Biochemist Arthur Kornberg (1918 - 2007)

 
Arthur Kornberg died yesterday of respiratory failure. He was 89 [Arthur Kornberg, Biochemist, Dies at 89.

Kornberg won the Nobel Prize in 1959 for his discovery of DNA polymerase (now known as DNA polymerase I). His son, Roger Kornberg was awarded the Nobel Prize last year for working out the structure of RNA polymerase [Nobel Laureate: Roger Kornberg]. Another son, Tom, was co-discoverer of the DNA replication enzymes DNA polymnerase II, and DNA polymerase III. Tom and I were graduate students together in the early 1970's and the lab I was in (B. Alberts) worked on the same problems as Arthur Kornberg's lab at Stanford. Bruce Alberts and Arthur Kornberg received the Gairdner Award here in Toronto in 1995.

Kornberg was proud to be known as a biochemist and he always defended the principles of biochemistry. His autobiography For the Love of Enzymes extolled the virtues of purifying and characterizing enzymes as a way to understanding how life works at the molecular level.

One of his most famous defenses of biochemistry is Kornberg (2004).

Fashions prevail in science as in all human affairs. In recent years, biochemistry has become less fashionable, but there is no doubt that the discipline is important for the full understanding of biology.

Biochemists also know him for creating the Ten Commandments of Enzymology. Unlike the author of the original ten commandments, Kornberg was able to modify and amend his commandments as new developments came along (Kornberg, 2003).

Thou shalt…

• I. Rely on enzymology to resolve and reconstitute biologic events
• II. Trust the universality of biochemistry and the power of microbiology
• III. Not believe something just because you can explain it
• IV. Not waste clean thinking on dirty enzymes
• V. Not waste clean enzymes on dirty substrates
• VI. Use genetics and genomics
• VII. Be aware that cells are molecularly crowded
• VIII. Depend on viruses to open windows
• IX. Remain mindful of the power of radioactive tracers
• X. Employ enzymes as unique reagents

My condolences to the family.

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[Photo Credit: University of Rochester Medical Center]

Kornberg, A. (2004) Biochemistry matters. Nature Structural & Molecular Biology 11:493. [PubMed]

Kornberg, A. (2003) Ten commandments of enzymology, amended. Trends Biochem Sci. 28:515-7. [PubMed]

Reconstituting a Virus

 
This week's citation classic from John Dennehy is
Fraenkel-Conrat and Williams (1955) [This Week's Citation Classic].

This week's citation classic is probably the coolest experiment you've never heard of.

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This Is so Sad!

 
Over the past several days Sandwalk has been spammed with hundreds of comments linking to sites like those listed below. Because I can't keep up with deleting them all, I've had to introduce word verification into the comments posting section of the blog. I'm really, really sad about this.

Why do people behave this way? What ever happened to common decency?

Is there anything I can do to get even?

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Where Am I?

 

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Nobel Laureate: James Batcheller Sumner

 

The Nobel Prize in Chemistry 1946.

"for his discovery that enzymes can be crystallized"



In 1946, James Batcheller Sumner (1887-1955) won the Nobel Prize in Chemistry for crystallizing the enzyme urease from jack bean [see: Dealing with Uric Acid and Monday's Molecule #48]. This was definitive proof that enzymes were proteins, something that was still controversial back when the work was done in the early 1920's.

The Presentation Speech was given by previous Nobel Prize winner Professor A. Tiselius, member of the Nobel Committee for Chemistry of the Royal Swedish Academy of Sciences.

Your Majesty, Royal Highnesses, Ladies and Gentlemen.

In 1897 Eduard Buchner, the German research worker, discovered that sugar can be made to ferment, not only with ordinary yeast, but also with the help of the expressed juices of yeast which contain none of the cells of the Saccharomyces. The discovery was considered so important that in 1907 Buchner was awarded the Nobel Prize for Chemistry.

Why was this apparently somewhat trivial experiment considered to be of such significance? The answer to this question is self-evident, if the development within the research work directed on the elucidation of the chemical nature of the vital processes is followed. Here, as in other fields of research, progress has taken place step by step, and the conquest of new fields has often been very laborious. But there, more than in most fields, a tendency has showed itself to consider the unexplained as inexplicable - which is actually not strange where problems of life and the vital processes are concerned. Thus ordinary yeast consists of living cells, and fermentation was considered by the majority of research workers - among them Pasteur - to be a manifestation of life, i.e. to be inextricably associated with the vital processes in these cells. Buchner's discovery showed that this was not the case. It may be said that thereby, at a blow, an important class of vital processes was removed from the cells into the chemists' laboratories, to be studied there by the chemists' methods. It proved, too, that, apart from fermentation, combustion and respiration, the splitting up of protein substances, fats and carbohydrates, and many other similar reactions which characterise the living cell, could be imitated in the test tube without any cooperation at all from the cells, and that on the whole the same laws held for these reactions as for ordinary chemical processes. But - and this is a very important reservation - this was only possible if extracts or expressed juices of such cells were added to the solution in the test tube. It was then natural to assume that these cell juices or cell extracts contained some substance which had the capacity of initiating and maintaining the reactions and guiding them into the paths they follow in the cell. These unknown active substances were called enzymes or ferments, and the investigation of their effects became one of the principal problems of chemistry during the first decades of this century, which for the rest it still is.

The important question of the nature of the enzymes remained unsolved, however, in spite of the energetic efforts of the research workers. It is manifestly a question of substances of complicated structures, which are present in such extremely small amounts that they, so to speak, slip through the fingers when one tries to grasp them. It is really remarkable to see how far it was possible to get in the study of the effects of the enzymes and the course of the enzymatic reactions, without knowing anything definite about the nature of these very active substances, nay, even without even being quite clear that they were substances which could be isolated in the pure form at all.

In 1926, however, in connection with his studies of a special enzyme "urease", James B. Sumner of Cornell University, Ithaca, U.S.A. succeeded in producing crystals which exhibited strikingly great activity. The basic material was the bean of a South American plant, Canavalia ensiformis, in America called the "jack bean", and the crystals had an activity that was about 700 times as great as that of bean flour. What was still more important was that it was possible to dissolve the substance and re-crystallize it several times without its activity being affected. The crystals proved to consist of a protein substance. Sumner expressed the opinion that in reality this protein substance was the pure enzyme.

As is so often the case with important discoveries, this result will probably to a certain degree have "been in the air", in that at the time it had been assumed in many quarters that the enzymes were protein substances of quite a special nature. On the other hand, Willstätter, the German chemist and Nobel Prize winner, had carried out far-reaching purifying experiments with enzymes and had arrived at results which caused him to doubt whether it was a question of protein substances or carbohydrates at all. We know now that this was due to the fact that Willstätter's purifying methods yielded solutions which were all too weak for it to be possible for chemical reactions to give a definite result.

For the chemist crystallization is the final goal in the preparation of a substance in pure form. Even though crystallizability is not such a reliable criterion of purity in the case of protein substances as in that of simpler substances, nevertheless Sumner's results have now been accepted as verified and thus also accepted as the pioneer work which first convinced research workers that the enzymes are substances which can be purified and isolated in tangible quantities. Thereby the foundation was laid for a more detailed penetration of the chemical nature of these substances, on which an understanding of the reactions taking place in living cells must finally depend.

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[Photo Credit: The photograph of urease crystals is from Sumner (1926) (urease crystals)]

Sumner, J.B. (1926) The Isolation and Crystallization of the Enzyme Urease. J. Biol. Chem. 69:435-441.

I Rank Number One on Google

 
David Ng at The World's Fair has invented a new blogging meme [The World's Fair exceptional "I rank number one on google" meme!!]. The rules are:

I'd like to suggest a meme, where the premise is that you will attempt to find 5 statements, which if you were to type into google (preferably google.com, but we'll take the other country specific ones if need be), you'll find that you are returned with your blog as the number one hit.

Here are my 5 statements ....

• Larry Moran
• Sandwalk
• Three Domain Hypothesis
• adaptationist-pluralist
• is there a genetic component to intelligence

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[Hat Tip: PZ Myers at Pharyngula (#1 on Google!)]

Tangled Bank #91

 
The latest version of the Tangled Bank has been posted on The Radula [Tangled Bank #91].

This one is remarkable because I finally figured out how to submit an article. The people who run this carnival don't make it easy.

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Dealing with Uric Acid

Most animals have to deal with excess nitrogen, which they get from food. One of the common sources is the nitrogen in purines such as adenosine, guanosine, deoxyadenosine, and deoxyguanosine. These nucleosides are broken down into the bases adenine and guanine plus the sugars, ribose and deoxyribose.

Adenine and guanine are converted to uric acid, via xanthine. Uric acid cannot be further metabolized in birds, some reptiles, and primates. These species excrete uric acid in their urine. They also excrete urea but this is derived from the breakdown of amino acids.

All other species convert uric acid to allantoin. This is the end product for most mammals, turtles, some insects, and gastropods. The remaining species can break down allantoin to allantoate and this product is excreted in some bony fishes.

The next step in the degradation pathway is the splitting of allantoate to two molecules of urea. Urea derived from purines is excreted by most fishes, amphibians, and freshwater mollusks. The remaining animal species degrade urea to ammonia and carbon dioxide using the enzyme urease.

In some cases the free bases adenine and guanine are salvaged to be used in synthesizing ATP, RNA, and DNA. The salvage pathways require special enzymes to recover the bases. Adenosine phosphoribosyltransferease converts adenine back to AMP and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) salvages hypoxantinine and guanine.

Lesch-Nyhan Syndrome and Gout

As with other pathways, defects in purine metabolism can have devastating effects. In 1964 Michael Lesch and William Nyhan described a severe metabolic disease characterized by mental retardation, palsylike spasticity, and a bizarre tendency toward self-mutilation. Individuals afflicted with this disease, called Lesch–Nyhan syndrome, rarely survive past childhood. Prominent biochemical features of the disease are the excretion of up to six times the normal amount of uric acid and a greatly increased rate of purine biosynthesis. The disease is caused by a hereditary deficiency of the activity of the enzyme hypoxanthine–guanine phosphoribosyltransferase ((HGPRT) [OMIM 300322]. The disease is usually restricted to males because the mutation is recessive and the gene for this enzyme is on the X chromosome (Xq26-27.2). Lesch–Nyhan patients usually have less than 1% of the normal activity of the enzyme and most show a complete absence of activity. In the absence of hypoxanthine–guanine phosphoribosyltransferase, hypoxanthine and guanine are degraded to uric acid instead of being converted to IMP and GMP, respectively. The PRPP normally used for the salvage of hypoxanthine and guanine contributes to the synthesis of excessive amounts of IMP, and the surplus IMP is degraded to uric acid. It is not known how this single enzyme defect causes the various behavioral symptoms. The catastrophic effects of the deficiency indicate that in some cells the purine salvage pathway in humans is not just an energy-saving addendum to the central pathways of purine nucleotide metabolism.

Gout is a disease caused by the overproduction or inadequate excretion of uric acid. Sodium urate is relatively insoluble, and when its concentration in blood is elevated, it can crystallize (sometimes along with uric acid) in soft tissues, especially the kidney, and in toes and joints. Gout has several causes, including a deficiency of hypoxanthine–guanine phosphoribosyltransferase activity, which results in less salvage of purines and more catabolic production of uric acid. The difference between gout and Lesch–Nyhan syndrome is due to the fact that gout patients retain up to 10% enzyme activity. Gout can also be caused by defective regulation of purine biosynthesis.

Gout can be treated by giving patients allopurinol, a synthetic C-7, N-8 positional isomer of hypoxanthine. Allopurinol is converted in cells to oxypurinol, a powerful inhibitor of xanthine dehydrogenase. (Xanthine dehydrogenase is the enzyme responsible for synthesis of uric acid.) Administration of allopurinol prevents the formation of abnormally high levels of uric acid. Hypoxanthine and xanthine are more soluble than sodium urate and uric acid, and when they are not reused by salvage reactions, they are excreted.

Allopurinol and oxypurinol. Xanthine dehydrogenase catalyzes the oxidation of allopurinol, an isomer of hypoxanthine. The product, oxypurinol, binds tightly to xanthine dehydrogenase, inhibiting the enzyme.

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[The text and figures in the box are from Horton et al. (2006) Principles of Biochemistry ©L.A. Moran and Pearson/Prentice Hall]

[The gout cartoon is by James Gillray 1799]

No Intelligence Allowed

 
Ben Stein is the star of a new film that's about to be released. It's called Expelled: No Intelligence Allowed and it's supposed to document the behavior of the evil atheist Darwinists who are suppressing the truth about how life began. (It was God that did it, dummy.)

Stein is interviewed by Bill O'Reilly, providing us with an excellent example of the intelligence that's being expelled from scientific debate. Why in the world should we have any respect for the opinion of Ben Stein?



One of the things that constantly amazes me about this issue is how people like Bill O'Reilly can survive on a major TV network. I guess intelligence isn't a requirement.

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[Hat Tip: PZ Myers at Pharyngula (Two people vying to out-stupid each other)]

Why Five Fingers?

Josh Rosenau is settling into his new job at the National Center for Science Education (NCSE). Part of his mission is to educate us in the ways of evolution and so far he's doing a great job. NCSE has always had a correct perspective on evolution, as far as I'm concerned, even though some of the people who used to work there tended to favor adaptationism.

Here's Josh's latest from his blog Traveling from Kansas [The Panglossian Paradigm, or as science moves forward, creationists move back]. Note that the opinions on his blog do not necessarily reflect those of NCSE.

For really confused students, I draw on a point Stephen Jay Gould made in Eight Little Piggies (in the essay by the same name), that the number of fingers we have is entirely contingent on history. While one can try to construct an explanation for the superiority of 5 fingers, paleontological history shows that there were potential ancestors of the tetrapod clade (which we are part of) which had as many as eight rays per fin. If they had succeeded, 8 fingers would be the norm, and the Simpsons would look very odd with only 4. As Gould says of historical contingency: "Other configurations would have worked and might have evolved, but they didn't--and five works well enough."

In the essay, Gould is building on a point he made most forcefully in an essay he wrote with Richard Lewontin, "The Spandrels of San Marcos and the Panglossian Paradigm: A Critique of the Adaptationist Program." The point was that biologists were too quick to insist that every feature was adaptive and a result of natural selection. Spandrels are triangular structures produced when two round arches meet. They are necessary byproducts of joining rounded and flat surfaces. Nonetheless, in many churches they are richly decorated and the entire artistic vision for a space can be shaped by the spandrels. One might, Gould points out, be lead to think that the spandrels are there in order to be used for paintings, and not that they are necessary by-products nicely dressed up. The worldview he criticizes treats anything, whether spandrels or five fingers, as the product of intense selection, a perfect solution to the problems it faces.

There's lot more where that came from so get on over to Travelling from Kansas for more information on the "correct" worldview.

By coincidence, today's Scientific American question is Why do most species have five digits on their hands and feet?. While there's a bit of catering to an adaptationist perspective the answer to the question is ...

Is there really any good evidence that five, rather than, say, four or six, digits was biomechanically preferable for the common ancestor of modern tetrapods? The answer has to be "No," in part because a whole range of tetrapods have reduced their numbers of digits further still. In addition, we lack any six-digit examples to investigate. This leads to the second part of the answer, which is to note that although digit numbers can be reduced, they very rarely increase. In a general sense this trait reflects the developmental-evolutionary rule that it is easier to lose something than it is to regain it. Even so, given the immensity of evolutionary time and the extraordinary variety of vertebrate bodies, the striking absence of truly six-digit limbs in today's fauna highlights some sort of constraint.

Remember the take-home lesson (mostly from Josh's article). Living organisms are not well designed in spite of what the creationists and the adaptationists would have you believe.

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Monday's Molecule #48

 
Today's molecule is several molecules and a reaction. You have to identify all the molecules in the reaction and name the common enzyme that catalyzes the reaction.

There's connection between this reaction and Wednesday's Nobel Laureate(s).

The reward goes to the person who correctly identifies the molecules, the enzyme, and the Nobel Laureate(s). Previous free lunch winners are ineligible for one month from the time they first collected the prize. There are only two ineligible candidates for this Wednesday's reward. The prize is a free lunch at the Faculty Club.

Send your guess to Sandwalk (sandwalk(at)bioinfo.med.utoronto.ca) and I'll pick the first email message that correctly identifies the molecules, the enzyme, and the Nobel Laureate(s). Correct responses will be posted tomorrow along with the time that the message was received on my server. This way I may select multiple winners if several people get it right. This one is easy. Get your response in quickly.

Comments will be blocked for 24 hours. Comments are not open.

UPDATE: We have a winner!

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Gene Genie #18

 

The 18th edition of Gene Genie has just been published on Eye on DNA [Gene Genie #18 with the PG Tips Chimp].

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Is There a Genetic Component to "Intelligence"?

 
This is not my field and, quite frankly, I don't really care about any differences or similarities in intelligence between different human demes. However, the recent kerfuffle over the intemperate remarks of a Jim Watson have raised a number of interesting issues. One of these is whether there is a genetic component to intelligence.

I have always thought there was. I remember reading Richard Dawkins' take on this subject some years ago. He pointed out that if the average "intelligence" of humans has increased over the past million years by evolution then it follows logically that there were genes (alleles) for differences in intelligence that were selected. It seems unreasonable to imagine that all the alleles have reached fixation so that in today's 7 billion members of the Homo sapiens species there is no genetic variation for "intelligence." (I'm putting "intelligence" in quotation marks because I don't want to get into protracted battles about how to measure it or even how to define it. Let's just agree that there's something called intelligence that exists.)

Up until now I have been under the impression that certain genetic defects resulted in lowered intelligence. For example, Down's Syndrome is strongly correlated with low scores on an IQ test suggesting that the presence of extra chromosome 21 genes affects intelligence. That's a genetic component of intelligence by most reasonable definitions.

In spite of evidence to the contrary, there seem to be a number of people who deny that there's a genetic component to intelligence. One of these is Greg Laden, whose opinion I greatly respect. In a recent posting [Watson’s Lecture Canceled] he even disputes the twin studies that show a strong correlation between intelligence and heritability.

Heritability does not distinguish in and of itself between traits passed on with genes from traits passed on via culture, learning, environment, and so on. For instance, which language a person speaks has a very high heritability value, but this “trait” is entirely, 100% learned with absolutely no genetic component whatsoever. Twin studies have been used to suggest that IQ has a component of heritability that is genetic since it is more correlated in twins than in, say, full sibs. However, non-genetic traits can follow the same pattern. Non-genetic traits can show this pattern because, with respect to environments, full sibs who are not twins do not share the same environment as twins. (And for other reasons.)

It seems to me that Greg is arguing against a genetic component to intelligence. He seems to be going out of his way to discredit any studies that suggest otherwise. I'm not sure where he's coming from on this and that's the reason for posing the question in this posting.

Later on in the comments section of Greg's article he says the following.

We have, on this site anyway, not discussed the fact that neural development in humans does not really allow for much influence from genetics in the way that is asserted by the Rushtonian race argument; we have seen some discussion that the allegations that intelligence = g = IQ = something measurable in a simple way = something that varies across individuals because of allelic differences in some set of genes. But there are a LOT of reasons to not accept this idea, aside from the major disconnect between the genome and the functioning of the brain owing to the actual way real brains actually develop in real life. There has been very little discussion regarding the disconnect between the concept of heritability and the concept of subspecies in animals (race is simply another term for subspecies).

There are so many levels at which this is so wrong that I can’t help but feel … and I’ve said this already … that the Race Concept and the intelligence piece of this are simply not valid scientific arguments, and are almost always either political arguments or arguments being made from ignorance. They are political in their motivation, because the science here is simply operating in a totally different place (a little place I call reality).

Clear as mud. I fully sympathize with the mixture of politics and science that confuses this issue. There are people who want there to be differences in intelligence between races because it fits with their political agenda.

I wonder if there aren't people who believe the opposite because it fits with their political agenda? I wonder if there aren't people who go out of their way to construct pseudo-scientific arguments denying that there can be a genetic component to intelligence. Why would they do this? Because if there's no genetic component to intelligence then there can be no differences between demes and this avoids a messy political debate.

Frankly, I'm not sure if Greg Laden is doing this so I'd like to see some clarification. Is there a genetic component to intelligence? Are there "intelligence" alleles segregating within the human population such that some people are smarter than others because of their parents and not just because of socioeconomic environment? Or, are all differences in intelligence due to environment?

Please, let's not let this thread degenerate into a discussion about racism. Let's talk about the science and stick to the question.

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The It's Its There Their They're Quiz

 

You Scored an A

You got 10/10 questions correct. It's pretty obvious that you don't make basic grammatical errors. If anything, you're annoyed when people make simple mistakes on their blogs. As far as people with bad grammar go, you know they're only human. And it's humanity and its current condition that truly disturb you sometimes.

The It's Its There Their They're Quiz

This is a quiz designed to find out whether you know the difference between its, it's, they're, their, and there. I doubt very much whether any blogger, or any reader, would get less than 10 on this quiz.

We all make mistakes from time to time. The problem isn't that we don't know the right word it's that we sometimes slip up when we're typing quickly and not concentrating on grammar. I am not one of those people who jump all over a fellow blogger when they make a mistake. I assume they're just like me. We're perfect in lots of things but attention to silly details like spelling isn't one of them.

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[Hat Tip: GrrlScientist at Living the Scientific Life (How is Your Punctuation and Grammar?]

I knew There Had to Be a Good Reason!

 
(for avoiding tofu)

Eating soya could slash men's sperm count.

Men who eat just half a serving of soya a day have drastically fewer sperm than those who do not consume such foods, according to a small, preliminary study.

The study's researchers say larger trials are needed to determine whether men hoping to conceive a child should try to avoid soya foods, such as tofu, tempeh and soya milk. However, soya industry representatives caution that the new findings contradict earlier studies that have shown no impact on sperm count from soya-based products.

Soya foods contain high amounts of isoflavones, compounds that mimic the effects of oestrogen in the body. For this reason, women sometimes increase their intake of soya foods to treat hot flushes caused by declining oestrogen levels in menopause.

Oestrogen-like compounds can also have a dramatic impact on the male body. And previous rodent studies have suggested that high intake of soya products can reduce male fertility. This has led scientists to wonder how isoflavones might influence men's reproductive function, which is highly sensitive to hormones.

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I'm skeptical of everything about nutrition and health but one of the important things about this study is that it alerts people to the presence of strange chemicals in natural plant foods. This is something that most people need to know in order to put nutritional studies into perspective. There are a lot of potentially dangerous chemicals in plants but the vast majority have no effect whatsoever.