Monday's Molecule #97

 
Today we're taking a bit of a break from boring old biochemical molecules and fruit flies to look at some specific individuals of the species Homo sapiens. Your task for today is to identify these men. I need all of their names and the name that collectively identifies them.

The answer is indirectly related to this week's Nobel Laureate. See if you can make the connection.

The first one to correctly identify the individuals 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 only three ineligible candidates for this week's reward: Bill Chaney of the University of Nebraska, Dima Klenchin of the University of Wisconsin and Dale Hoyt from Athens, Georgia. Dale has agreed to donate the free lunch to a deserving undergraduate so the first undergraduate to win and collect a free lunch can also invite a friend.

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 reserve the right to select multiple winners if several people get it right.

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

The band is Aerosmith and this should remind you of the book "Arrowsmith" by Sinclair Lewis who won the Nobel Prize for Literature in 1930. Arrowsmith is a book about scientists.

Three people knew who the band was—one of them was Ms. Sandwalk! Only one person saw the connection between Aerosmith and a Nobel Laureate but that person (Dima) is ineligible. I decided to award the free lunch to Ms. Sandwalk, making her ineligible for any more lunches for one month!!!

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Hide it under a bushel? NO!

 

This is the latest in Christmas decorations from the American Family Association.

Let Your "Light" Shine For Christ This Christmas Season!

Looking for an effective way to express your Christian faith this Christmas season to honor our Lord Jesus? Now you can.... with the "Original Christmas Cross" yard decoration.

Light up your front yard, porch, patio, driveway, business, organization or church this holiday season with a stunning Christmas cross.

Can't you just picture these five and-a-half foot crosses in the middle of front yards all across America?

What in the world are they thinking?

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[Hat Tip: LuLu at Canadian Cynic]

Be Afraid

 
There have been some changes on Uncommon Descent. Bill Dembski won't be posting as often (Boo!) and the chief web person will be Barry Arrington [What’s New At UD].

Here's a warning from the new chief IDiot.

We live in exciting times. The Darwinist/materialist hegemony over our culture has definitely peaked, and we are privileged to watch the initial tremors that are shaking the Darwinist house of cards. These are only the beginning of woes for St. Charles’ disciples, and I look forward to one day watching the entire rotten edifice come crashing down. I am persuaded that just as when the Soviet Union went seemingly overnight from “menacing colossus astride the globe” to “non-existent,” the final crash of the House of Darwin will happen with astonishing suddenness. You can be sure that we at UD will be there not only reporting on events, but also lending our intellectual pry bars to the effort.

Hmmm ... "intellectual pry bars" ... that's an image that's going to be hard to shake.

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Why do we blog and other important questions

 
OK, so I'm not a Nature Network blogger, but I thought I'd answer the questions anyway.

1. What is your blog about?
   It's about science, religion, universities, politics, and almost everything else I'm interested in. Mostly science and science education.


2. What will you never write about?
   Aha! A trick question! You almost got me!


3. Have you ever considered leaving science?
   No.


4. What would you do instead?
   I dunno, what do other people do? (Eva has a much funnier reply to this question)


5. What do you think will science blogging be like in 5 years?
   Pretty much the same as it is now. Which is pretty much the same as it's been for the past five years. Which isn't a lot different than the newsgroups were for the previous 20 years before that.


6. What is the most extraordinary thing that happened to you because of blogging?
   I've made dozens of new friends. (For me, that's extraordinary.)


7. Did you write a blog post or comment you later regretted?
   Yes.


8. When did you first learn about science blogging?
   I don't recall exactly. It was probably sometime around 2002 when I first learned that people were actually reading them.


9. What do your colleagues at work say about your blogging?
   Most of them don't understand the blogging culture. They think it's bizarre. They think I'm bizarre—but they thought that even before I started Sandwalk

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Be the First in Your School

 
Be the first in your school, or church, to have one of these T-shirts—or others like it. (It also comes in red and black.) Go to Evo-Ts.

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Making Sense in Biology

When I teach students how to read the scientific literature, I caution them not to believe everything they read. Science is, by it's very nature, tentative and exploratory. Much of what is published doesn't get confirmed and is quietly ignored. Many of the ideas and speculations that are published never amount to anything. Some experiments are flawed. Many skim over hidden assumptions so that the conclusions aren't valid.

How do you tell the difference between the wheat and the chaff? Well, for one thing, you ask yourself whether the results "make sense" in light of what you already know. Are there any basic principles of biology that conflict with the conclusions? You always have to be on the lookout for papers that just don't fit in with your current model of how things work.

There are two potential problems with this approach. First, your model may not be correct. Maybe you don't know enough to make a judgment. Second, it prevents you from recognizing truly novel results that may change your idea of what makes sense.

The first problem is curable. The second is more serious. Science is basically conservative in its acceptance of new ideas. This may seem like a bad thing but, in fact, it's the only way to do good science. You simply can't afford to believe in several paradigm shifts every day before breakfast because most of them will turn out to be wrong. Today, when scientists want to convince their colleagues of something new that may not "make sense", they are obliged to present solid evidence that will convince the skeptics. It's an uphill fight. And it should be.

One of my colleagues has been following the discussion about alternative splicing and he directed my attention to a paper he just published in Nature Genetics. He pointed out that far from being an overestimate of alternative splicing, the EST data actually underestimates the extent of alternative splicing.

The paper by Pan et al. (2008) makes two extraordinary claims.

1. Their data indicates that about 95% of all multiexon human genes undergo alternative splicing.
2. They estimate that there are, on average, seven (7) alternative splicing events per multiexon human gene.

Neither of these claims make sense. It's not reasonable to assume that most conserved housekeeping genes produce variants by alternative splicing yet that's exactly what would have to happen if 95% of all genes undergo alternative splicing. It means that most most genes for things like metabolic enzymes, RNA polymerase, ribosomal proteins and transport proteins will have variants due to alternative splicing. This doesn't make sense from an understanding of biochemistry and it doesn't make sense in light of evolution.

That's good reason to be skeptical.

But surely the data must be convincing? Surely the proponents of these extraordinary claims have extraordinary data to back their cease?

Frankly, I don't know. I can't evaluate the Pan et al. (2008) paper because I have no idea how they actually do their experiments and whether those experiments are reliable. Part of the problem is that the authors don't tell me enough and part of it is that this is unfamiliar technology (to me).

All I know is that it doesn't make sense. I've asked the author to give me some specific examples of alternative splicing predictions for common genes, like those in the citric acid cycle. By looking at specific, rather than global, data it might be possible to see whether the results make sense.

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Pan, Q., Shai, O., Lee, L.J., Frey, B.J. and Blencowe, B.J. (2008) Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nature Genetics, published online Nov. 2, 2008. [DOI:10.1038/ng.259]

Students and a Sense of Entitlement

 
A recent study by Greenberger et al. (2008) looked at student's sense of entitlement in order to see where it comes from. Here's the abstract ...

Abstract Anecdotal evidence suggests an increase in entitled attitudes and behaviors of youth in school and college settings. Using a newly developed scale to assess ‘‘academic entitlement’’ (AE), a construct that includesexpectations of high grades for modest effort and demanding attitudes towards teachers, this research is the first to investigate the phenomenon systematically. In two separate samples of ethnically diverse college students comprised largely of East and Southeast Asian American, followed by Caucasians, Latinos, and other groups (total N = 839, age range 18–25 years), we examined the personality, parenting, and motivational correlates of AE. AE was most strongly related to exploitive attitudes towards others and moderately related to an overall sense of entitlement and to narcissism. Students who reported more academically entitled attitudes perceived their parents as exerting achievement pressure marked by social comparison with other youth and materially rewarding good grades, scored higher than their peers in achievement anxiety and extrinsic motivation, and engaged in more academic dishonesty. AE was not significantly associated with GPA.

I don't put a lot of credence in these studies but I thought it was interesting that the problem was at least being investigated. The survey results, below, are interesting.

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[Hat Tip: Musings of the Mad Biologist]

Greenberger, E., Lessard, J., Chen, C. and Farruggia, S.P. (2008) Self-Entitled College Students: Contributions of Personality, Parenting, and Motivational Factors. Journal of Youth and Adolescence 37:1193-1204 [Springerlink]

Tangled Bank #118

 
The latest issue of Tangled Bank has been published on Submitted to a Candid World [Tangled Bank #118: Yes We Did Edition].

It’s my pleasure to bring you this edition of Tangled Bank, a biweekly collection of posts on important issues of biology and science. How I managed to secure the first post-election Tangled Bank for this little politics blog is beyond me: far be it for me to complain, but it really makes you wonder about PZ Myers’ processes for vetting new hosts… I’ll try my best not to play Sarah Palin to his John McCain.

Common readers of this site will know from experience that I, like all the co-writers of this blog, pushed hard for Obama’s election, and new visitors will guess as much from the site’s browser icon (surprise!). Now that the man’s elected, though, there’s a lot of work to be done - especially because, over the past eight years, scientific integrity somehow became a Democrats-only issue. America’s science community has a lot of ground to recover and, until Obama decides to restore the office to its pre-Bush grandeur, we, the concerned netroots, are the closest thing he has to White House science advisers. Thus, I present to you President-Elect Barack Obama’s first science briefing -

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Send an email message to host@tangledbank.net if you want to submit an article to Tangled Bank. 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.

Nobel Laureate: Edward Lewis

 

The Nobel Prize in Physiology or Medicine 1995.

"for their discoveries concerning the genetic control of early embryonic development"

Edward B. Lewis (1918 - 2004) won the Noble Prize for his studies on the genetics of Drosophila melanogaster, especially the homeotic mutants in the bithorax complex. These are the mutations that cause transformation of the 3nd thoracic segment into the 2nd, giving rise to a fly with four wings instead of two.

The significance of this work can't be underestimated. It led to our modern understanding of development and evolution. Thanks to Lewis, we now know that small changes in the regulation of gene expression can have large effects on phenotype. It means that the number of mutations required to make the difference between mice and humans, for example, may be far less that what people imagined 50 years ago.

Edward Lewis shared the prize with Christiane Nüsslein-Volhard and Eric Wieschaus. Here's what the press release said about Lewis.

THEME:
Nobel Laureates

The fly with the extra pair of wings

Already at the beginning of this century geneticists had noted occasional malformations in Drosophila. In one type of mutation the organ that controls balance (the halteres), was transformed into an extra pair of wings (Fig. 2). In this type of bizarre disturbance of the body plan, cells in one region behave as though they were located in another. The Greek word homeosis was used to describe this type of malformations and the mutations were referred to as homeotic mutations.
Figure 2.

Fig. 2. Comparison of a normal and a four-winged fruit fly. The third thoractic segment has developed as a duplicate of the second due to a defectic homeotic gene. In the normal fly only the second segment develops wings.

The fly with the extra pair of wings interested Edward B. Lewis at the California Institute of Technology in Los Angeles. He had, since the beginning of the forties, been trying to analyze the genetic basis for homeotic transformations. Lewis found that the extra pair of wings was due to a duplication of an entire body segment. The mutated genes responsible for this phenomenon were found to be members of a gene family ( bithorax-complex) that controls segmentation along the anterior-posterior body axis (Fig. 3). Genes at the beginning of the complex controlled anterior body segments while genes further down the genetic map controlled more posterior body segments (the colinearity principle). Furthermore, he found that the regions controlled by the individual genes overlapped, and that several genes interacted in a complex manner to specify the development of individual body segments. The fly with the four wings was due to inactivity of the first gene of the bithorax complex in a segment that normally would have produced the halteres, the balancing organ of the fly (Fig 3). This caused other homeotic genes to respecify this particular segment into one that forms wings.

Edward Lewis worked on these problems for decades and was far ahead of his time. In 1978 he summarized his results in a review article and formulated theories about how homeotic genes interact, how the gene order corresponded to the segment order along the body axis, and how the individual genes were expressed. His pioneering work on homeotic genes induced other scientists to examine families of analogous genes in higher organisms. In mammalians, the gene clusters first found in Drosophila have been duplicated into four complexes known as the HOX genes. Human genes in these complexes are sufficiently similar to their Drosophila analogues they can restore some of the normal functions of mutant Drosophila genes.

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[The book is a tribute to Edward Lewis, edited by my colleague Howard D. Lipshitz.]

[Image Credit: California Institute of Technology]

Two Examples of "Alternative Splicing"

THEME:
Transcription
Last week I bumped into a colleague who teaches in our third year molecular biology course. I was lamenting about the sad state of science these days and we got to talking about alternative splicing. I repeated my complaint that much of the predicted alternative splice variants are artifacts. It makes no sense that conserved genes would be producing alternative protein variants that are species specific. I am convinced that the EST databases are full of artifacts and that most predicted splice variants do not exist.

My colleague was shocked. He is firmly convinced that most human genes express a number of different protein products that are produced as the result of alternatively spliced mRNA precursors. I asked him if he had ever looked at his favorite genes to see if the predicted variants make any sense. The ones that I've looked at certainly don't. (Join in the fun: see the challenge below.)

My colleague is very knowledgeable about the genes for the major subunits of eukaryotic RNA polymerase since it was his lab that cloned the first one. I suggested that he look at the predicted alternative splice variants of the two human genes and let me know if he is still convinced that these variants make biological sense. I'm not sure he will do it so let's take a look ourselves.

Eukaryotic RNA polymerase is a complex protein machine consisting of ten different subunits. Two of the subunits, Rpb1 and Rbp2, are more commonly known as A and B. In the human genome they are encoded by the genes POLR2A and POLR2B respectively [RNA Polymerase Genes in the Human Genome].

If you click on the Entrez Gene URLs you will end up at a page that summarizes what is known about the gene. Down the right-hand side of the page there are links to several other webpages, including a link to AceView, a database of alternative splice variants. Before following this link to the POLR1A variants, let's note that on the annotated Entrez Gene website there are no alternative splice variants listed. Apparently someone has decided that the predicted variants are probably artifacts.

Go to the AceView page for AceView POLR2A. The first thing you see is a short explanation.

RefSeq annotates one representative transcript (NM included in AceView variant.a), but Homo sapiens cDNA sequences in GenBank, filtered against clone rearrangements, coaligned on the genome and clustered in a minimal non-redundant way by the manually supervised AceView program, support at least 11 spliced variants.

AceView summary
Note that this locus is complex: it appears to produce several proteins with no sequence overlap.
Expression: According to AceView, this gene is expressed at very high level, 4.8 times the average gene in this release. The sequence of this gene is defined by 537 GenBank accessions from 518 cDNA clones, some from breast (seen 40 times), marrow (29), head neck (19), brain (18), eye (18), leukopheresis (18), lung tumor (18) and 132 other tissues. We annotate structural defects or features in 13 cDNA clones.
Alternative mRNA variants and regulation: The gene contains 29 different introns (28 gt-ag, 1 gc-ag). Transcription produces 13 different mRNAs, 11 alternatively spliced variants and 2 unspliced forms. There are 7 probable alternative promotors and 5 non overlapping alternative last exons (see the diagram). The mRNAs appear to differ by truncation of the 5' end, truncation of the 3' end, overlapping exons with different boundaries, alternative splicing or retention of 4 introns. 337 bp of this gene are antisense to spliced gene pluvu, raising the possibility of regulated alternate expression.
Protein coding potential: 10 spliced and the unspliced mRNAs putatively encode good proteins, altogether 11 different isoforms (3 complete, 4 COOH complete, 4 partial), some containing domains RNA polymerase Rpb1, domain 1, RNA polymerase, alpha subunit, RNA polymerase Rpb1, domain 3, RNA polymerase Rpb1, domain 4, RNA polymerase Rpb1, domain 5, RNA polymerase Rpb1, domain 6, RNA polymerase Rpb1, domain 7, Eukaryotic RNA polymerase II heptapeptide repeat [Pfam]. The remaining 2 mRNA variants (1 spliced, 1 unspliced) appear not to encode good proteins.

Here's the figure showing the various predicted alternatively spliced transcripts and the various different proteins.


It's really difficult to imagine that any of these are biologically relevant. How could a small bit of the large RNA polymerase subunit ever be part of the RNA polymerase protein complex? It's not a surprise that the Entrez Gene annotators have ignored these predictions.

If, as I believe, most of the small ESTs on which these predictions are based are artifacts, then the overall pattern makes sense. What you see are examples of splicing errors where an intron has not been correctly removed. These extremely rare splicing errors are copied into cDNA during construction of EST libraries and specifically selected by screening out all the correctly spliced mRNAs. (That's how you make most EST libraries.)

Here's what AceView says about the gene for the other large subbunit [AceView: POLR2B].

RefSeq annotates one representative transcript (NM included in AceView variant.a), but Homo sapiens cDNA sequences in GenBank, filtered against clone rearrangements, coaligned on the genome and clustered in a minimal non-redundant way by the manually supervised AceView program, support at least 9 spliced variants.

One again, AceView notes that the annotated human genome has ignored the predicted alternative plice variants but maintains that there are at least nine of them.

Here's the figure, decide for yourself whether this is credible.


There are several well-known examples of human genes producing different protein variants due to alternative splicing. The ones I can think of off the top of my head are the genes for class I antigens, α-tropomyosin, and calcitonin. I'm sure there are half a dozen others.

Here's the challenge. See if you can find a human gene for a well-studied protein where the structure of the protein is known and there are multiple protein variants derived by alternative splicing. I bet that readers of Sandwalk can't find very many where the predicted variants many any sense and are likely to be biologically significant.

What does this mean? Whenever you look at your favorite well-studied gene you see that the predictions of alternative splicing are silly. So why should we believe the genome wide analyses? Is it just a coincidence that the more we learn about a given gene the most we become willing to reject the ESTs as artifacts? Or is it possible that alternative splicing is mostly confined to those genes that have not been well studied?

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Genes and Straw Men

Just in case there's someone who doesn't understand the concept of "straw man," here's a good description from Wikipedia: Straw Man.

A straw man argument is an informal fallacy based on misrepresentation of an opponent's position.[1] To "set up a straw man," one describes a position that superficially resembles an opponent's actual view, yet is easier to refute. Then, one attributes that position to the opponent. For example, someone might deliberately overstate the opponent's position.[1] While a straw man argument may work as a rhetorical technique—and succeed in persuading people—it carries little or no real evidential weight, since the opponent's actual argument has not been refuted.[2]

The term is derived from the practice in ages past of using human-shaped straw dummies in combat training. In such training, a scarecrow is made in the image of the enemy, sometimes dressed in an enemy uniform or decorated in some way to vaguely resemble them. A trainee then attacks the dummy with a weapon such as a sword, club, bow or musket. Such a target is, naturally, immobile and does not fight back, and is therefore not a realistic test of skill compared to a live and armed opponent. It is occasionally called a straw dog fallacy, scarecrow argument, or wooden dummy argument.[citation needed] In the UK, it is sometimes called Aunt Sally, with reference to a traditional fairground game.

You'd be surprised how often this fallacy comes up—and it's not just IDiots who use it.

The other day I attended a seminar by Jacek Majewski of McGill University (Montreal, Quebec, Canada). The subject was alternative splicing.

As most of you already know, this is a controversial field. Many people believe that alternative splicing is very common and that 50-70% of all human genes produce multiple versions of proteins due to alternative splicing. Majewski is one of those people.

Others, I am one, believe that much of the data is based on artifacts—especially expressed sequence tag (EST) artifacts. We believe that there are some very well established, and well-studied examples of alternative splicing but these represent only a small percentage of the total genes in the human genome.¹ We'll call these two groups the "splicing is common" advocates and the "splicing is rare" advocates.

The "common" group likes to think of themselves as the leading edge of a paradigm shift. They believe that alternative splicing is so common that it requires a new way of looking at biology. Unfortunately, in their haste to promote the new paradigm, they often misrepresent the other side. As a matter of fact, the very existence of a legitimate scientific controversy is often deliberately overlooked because they set up a straw man that is easily refuted.

Here's an example. In Majewski's seminar he started by describing the current "dogma" of one gene-one enzyme. According to him, most biologists are wedded to the idea that each gene makes a single protein. They believe, according to Majewski, that the intermediate step of mRNA synthesis is unimportant. He even showed a slide illustrating the dogma. It represents the old paradigm.

At the end of the seminar I pointed out that we have been teaching a different version of information flow for over thirty years. I mentioned that all the leading textbooks talk about splicing and alternative splicing and, furthermore, this material has been in the textbooks for 25 years (e.g. Genes II by Benjamin Lewin published in 1983). I asked him if he actually knew any scientists who believed in the dogma that he described. His response was confusing but he didn't back down.

Why is this important? Because most of the "common" advocates focus on convincing us that alternative splicing is real rather than focusing on whether it is common. By refuting the straw man they hope to bolster their case for the prevalence of alternative splicing. But they do no such thing. Most scientists are well aware of alternative splicing and have been for decades. The dispute is not over whether it occurs but whether it is common. The straw man version of the opposition does not exist.

I was prompted to write about this form of rhetorical device by reading an article in Monday's New York Times. The article (Now: The Rest of the Genome) was written by Carl Zimmer. Most of you know what I think of Carl Zimmer. He is one of the best science writers on the planet [Carl Zimmer at Chautauqua] but this time he slipped up.

Zimmer writes about Sonja Prohaska, a bioinformatician at the University of Leipzig in Germany.

... new large-scale studies of DNA are causing her and many of her colleagues to rethink the very nature of genes. They no longer conceive of a typical gene as a single chunk of DNA encoding a single protein. “It cannot work that way,” Dr. Prohaska said. There are simply too many exceptions to the conventional rules for genes.

It turns out, for example, that several different proteins may be produced from a single stretch of DNA. Most of the molecules produced from DNA may not even be proteins, but another chemical known as RNA. The familiar double helix of DNA no longer has a monopoly on heredity. Other molecules clinging to DNA can produce striking differences between two organisms with the same genes. And those molecules can be inherited along with DNA.

The gene, in other words, is in an identity crisis.

I don't think there are any significant number of biochemists or molecular biologists who literally believe that every gene encodes a single protein. Everyone I know understands that there are ribosomal RNA genes, tRNA genes, and genes for all kinds of small RNAs. Everyone I know understands alternative splicing. (On the other hand, nobody I know thinks that epigenetics is any threat to our definition of a gene.)

If the gene has an identity crisis, which it does, it's not because of ignorance of these phenomena, it's because we can't all agree on a good definition. My own preference is to define as a gene as, "A gene is a DNA sequence that is transcribed to produce a functional product" [What Is a Gene?] and I've been using that definition in my own textbooks since 1989.

It's sad to hear that up until recently Sonja Prohaska and her colleagues believed in a long-discredited definition of a gene. It suggests that throughout her undergraduate and graduate education she never heard of ribosomal RNA genes or alternative spicing. (She got her Ph.D. in 2005.) Either that or she's deliberately setting up a straw man.

Carl Zimmer goes on to describe recent work on the analysis of the human genome, especially the work done by the ENCODE project.

Encode’s results reveal the genome to be full of genes that are deeply weird, at least by the traditional standard of what a gene is supposed to be. “These are not oddities — these are the rule,” said Thomas R. Gingeras of Cold Spring Harbor Laboratory and one of the leaders of Encode.

A single so-called gene, for example, can make more than one protein. In a process known as alternative splicing, a cell can select different combinations of exons to make different transcripts. Scientists identified the first cases of alternative splicing almost 30 years ago, but they were not sure how common it was. Several studies now show that almost all genes are being spliced. The Encode team estimates that the average protein-coding region produces 5.7 different transcripts. Different kinds of cells appear to produce different transcripts from the same gene.

With all due respect to Carl, these sentences contradict what he implied earlier on. Yes, it's true that scientists have known about alternative splicing for 30 years. In other words, they have known for at least that long that the old idea about one gene-one protein is incorrect. So what was the point of letting readers think that Sonja Prohaska's personal misunderstanding of a gene has any relevance?

As I mentioned above, the scientific controversy over alternative splicing is about how common it is and not about whether modern scientists recognize its existence. And it has nothing to do with the modern understanding of a gene since for the past 20 years everyone has incorporated alternative splicing into their understanding of a gene.

Thomas Gingras is clearly on the "common" side of the issue and not on the "rare" side. Unfortunately Zimmer doesn't do a good job of balance here. A better way to describe the results would be ...

Taken a face value, some of the published results from the ENCODE project suggest that, far from being a rare event, alternative splicing may be very common. In fact, some scientist think that most of our genes produce several different proteins due to alternative splicing. They even suggest that an average gene may produce five or six different alternatively spliced transcripts.

Other scientists dispute these results, pointing out that the predicted alternatively spliced transcripts make no sense for those genes that have been well-studied. These predictions are being quietly removed from the annotated human genome database. As more and more genes are being looked at, the number of proven protein variants gets smaller and smaller.

The original predictions rely heavily on the sequences of small bits of RNA called "ESTs" and it is becoming increasingly clear that many, perhaps most, ESTs are artifacts. It is quite possible that talk of changing paradigms is premature and the number of genes exhibiting alternative splicing may be closer to what scientists thought twenty years ago.

These are interesting times in genome research and, like all new fields, the preliminary results are exciting and provocative. Who knows whether the preliminary results will lead to new ways of looking at biology? Time will tell.

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1. I'm using the human genome as an example. The same arguments apply to other genomes.

[Image Credit The Information Paradox: A Favorite Theist Logical Fallacy: The Straw Man]

November 11, 2008

 
This is what the front campus of the University of Toronto looks like today, Remembrance Day 2008. This is the 90th anniversary of the end of World War I.

Each cross bears the name of one of 628 alumni, students, or faculty members who died in World War I. It reminds us of what happens when we fail to resolve our differences peacefully. War is the failure of peace.

The crosses remind us that war is evil and horrible. All of these lives were wasted in a war that never should have happened. War is not glorious. War is not something we should be proud of even though we may honor those individuals who answered the call, and sacrificed their lives, when the politicians and diplomats failed to do their duty.

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Enzyme Efficiency: The Best Enzyme

One of the first things you learn about enzymes is that they catalyze, or speed up, reactions that would normally take place at a much slower rate. This is a difficult concept for students to understand because they're used to thinking of biochemical reactions in terms of reactions that would never happen without an enzyme.

The trick in understanding the role of enzymes is to appreciate the difference in rates between the enzyme-catalyzed reaction and the spontaneous reaction. While it's true that all enzyme-catalyzed reactions would eventually proceed even in the absence of enzyme, the rate of the spontaneous reaction might be way too slow. We often emphasize that the spontaneity of a reaction can be determined from the thermodynamics (i.e. if ΔG <0 the reaction is spontaneous) but we sometimes forget to show real data on how fast such a reaction can occur under physiological conditions. Typical rates for enzyme-catalyzed reactions are described by a constant called k_cat.¹ These values are usually in the range of 100-1000 reactions per second but there are some enzymes than have rates of over 1,000,000 reactions per second.

Spontaneous reactions can often approach these rates but, as you might imagine, the ones that require enzymes are very much slower. Proteins, for example, will eventually break down into amino acids but the rate of the reaction is so slow that spontaneous protein degradation is not a problem in living cells. In order to degrade proteins for food, we need to make enzymes such as chymotrypsin, trypsin, pepsin, and elastin to do the job at a faster rate.

Most of the important metabolic reactions take years in the absence of enzyme. The spontaneous degradation of a protein, for example, takes about 100 years (rate constant ~ 4 × 10^-9). Since chymotrypsin catalzyes this reaction at a rate of about 1000 molecules per second, this means that the enzyme speeds up the reaction by a factor of more than 10¹¹ (100 billion times)!

This value (10¹¹) is sometimes called the catalytic proficiency of an enzyme although for technical reasons we won't go into here, the real measure of catalytic proficiency is higher by several orders of magnitude.¹ The catalytic proficiency of chymotrypsin is 2 × 10¹⁶.

Naturally, this invites a comparison with those enzymes showing the greatest rate enhancements. But there's a problem. You can measure spontaneous rates that are on the order of a few years because you don't have to wait until the reaction goes to completion. But if the spontaneous reaction takes hundreds of years it can be difficult to measure—even the most dedicated graduate student won't wait that long!

Fortunately there are a few tricks that will make the job easier. You can observe the spontaneous reaction at high temperatures, for example, and calculate what the rate would be at physiological temperatures. That's what Radzicka and Wolfenden did in 1995 when they reported that the spontaneous decarboxylation of ornithine 5′-phosphate (OMP) had a rate constant of 3 × 10^-16 s^-1. This is a half-life of 78 million years.

The enzyme that catalyzes this reaction is ornithine 5′-phosphate decaboxlyase and up until last week it was the record holder with a catalytic proficiency of 2 × 10²³. (OMP decarboxylase catalyzes an essential step in the synthesis of pyrimidine nucleotides that are required to make RNA and DNA.)

That record has now been broken. Lewis and Wolfenden (2008) studied a reaction catalyzed by uroporphyrinogen decarboxylase, an enzyme involved in the synthesis of porphyrins such as heme, the cofactor in hemoglobin, and the chlorophylls. There were able to model the reaction and determine that the rate of spontaneous decarboxylation is 9.5 × 10^-18 s^-1, which corresponds to a half-life of 2.3 billion years! Lewis and Wolfenden published a chart showing typical half-lives of spontaneous reactions.

The catalytic proficiency of uroporphyrinogen decarboxylase is 2.5 × 10²⁴, a new record.

Into the textbook it goes.

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1. A better description of an enzyme's real rate constant is k_cat/K_m.

Radzicka, A. and Wolfenden, R. (1995) A proficient enzyme. Science 267:90-93.

Lewis,C.A. Jr. and Wolfenden, R. (2008) Uroporphyrinogen decarboxylation as a benchmark for the catalytic proficiency of enzymes. Proc. Natl. Acad. Sci. (USA) published online November 6, 2008 [Abstract] [doi:10.1073/pnas.0809838105]

Saturday Night Live: Joan Baez

 
On Saturday night we went to see Joan Baez. She older than she used to be but still wonderful. I remember her from the 60s in spite of what they say.¹

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If you remember the 60s, you weren't there.

Molecular and Cell Biology Carnival #4

 

The 4th issue of the Molecular and Cell Biology Carnival has been posted by steppen wolf at the skeptical alchemist [Molecular and Cell Biology Carnival #4].

Welcome to the fourth edition of the Molecular and Cell Biology Carnival! Let's get down to business right away...

Submit your articles here.

The previous editions are ...

1. the skeptical alchemist
2. Cotch.net
3. ScienceRoll
4. the skeptical alchemist

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Monday's Molecule #96

 
You haven't been very successful lately at guessing Monday's "Molecule" so this week is going to be an easy one. All you have to do is identify the molecules (plural) that are responsible for this strange looking fly. Just naming the genes will be sufficient.

This week's Nobel Laureate won the prize for his work on these genes (and several others).

The first one to correctly identify the molecules/genes 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 only two ineligible candidates for this week's reward: Bill Chaney of the University of Nebraska and Dima Klenchin of the University of Wisconsin. Since they are two of the three most frequent winners, the competition is a bit easier this week.

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 reserve the right to select multiple winners if several people get it right.

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

UPDATE: The mutant Drosohila melanogaster is called "bithorax" because it has two pairs of wings instead of just one pair. It actually doesn't have two thoraces, instead the 3rd thoracic segment is transformed into a duplicate of the second thoracic segment. The complete transformation requires two different mutations called bx, and pbx. Both mutations are in the regulatory region of the gene UBX and they affect expression of that gene. The Nobel Laureate is Edward Lewis.

The winner is Dale Hoyt from Athens, Georgia (USA).

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How 'molecular machines' kick start gene activation revealed

 
That's the title of a press release published on Biology News Net, and several other science news sites. Here's the opening sentence ...

How 'molecular machines' inside cells swing into action to activate genes at different times in a cell's life is revealed today (6 November) in new research published in Molecular Cell.

How could you not want to find out more? This sounds like a real breakthrough.

Try and guess what the new discovery is all about before reading on ...

From the website Biology News Net and Imperial College London ...

Genes are made of double stranded DNA molecules containing the coded information an organism's cells need to produce proteins. The DNA double strands need to be 'melted out' and separated in order for the code to be accessed. Once accessed, the genetic codes are converted to messenger RNAs (mRNA) which are used to make proteins. Cells need to produce particular proteins at different times in their lives, to help them respond and adapt to changes in their environment.

The new study outlines exactly how a molecular machine called RNA polymerase, which reads the DNA code and synthesizes mRNA, is kickstarted by specialised activator proteins. The scientists have discovered that RNA polymerase uses a tightly regulated internal blocking system that prevents genes from being activated when they are not needed.

I'm underwhelmed. How is science journalism ever going to be taken seriously if this is the sort of thing that university press offices publish?

We've known and understood the basics of transcription initiation by RNA polymerase and its activators for thirty years. This study concerns a minor variation of that process involving σ⁵⁴ in bacteria.

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Never Let Your Gas Tank Get Below Half Full

 
Friday's Urban Legend: True

How many of you have heard the story that you should always drive your car with the gas tank as full as possible? According to many, you should never let the gas in your tank fall below the half full mark on your gas gauge.

You probably thought this was a tale told by elderly wives—with apologies to old men who also tell tales.

Well, it turns out that there is actual, scientific, evidence to support this warning. Cliff Allen did the experiment according to the Sept. 13, 2008 issue of New Scientist [Petrol Gauge Challenge].

SLIGHTLY more practical routes to fuel economy occurred to Cliff Allen when he noticed that, according to his petrol gauge, the fuel in the top half of his tank lasted considerably longer than the bottom half. As any Feedback reader (and possibly only a Feedback reader) would, he investigated. Systematically.

Over several months he recorded the distances travelled using the fuel from the top and bottom halves. The average for the top was 400 kilometres (250 miles) and for the bottom a mere 300 kilometres (185 miles). Since then, he writes, "of course I have only used the top of my tank and have consistently achieved around 250 miles - I'm not stupid!"

Cliff was obviously keen to discuss this, at length, with his learned friends, "some of whom gained General Certificate of Secondary Education qualifications" at age 14. He was "mostly appalled at their incredulity and lack of interest".

However, his friend Alan suggested that the fact that petrol always comes out of the bottom of the tank causes it to use more petrol so we might benefit from turning the tank upside-down. John suggested the increased efficiency might be due to the height of the fuel, so the tank should be put on the roof. Mostyn proposed putting a brick in the tank, as this apparently works very well for saving water in toilet cisterns. Tony wants to make the top of the tank larger than the bottom, to increase the proportion of its volume at the top, and thinks a carrot shape would be optimal.

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P.S. for the irony impaired.

The Awesome Power of Prayer

 
James C. Dobson, Ph.D. is Founder and Chairman of Focus on the Family. He is not a fan of Barrack Obama and came to the realization that John McCain and Sarah Palin would be much better for the country.

Dobson urged his followers to pray [Dr. Dobson’s October Newsletter].

Regardless of your political views, I want to urge Christians everywhere to be in prayer about this election. There are many scriptural references wherein King David “inquired of God” when he was faced by troubling circumstances (1 Samuel 23:2,4; 30:8; 2 Samuel 2:1; 5:19,23). It is time for Christians everywhere to turn to Him for guidance and wisdom. Find some time to be still and listen to what He wants to tell you. The National Day of Prayer Task Force, led by my wonderful wife, Shirley, has embarked on a national campaign entitled “Pray for Election Day.” All around the country, individuals and groups are being encouraged to gather every Thursday leading up to Nov. 4 between 12 noon and 12:30 p.m. Spend time with the Lord, asking Him to guide and direct those privileged to cast a ballot. If you are able, I would also encourage you to fast and pray immed”ately before the election. After all, it was the Reverend Billy Graham who once said that “To get nations back on their feet, we must first get down on our knees.”20 Amen, Dr. Graham.

This election is about the future of the nation, but it will also go a long way toward determining the culture your children and grandchildren will come to know. I know you will vote with your children and your children’s children in mind. That certainly puts the election in a different light, doesn’t it?

Apparently God was listening. He answered their prayers on Tuesday. Here's how Tom Hess describes the result [‘We Need to Continue to be in Prayer for America’].

With an Obama administration forthcoming, Focus Action’s Tom Minnery says, “We’ve got a big challenge ahead of us.”

He and FRC Action President Tony Perkins encouraged CitizenLink viewers to remain hopeful of what God might do in the next four years — and to be in prayer.

“For those who have been praying for weeks, our responsibility does not end today,” Perkins said. “In Luke 18, Jesus said men should not lose heart, but they should pray. We need to continue to be in prayer for America.”

Minnery pointed out that in the Bible, God worked through pagan rulers such as Nebuchadnezzar, Darius and Cyrus to accomplish his purposes, and that values voters ought to begin praying for President-elect Obama.

“God can use any president for his own purposes,” Minnery said.

You can't make this stuff up.

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[Hat Tip: Primordial Blog]

It's Her Last Saturday in the Lab

 
Eva Amsen blogs at Expression Patterns on the Nature Network [Last Saturday]. My department will miss her when she leaves.

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Small Science Is Good Science?

 
I've been thinking a lot lately about what's wrong with science in the 21st century. Part of the problem is sloppy thinking that becomes apparent when you realize how many widely believed models are inconsistent with what we know about biology. I assume that similar problems occur in other disciplines.

One wonders if the proliferation of papers with huge numbers of authors is part of the problem. Maybe this fad of "multidisciplinary" science is part of the problem and not part of the solution? Is it possible to be an expert in two or more different disciplines?

I've seen plenty of example of biochemists and molecular biologists who publish papers about evolution without knowing much about evolution. Is this an isolated example?

Speaking of "big science," I was reminded of a paper published by Bruce Alberts back in 1985 in Cell. The title was "Limits to growth: In biology, small science is good science" (Alberts 1985).

These days, many people grow up believing that bigger is better. Giant factories that produce Wonder Bread have replaced thousands of corner bakeries, driven by the increased efficiency of scale. There is an unfortunate tendency to extend this view to the biological research community, and I have on occasion heard a major symposium speaker introduced in glowing terms as the coauthor of more than fifty papers per year. While I can admire the energy and management skills required to maintain a very large laboratory, the best biology is rarely done in this way. With a few notable exceptions, the biochemists and molecular biologists I most respect run relatively small laboratories and publish when they have something important to report. As I shall argue here, doing good science is very different from producing bread, and there are compelling reasons why large laboratories are in general less efficient and less interesting than smaller ones. To reflect this fact, I believe that changes in funding patterns and expectations would be useful in the biological sciences.

Some "big science" is good. The sequencing of the human genome, and other genomes, for example, was a big science project that benefited the entire biological community. But I'm not sure that significant advances in our understanding of how life works come from big labs. Does anyone have examples? What are the most significant conceptual advances to come out of big labs?

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Alberts, B.M. (1985) Limits to growth: In biology, small science is good science. Cell 41:337-338. [PubMed] [doi:10.1016/S0092-8674(85)80001-5]

Ignore, Reject, Answer? What to Do about Student Email Messages

 
Some of my colleagues are running courses where they ask students to write essays on science subjects. Part of the assignment is to contact a Professor in the discipline and get them to help with the scientific content of the essay. The idea is for the students to make sure they have their facts correct. A side benefit is that it gets the students in touch with active researchers.

Some of us object to this procedure on the grounds that if it became widespread there would be hundreds of students looking for Professors to help them on their assignment. Most Professors have other priorities, like teaching their own classes. To some extent, our colleagues who engage in this practice are downloading their teaching responsibilities onto others.

From 1992-2000 I ran a molecular biology course where the students had to write a major essay. They were told to do the research themselves but the instructors would be available if they need help with the interpretation of some papers. If necessary, we would put them in touch with an expert but only after the student had done enough work to ask intelligent questions on difficult material.

Here's an email message that was sent to my Sandwalk address last night. How should I respond? I don't feel comfortable ignoring the message. I will feel awkward if I refuse to help. I don't had time to answer the question—it's complicated and, besides, it's not my area of expertise.

Dear Professor Moran,

As part of a University assignment, I have been asked to email a group of experts to request their professional opinion on a particular question.

I have come to understand that a child with Dyspraxia should supplement their diet with a high dose of essential fatty acids. However, as non-Dyspraxic people age it is advised that they also should supplement their diet with these oils to combat age-related memory loss. Does this mean that people with Dyspraxia should augment their intake yet again when they age? If so, could this have an adverse effect on their health?

As your organisation came up in an internet search as being reputable, your answer to this question would be much appreciated.

I would like to thank you for taking the time to read this email and I hope to hear from you soon.

Yours sincerely,

This makes me angry. No matter what I do, I'm going to be disappointing a student who might really benefit from a reply. In my opinion the student's Professor is at fault for assigning such a task to the students.

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Barack Obama Will Save Religion in America

 
Frank Scaheffer writes in The Huffington Post [President Obama: Bad News For the New Atheists and Other Fundamentalists].

The Obama presidency is great news for almost everyone. It's bad news for some odd ideological bedfellows: the Religious Right and the so-called New Atheists.

Into the all or nothing culture wars, and the all or nothing wars between the so-called New Atheists and religion the election of President elect Obama reintroduces nuance. President elect Obama's ability to believe in Jesus, yet question, is going to rescue American religion in general and Christianity in particular, from the extremes.

There is no way to understand President elect Obama's victory as anything less than the start of not just a monumental political change but a spiritual revolution as well.

Who knew? I bet all atheists and agnostics are feeling pretty stupid right now knowing that they've been tricked by the slick-talking Obama.

And what is the "nuanced" spiritual revolution going to look like?

To the New Atheists who think that with the resounding defeat of the Religious Right, we are entering a secular age, think again. Obama will block your path. He'll do it for the same reason he'll make the Religious Right's paranoid fantasies about him soon seem shamefully ridiculous. That's because President elect Obama is that rarest of all rare people: a thoughtful, compassionate and likable statesman who also is a thoughtful, compassionate and likable religious believer.

Sounds like trouble. President Obama is going to block the path to a secular society. Gosh. I knew that American Presidents were leaders of the free world and the most powerful men (no women so far) on the planet but even I had no idea they were that powerful.

President-elect Obama brings another perspective to faith . It goes something like this:

How do cultures define themselves if not through ritual? In the "big moments" of life; birth, marriage, sickness, death "who" -- in the inimitable words of Ghost Busters -- "you gonna call?" As President elect Obama has said, and I paraphrase: Strip the human race of our spiritual language and what do we tell each other about hope?

As President elect Obama has pointed out, a world of all math but no poetry is not fit for human habitation. If everything feels flat and dull, stripped of mystery and meaning who will bother to do the science? Why bother, if all we're doing is serving those selfish genes for another round of meaningless propagation?

So does this faith always make "sense?" No. Because our perspective is from the inside, something like paint contemplating the painting of which it's a part. We're all in the same boat, all stuck on the same "canvas."

Ohmygod. Frank Shaeffer and Barack Obama have discovered the atheist dirty little secret. All of us atheists are flat and dull—we can't be born, get married, or die without calling upon God to help us.

Does anyone actually believe this stuff?

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[Hat Tip: RichardDawkins.net]

Evolution by Gene Duplication

Chymotrypsin (Monday's Molecule #95), trypsin, and elastase are enzymes that digest proteins in the stomach and intestine. All three enzymes have a similar mechanism of hydrolysis characterized by the presence of a catalytic triad of amino acid side chains consisting of aspartate, histidine, and serine residues. The serine side chain is directly involved in catalyzing the cleavage of proteins and that's why these enzymes are called serine proteases.

The three enzymes differ in specificity. Chymotrypsin cleaves foreign proteins primarily at tyrosine (Tyr) resides, trypsin is specific for cleavage at arginine (Arg) or lysine (Lys) resideus, and elastin cleaves at alanine (Ala) residues.

The genes for the three enzymes are homologous and the structures of the three enzymes are very similar as shown below (left: chymotrypsin [PDB 5CHA], middle: trypsin [PDB 1TLD], right: elastase [PDB 3EST]).


The active sites of the enzymes are slightly different so that specificity depends on which amino acid side chains of the substrate protein fit into the binding pocket.


It's reasonable to suppose that the primitive enzyme could bind weakly to many different substrates and cleave many different kinds of proteins inefficiently. An ancient gene duplication allowed one copy of the gene to evolve toward a much more active enzyme that cleaved only at certain residues. A second gene duplication gave rise to a third enzyme that cleaved at another residue. Finally the remaining gene evolved into a very active enzyme that cut at a third position.

The end result was a set of three enzymes that could cut up any protein into small peptides that can be taken up by the cells lining the intestine. The original non-specific enzyme was slower and less efficient.

This is an example of evolution by gene duplication and the important point is that the ancestral gene probably encoded a non-specific enzyme that could carry out several different reactions with different substrates. It's not a question of the duplicated copy evolving an entirely new specificity. Instead, the duplicated gene usually "perfects" an already existing minor activity by becoming more specific. Meanwhile, the other copy can also be selected for enhanced specificity for another substrate.

This model also explains the evolution of lactate dehydrogenase and malate dehydrogenase (Evolution and Variation in Folded Proteins) and the pyruvate dehydrogenase family (Pyruvate Dehydrogenase Evolution).

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Nobel Laureate: John Howard Northrop

 

The Nobel Prize in Chemistry 1946.

"for their preparation of enzymes and virus proteins in a pure form"



John Howard Northrop (1891 - 1987) was a renowned protein chemist who developed techniques for purifying and crystallizing enzymes.

He shared the prize with James Sumner, who first showed that proteins could be crystallized and with Wendell Stanley who crystallized tobacco mosaic virus.

Most biographers note that Northrop was very interested in genealogy and was proud to point out that he was a direct descendant of Joseph Northrop who settled in New Milford Connecticut in 1636 (John H. Northrop). I don't know if any other Nobel Laureates can trace their North American ancestors back 400 years.

The significanc of Northrops work is summarized in this excerpt from the presentation speech on the Nobel Prize website.

THEME:
Nobel Laureates

Doctor John Northrop. You and your collaborators have developed the crystallization of enzymes and other active proteins into an art, of which you are the masters. The conditions for successful work in this field were explored by you, and in the course of that work interesting relationships between enzymes and related proteins were discovered, which may ultimately afford a clue to a fuller understanding of the mode of action of these substances.

We now know that trypsin, pepsin, and chymotrypsin are similar proteases that cleave other proteins. We also know that the active enzymes are derived from inactive precursors called zymogens. The zymogens (pepsinogen, trypsinogen, and chymtrypsinogen) are cleaved to remove part of the protein making the remainder into an acive enzyme. It's interesting to see how John H. Northrop described this discovery in his acceptance speech.

Formation of enzymes from their precursors. Pepsin, trypsin, and chymotrypsin are derived from inactive precursors. These precursors were isolated and crystallized and the formation of the active enzyme studied. The formation of pepsin from pepsinogen and trypsin from trypsinogen are autocatalytic reactions. These enzymes may therefore be "propagated", just as are bacteria. The formation of trypsin from trypsinogen may also be catalyzed by enterokinase, an enzyme of the digestive tract, or by an enzyme produced by a mold (Penicillium.) The formation of chymotrypsin from chymotrypsinogen is catalyzed only by trypsin, so far as is known. In all these reactions the increase in enzymatic activity is accompanied quantitatively by the appearance of the new enzyme protein which is quite different in all its properties from the original precursor. It seems to me that these results are perhaps the most convincing evidence that the enzymatic activity is actually a property of the protein molecule.

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What Does Change Look Like?

 
I'm glad Barrack Obama won the election. He is much less conservative than John McCain and much more likely to do good things for America.

Change is in the air, everybody is talking about a new direction for America under Barack Obama. What kind of changes can we expect? Here's a sample from last night's vote on several propositions [CNN.com].

This measure would amend the state constitution so that only a union between one man and one woman would be valid or recognized as a marriage in the state. A similar measure was on the ballot in 2006 but failed.

According to the exit poll [Arizona Prop.102], 67% of Protestants voted to ban gay marriage as did 51% of Catholics. About 13% of voters said they had no religion and 69% of them voted against Proposition 102.

This measure would prohibit unmarried "sexual partner[s]" from adopting children or from serving as foster parents. The measure specifies that the prohibition applies to both opposite-sex as well as same-sex couples.

According to the exit poll [Arkansas Initiative 1], the voters are evenly split between Democrats, Republicans, and Independents. Democrats voted against the initiative (52%) but the other two groups voted in favor of the ban. A majority of college graduates (52%) and those with postgraduate education (54%) voted in favor of the ban on adoptions.

This measure would amend the state constitution to specify that only marriages between one man and one woman would be recognized as valid in the state. If passed, the measure would trump a May 2008 ruling by the California Supreme Court that legalized same-sex marriage.

According to the exit poll [California Proposition 8], a majority of whites (53%) and Asians (53%) voted against Proposition 8 while a majority of African-Americans (70%) and Latinos (51%) voted in favor of the ban. Democrats (65%) and Independents (56%) were against the ban but 81% of Republicans voted in favor of the ban on gay marriage.

This measure would amend the state constitution to define the term "person" to include "any human being from the moment of fertilization." This definition would be applied to all aspects of the state constitution, including the provisions that ensure that no person has his or her life, liberty, or property taken away without due process of law. Thus, the measure would essentially have the effect of banning abortion.

According to the exit poll [Colorado Amendment 48], this amendment should have been approved by a substantial majority.

This measure would amend the state constitution to define marriage as a union between one man and one woman. In order to amend the Florida constitution, 60 percent of voters must vote in favor of the amendment.

According to the exit poll [Florida Amendment 2], 71% of Protestants and 66% of Catholics voted in favor of the amendment to ban gay marriage. A majority of Whites (60%), African-Americans (71%), and Latinos (64%) voted for the ban.

This measure would prohibit all abortions in the state except in cases where mother's life or health is at risk or in cases of rape or incest for pregnancies of less than 20 weeks. A similar measure that did not include exceptions for rape or the health of the mother was on the ballot in 2006, but was rejected by voters 44 to 56 percent.

According to the exit poll [South Dakota Initiative 11], only evangelical born-again Christians and conservative Republicans supported the initiative. A majority of all other groups voted against it.

This measure would allow terminally ill, competent, adult residents of the state to request and self-administer lethal medication prescribed by a physician. The person requesting to end his or her life must be medically predicted to have six months or less to live.

According to the exit poll [Washington Initiative 1000], this initiative was supported by liberals (81%) and moderates (63%) and opposed by conservatives (66%). There are more liberals (29% of the voters) than in most states. Republicans (63%) voted against the initiative while Democrats (75%) and Independents (59%) voted for it.

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