slowly. I think a large number of mediocre people are in science today, and carried along by the system. General concepts are rare. Nobody publishes theory in biology—with few exceptions. Instead they get out the structure of still another protein. I'm not saying it's mindless. But the mind only acts on the day-to-day.

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There will be no difficulty in computer's being adapted to biology. There will be Luddites. But they will be buried.

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There is a strong and widely held belief that all organisms are perfect and that everything within them is there for a function. Believers ascribe to the Darwinian natural selection process a fastidious prescience that it cannot possible have and some go so far as to think that patently useless features of existing organisms are there as an investment for the future ...

Even today, long after the discovery of repetitive sequences and introns, pointing out that 25% of our genome consists of millions of copies of one boring sequence, fails to move audiences. They are all convinced by the argument that if this DNA were totally useless, natural selection would already have removed it. Consequently, it must have a function that still remains to be discovered. Some think that it could even be there for evolution of the future—that is, to allow the creation of new genes. As this was done in the past, they argue, why not in the future? ...

Some years ago I noticed that there are two kinds of rubbish in the world and that most languages have different words to distinguish them. There is the rubbish we keep, which is junk, and the rubbish we throw away, which is garbage. The excess DNA in our genomes is junk, and it is there because it is harmless, as well as being useless, and because the molecular processes generating extra DNA outpace those getting rid of it. Were the extra DNA to become disadvantageous, it would become subject to selection, just as junk that takes up too much space, or is beginning to smell, is instantly converted to garbage.

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The Sydney Brenner quotations above are from Stephen Jay Gould's book The Structure of Evolutionary Theory

Most of what I have said over the years has probably been wrong or uninteresting and deserves to be ignored and forgotten. Consequently I was pleasantly surprised when I recently received a request for a reprint of one of my old columns, published elsewhere, with the exciting news - to me - that it had been quoted by the late Stephen J Gould in his massive book The Structure of Evolutionary Theory and that it had caused him to change his mind on one important issue. I had acquired the book on publication with the intention that as soon as I could find the time I would get down to read all 1,464 pages. Needless to say, all I have now read are the pages that refer to my column.

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I learnt very quickly that the only reason that would be accepted for not attending a committee meeting was that one already had a previous commitment to attend a meeting of another organization on the same day. I therefore invented a society, the Orion Society, a highly secret and very exclusive society that spawned a multitude of committees, sub-committees, working parties, evaluation groups and so on that, regrettably, had a prior claim on my attention. Soon people wanted to know more about this club and some even decided that they would like to join it. However, it was always made clear to them that applications were never entertained and that if they were deemed to qualify for membership they would be discreetly approached at the appropriate time.

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...we need to put everything into an evolutionary framework, simply because complexity arises in biological systems by accretion and modification and not by reinvention. Thus, the properties of many of the components in our cells, whether these are mRNAs or proteins, will be conditioned not only by processes of selection for specified activities and levels because these are positively required but may also take up any value because there are no negative consequences for the organism. This ‘don't care’ condition will almost certainly be present because it is a cheap solution to the regulation problem of complex systems. Thus a 20% or a twofold increase, or indeed the very presence, of a protein may be very significant or totally irrelevant depending on whether it is following a ‘don't care’ condition. Only experiment can decide that.

I once made the remark that two things disappeared in 1990: one was communism, the other was biochemistry and that only one of these should be allowed to come back. Of course, biochemistry never really went away but continued to flourish in the thousands of unread pages of biochemical journals. Protein interactions will not be solved by proteomics or protein chips but by protein biochemistry. The genome sequences tell us about the proteins we can expect to find in cells and give us the tools to make large amounts of the proteins for reconstitution studies and for detailed structural analysis. We do not have to resurrect biochemistry, and it will flourish because it provides the only experimental basis for causal understanding of biological mechanisms. That is why this article is not called ‘The return of biochemistry.’ [from "Biochemistry Strikes Back"]

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Nobel Laureates: Sydney Brenner, Robert Horvitz, John Sulston

 

The Nobel Prize in Physiology or Medicine 2002.

"for their discoveries concerning 'genetic regulation of organ development and programmed cell death'"

Sydney Brenner (1927 - ), H. Robert Horvitz (1947 - ), and John E. Sulston (1942 - ) received the Nobel Prize in Physiology or Medicine for making the nematode Caenorhabditis elegans into a model system that is now studied in hundreds of labs all over the world.

Bob Horvitz was a post-doc with Brenner in Cambridge in the mid-1970s and John Sulstron held a junior staff position at Cambridge under Brenner. Although there were other post-docs and graduate students who began working on C. elegans at this time, Horvitz and Sulstron were the ones making key contributions toward working out the total cell lineage. They were able to trace the fate of each cell from the zygote right through to the adult worm [see Monday's Molecule #89 for an example of a cell lineage].

The Nobel Prize was actually awarded for this achievement and not for establishing C. elegans as an experimental system but most people recognize that Brenner's many achievements had to be recognized in some way or another. The cell lineage work was clearly of Nobel Prize quality, but so were many other things that Brenner did in his career.

If there was a Nobel life-time achievement award, Brenner would have won that.

The press release announcing the 2002 Nobel Prizes does an excellent job of describing the work so I've included the entire thing below.

THEME:
Nobel Laureates

7 October 2002

The Nobel Assembly at Karolinska Institutet has today decided to award The Nobel Prize in Physiology or Medicine for 2002 jointly to

Sydney Brenner, H. Robert Horvitz and John E. Sulston

for their discoveries concerning "genetic regulation of organ development and programmed cell death"

Summary

The human body consists of hundreds of cell types, all originating from the fertilized egg. During the embryonic and foetal periods, the number of cells increase dramatically. The cells mature and become specialized to form the various tissues and organs of the body. Large numbers of cells are formed also in the adult body. In parallel with this generation of new cells, cell death is a normal process, both in the foetus and adult, to maintain the appropriate number of cells in the tissues. This delicate, controlled elimination of cells is called programmed cell death.

This year's Nobel Laureates in Physiology or Medicine have made seminal discoveries concerning the genetic regulation of organ development and programmed cell death. By establishing and using the nematode Caenorhabditis elegans as an experimental model system, possibilities were opened to follow cell division and differentiation from the fertilized egg to the adult. The Laureates have identified key genes regulating organ development and programmed cell death and have shown that corresponding genes exist in higher species, including man. The discoveries are important for medical research and have shed new light on the pathogenesis of many diseases.

Sydney Brenner (b 1927), Berkeley, CA, USA, established C. elegans as a novel experimental model organism. This provided a unique opportunity to link genetic analysis to cell division, differentiation and organ development – and to follow these processes under the microscope. Brenner's discoveries, carried out in Cambridge, UK, laid the foundation for this year's Prize.

John Sulston (b 1942), Cambridge, England, mapped a cell lineage where every cell division and differentiation could be followed in the development of a tissue in C. elegans. He showed that specific cells undergo programmed cell death as an integral part of the normal differentiation process, and he identified the first mutation of a gene participating in the cell death process.

Robert Horvitz (b 1947), Cambridge, MA, USA, has discovered and characterized key genes controlling cell death in C. elegans. He has shown how these genes interact with each other in the cell death process and that corresponding genes exist in humans.
Cell lineage – from egg to adult

All cells in our body are descendents from the fertilized egg cell. Their relationship can be referred to as a cellular pedigree or cell lineage. Cells differentiate and specialize to form various tissues and organs, for example muscle, blood, heart and the nervous system. The human body consists of several hundreds of cell types, and the cooperation between specialized cells makes the body function as an integrated unit. To maintain the appropriate number of cells in the tissues, a fine-tuned balance between cell division and cell death is required. Cells have to differentiate in a correct manner and at the right time during development in order to generate the correct cell type.

It is of considerable biological and medical importance to understand how these complicated processes are controlled. In unicellular model organisms, e.g. bacteria and yeast, organ development and the interplay between different cells cannot be studied. Mammals, on the other hand, are too complex for these basic studies, as they are composed of an enormous number of cells. The nematode C. elegans, being multi-cellular, yet relatively simple, was therefore chosen as the most appropriate model system, which has then led to characterization of these processes also in humans.

Programmed cell death

Normal life requires cell division to generate new cells but also the presence of cell death, so that a balance is maintained in our organs. In an adult human being, more than a thousand billion cells are created every day. At the same time, an equal number of cells die through a controlled "suicide process", referred to as programmed cell death.

Developmental biologists first described programmed cell death. They noted that cell death was necessary for embryonic development, for example when tadpoles undergo metamorphosis to become adult frogs. In the human foetus, the interdigital mesoderm initially formed between fingers and toes is removed by programmed cell death. The vast excess of neuronal cells present during the early stages of brain development is also eliminated by the same mechanism.

The seminal breakthrough in our understanding of programmed cell death was made by this year's Nobel Laureates. They discovered that specific genes control the cellular death program in the nematode C. elegans. Detailed studies in this simple model organism demonstrated that 131 of totally 1090 cells die reproducibly during development, and that this natural cell death is controlled by a unique set of genes.

The model organism C. elegans

Sydney Brenner realized, in the early 1960s, that fundamental questions regarding cell differentiation and organ development were hard to tackle in higher animals. Therefore, a genetically amenable and multicellular model organism simpler than mammals, was required. The ideal solution proved to be the nematode Caenorhabditis elegans. This worm, approximately 1 mm long, has a short generation time and is transparent, which made it possible to follow cell division directly under the microscope.

Brenner provided the basis in a publication from 1974, in which he broke new ground by demonstrating that specific gene mutations could be induced in the genome of C. elegans by the chemical compound EMS (ethyl methane sulphonate). Different mutations could be linked to specific genes and to specific effects on organ development. This combination of genetic analysis and visualization of cell divisions observed under the microscope initiated the discoveries that are awarded by this year's Nobel Prize.

Mapping the cell lineage

John Sulston extended Brenner's work with C. elegans and developed techniques to study all cell divisions in the nematode, from the fertilized egg to the 959 cells in the adult organism. In a publication from 1976, Sulston described the cell lineage for a part of the developing nervous system. He showed that the cell lineage is invariant, i.e. every nematode underwent exactly the same program of cell division and differentiation.

As a result of these findings Sulston made the seminal discovery that specific cells in the cell lineage always die through programmed cell death and that this could be monitored in the living organism. He described the visible steps in the cellular death process and demonstrated the first mutations of genes participating in programmed cell death, including the nuc-1 gene. Sulston also showed that the protein encoded by the nuc-1 gene is required for degradation of the DNA of the dead cell.

Identification of "death genes"

Robert Horvitz continued Brenner's and Sulston's work on the genetics and cell lineage of C. elegans. In a series of elegant experiments that started during the 1970s, Horvitz used C. elegans to investigate whether there was a genetic program controlling cell death. In a pioneering publication from 1986, he identified the first two bona fide "death genes", ced-3 and ced-4. He showed that functional ced-3 and ced-4 genes were a prerequisite for cell death to be executed.

Later, Horvitz showed that another gene, ced-9, protects against cell death by interacting with ced-4 and ced-3. He also identified a number of genes that direct how the dead cell is eliminated. Horvitz showed that the human genome contains a ced-3-like gene. We now know that most genes that are involved in controlling cell death in C. elegans, have counterparts in humans.

Of importance for many research disciplines

The development of C. elegans as a novel experimental model system, the characterization of its invariant cell lineage, and the possibility to link this to genetic analysis have proven valuable for many research disciplines. For example, this is true for developmental biology and for analysis of the functions of various signaling pathways in a multicellular organism. The characterization of genes controlling programmed cell death in C. elegans soon made it possible to identify related genes with similar functions in humans. It is now clear that one of the signaling pathways in humans leading to cell death is evolutionarily well conserved. In this pathway ced-3-, ced-4- and ced-9-like molecules participate. Understanding perturbations in this and other signaling pathways controlling cell death are of prime importance for medicine.

Disease and programmed cell death

Knowledge of programmed cell death has helped us to understand the mechanisms by which some viruses and bacteria invade our cells. We also know that in AIDS, neurodegenerative diseases, stroke and myocardial infarction, cells are lost as a result of excessive cell death. Other diseases, like autoimmune conditions and cancer, are characterized by a reduction in cell death, leading to the survival of cells normally destined to die.

Research on programmed cell death is intense, including in the field of cancer. Many treatment strategies are based on stimulation of the cellular "suicide program". This is, for the future, a most interesting and challenging task to further explore in order to reach a more refined manner to induce cell death in cancer cells.

Using the nematode C. elegans this year's Nobel Laureates have demonstrated how organ development and programmed cell death are genetically regulated. They have identified key genes regulating programmed cell death and demonstrated that corresponding genes exist also in higher animals, including man. The figure schematically illustrates the cell lineage (top left) and the programmed cell death (below) in C. elegans. The fertilized egg cell undergoes a series of cell divisions leading to cell differentiation and cell specialization, eventually producing the adult organism (top right). In C. elegans, all cell divisions and differentiations are invariant, i.e. identical from individual to individual, which made it possible to construct a cell lineage for all cell divisions. During development, 1090 cells are generated, but precisely 131 of these cells are eliminated by programmed cell death. This results in an adult nematode (the hermaphrodite), composed of 959 somatic cells.

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McCain Snubs Letterman

 
Ms. Sandwalk often watches David Letterman but I don't.¹ Last night John McCain called up David Letterman at the last minute to cancel his appearance. Apparently McCain had to rush back to Washington to save the country.

I was told in no uncertain terms that I had to start watching David Letterman because I had missed a good show last night. Well, as it turns out, the best part is already on YouTube. Not a good idea to piss off David Letterman.

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1. It's past my bedtime.

Discussing Junk DNA with an Adaptationist

Adaptationists are scientists who like to find adaptive explanations for all features of organism. For them the concept of junk DNA is difficult to swallow in spite of abundant scientific evidence and in spite of the fact that counter-explanations do not account for the data. Nils Reinton is a molecular biologist working in the field of medical diagnostics and he has been challenging the concept of junk DNA in the comment section of a recent posting. The title of that posting, Everything Is There for a Reason?, was direct response to an earlier posting from Nils where he claimed that we shouldn't label DNA as "junk" because it's a science stopper.

During the discussion in the comment to my posting, I challenged Nils to answer a number of questions. He has responded on his blog SciPhu with Hey junk people, I accept your challenge (part I).

Here are the first four questions with my personal summary of his answers.

Q: Why do pseudogenes and most of the transposon-related sequences look so much like broken genes?

A: They may look like broken genes but they probably have some function.

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Q: Why is the DNA sequence in most of our DNA not conserved?

A: It's not conserved because it's a reservoir for evolution. In addition, it probably contains genes for small RNAs and, as we all know, those predicted small RNA genes are not conserved.

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Q: Why can we delete large segments of mammalian DNA with no observable effect?

A: There is an effect. We just haven't found it yet.

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Q: Why is there so much variations in repetitive DNA within a species? Some people have segments that are ten times longer than segments found in other people. Are all of the nucleotides in the longer segments functional?

A: There are some examples of differences in repeats that do make a difference. Therefore, it is wrong to conclude that most of the variation has no effect. Furthermore, the discovery of copy number variation is a new phenomenon and it may turn out the have profound effects.

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Nils concludes Part 1 by repeating his earlier complaint ..

This belief that there’s hidden function to be found, treasures to unearth if you will, is the difference between those advocating these parts of DNA as “junk” and me. In my opinion, It’s not the details of what is junk and what isn’t, ..- and how much, that bothers me…..

It’s the attitude. To dismiss something as junk is contrary to my idea of science being driven out of curiosity and the need to explore. Curiosity may kill a cat every now and then, but I’ll take that risk and continue to praise the scientist who recognize possibilities in the junk rather than dismissing it.

This is nonsense but I already covered that complaint in my previous posting.

Nils seems to think that the adaptationist program is the only way to remain curious and excited about science. This is in direct contrast to the original Spandrels paper by Gould and Lewontin. They argued that strict application of the adaptationist program prevents people from seeing other possibilities. It's a science stopper.

Gould and Lewontin argued that a pluralist worldview was far superior because it considers a wider range of possible explanations.

Personally, I'm as excited about the possibility that our genome could be 95% junk as I am about the possibility that there may be strange new features that we don't know about. At least the tentative conclusion that much of it is junk has the advantage of being a superior explanation of the data.

The conclusion that most of the DNA has some unknown function in spite of much evidence to the contrary strikes me as non-scientific. To justify it on the ground that such a belief is required in order to maintain an interest in the subject is almost unbelievable.

Incidentally, despite some initial skepticism¹, Richard Dawkins—not usually thought of as the best example of a pluralist—has now resorted to using junk DNA as one of his arguments against Intelligent Design Creationism.

Gene duplications have occurred from time to time throughout the genomes. It is by these, and similar means, that genome size can increase in evolution. But remember the distinction between the total capacity of the whole genome, and the capacity of the proportion that is actually used. Recall that not all the globin genes are actually used. Some of them, like theta in the alpha cluster of globin genes, are pseudogenes, recognizably kin to functional genes in the same genomes, but never actually translated into the action language of protein. Genomes are littered with with nonfunctional pseudogenes, faulty duplicates of functional genes that do nothing, while their functional cousins (the word doesn't even need scare quotes) get on with their business in a different part of the same genome. And there's lots more DNA that doesn't even deserve the name pseudogene. It, too, is derived by duplication, but not duplication of functional genes. It consists of multiple copies of junk, "tandem repeats," and other nonsense that may be useful for forensic detectives but which doesn't seem to be useful in the body itself.
            Richard Dawkins in "The "Information Challenge",
            The Skeptic magazine, 1998

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1. The Extended Phenotype p. 157

What Happened to 30 Biochemistry Graduate Students at Yale?

 
In 1991 there were 30 young people beginning graduate school in the Molecular Biophysics and Biochemistry Progam at Yale University. Where are they now? How many have tenure at a university? The answer might surprise you. Read about the fate of these students in this week's issue of Science [And Then There Was One].

Looking at my own department, there are about 10 Ph.D.'s from a similar cohort and four of them have academic positions in 2008.

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[Hat Tip: Chance and Necsssity]

The Value of Science Blogs

 
Three well-known science bloggers, Shelley Batts (Of Two Minds), Nicholas Anthis (The Scientific Activist), and Tara Smith (Aetiology) have just published an article in PLoS Biology entitled Advancing Science through Conversations: Bridging the Gap between Blogs and the Academy.

I agree with most of what they have to say but there are a couple of problems that aren't addressed in the article. First, the more science blogs we have the more difficult it is to read them all. I'm currently trying to follow 104 science blogs on a daily basis and it's quite a chore. How are we going to sort out the wheat from the chaff and what are we going to do when there's too much wheat?

The second problem concerns the definition of a science blog. We all know that strictly science blogs aren't nearly as entertaining as those that branch off into religion, politics, and other non-science topics. All three of the authors know this because their own blogs are an interesting mix of real science and other things. The authors propose that institutions, such as universities, encourage more science blogging but that will only work for the strictly science blogs and we know that those kind of blogs aren't very popular. Institutions are reluctant to be directly associated with the more popular science blogs, like Pharyngula, because they don't want to be seen as endorsing the private views of faculty members.

The PLoS Biology article says,

Institutions may wish to implement more formal vetting mechanisms, however, such as periodic review by institutional moderators or peer review by official committees of blog-literate individuals, established scientists, and bloggers. Institutions might use one of a variety of mechanisms to confer a visible token of this review—such as a “blog badge”—in order to both reward quality bloggers and help readers identify trusted blogs. A blog badge is simply a small picture or icon that is prominently featured on the blog and represents an award or achievement. Such badges are usually given as awards (such as the “Weblog Awards” or the “MedBlog Awards”), and are awarded to particular outstanding blogs in a variety of categories, such as “Best Group Blog,” “Most Informative,” and “Best Translation of Published Research.” Traditional blogging awards are conferred by a committee who invites submissions until a deadline, reviews them, and then posts the winners on their Web site. The winners can then download the badge to post on their blog. Institutions might find it useful, and bloggers might find it motivating, if institutional blog badges were conferred for particularly insightful posts or as a token for passing their test or review periods. Accumulating these badges would be a public and official way for the institution to reward and validate the blogger, while conferring authority to the blog by letting readers know it has met the criterion for institutional peer review.

I think this may be missing the point of blogs. Their value is based on the fact that there's no "institutional" control or monitoring. There is no peer review. This is the internet and it's free-wheeling and opinionated. I don't know of an "institution" that can officially attach its name to those kind of blogs—although they must tolerate them in the name of academic freedom. (Besides, if we use science press releases as our criterion for judging institutional accuracy, then institutional blog badges aren't going to be worth very much.)

I think we need to rely on bloggers themselves to identify the best blogs.

UPDATE: DrugMonkey does a better job of discussing some of these same issues at Blogging in the Academy: Batts et al, 2008, In addition, the conflict between anonymous blogging—is it desirable?—and institutional support is raised in the article and in the comments.

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[Hat Tip: John Dennehy]