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Maps and Figures

"Hitler or Coulter?" Quiz
Map1 - Teen Pregnancy
Map2 - Incarceration
Map3 - Homicide Rates
Map4 - Drop-out Rates
Map5 - Bankruptcy Rates
Map6 - Driving Distances
Map7 - Energy Use
Map8 - Gonorrhea!
Map9 - Tax Burden
Map10 - State GDP
Map11 - DHS funding
Map12 - Adult Illiteracy.
Map13 - Abortion Bans:
Map14 - ER Quality
Map15 - Hospital Quality
Map16 - Coal Burners
Map 17 - Infant Mortality
Map 18 - Toxic Waste
Map 19 - Obesity
Map 20 - Poverty
Map 21 - Occupational safety
Map 22 - Traffic deaths
Map 23 - Divorce
Figure 1 - Wages vs Right to work
Figure 2 - Unemployment vs Right to work
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Monday, March 19, 2007

Wow does this guy get it wrong
I have been alerted to this article in slate blaming the United States' high infant mortality rate on fertilization treatments and emphasis on neonatal care rather than healthcare inequality between the rich in the poor. Dr. Singhavi argues that it is these interventions, and not the absence of a single-payer health system that explains our exceedingly high rate for a developed country.

Comparing infant mortality rates between countries is fraught with uncertainty—after all, it's hard to argue that every country's figures are reliable. But it's still worth asking what more we can do to stop babies from dying. Defined as death before one year of age, infant mortality frequently gets framed in the United States as a problem of insufficient health-care funding. In December, for example, a New York Times column blamed it on the lack of a single-payer health insurer. However, a closer look reveals the counterintuitive possibility that high infant mortality in the United States might be the unintended side effect of increased spending on medical care.


Uh oh, beware the inversion, that most insidious of emotionally appealing arguments because they make you feel as though you have privileged or special knowledge that no one else knows about. Inversions are arguments which appear to upset the consensus view that is supported by most of the data. Sometimes they are correct, and the consensus view or what appears to be "common sense" is incorrect, but usually inversions are just bullshit (remember the George Bush is good for science inversion? or worse, the H2 is more environmentally sound than a Prius inversion?).

Infant deaths in poor nations are roughly six times more common than in developed areas and result mainly from easily treated infections like diarrhea in the first few months. By contrast, the majority of deaths in developed countries result from extreme prematurity or birth defects that kill a newborn in the first few days or weeks of life. According to a 2002 analysis by the Centers for Disease Control and Prevention, at least a third of all infant mortality in the United States arises from complications of prematurity; other studies assert the figure is closer to half. Thus—at the risk of oversimplifying—infant mortality in the United States principally is a problem of premature birth, which today complicates just over one in 10 pregnancies.

To reduce infant mortality, then, we need to prevent premature births, and if that fails, improve care of premature babies once born. (Prematurity is also linked to other problems; for example, it's the leading cause of mental retardation and cerebral palsy in children.) But modern medicine isn't good at preventing prematurity—just the opposite. Better and more affordable medical care actually has worsened the rate of prematurity, and likely the rate of infant mortality, by making fertility treatment widespread. According to a 2006 Institute of Medicine report, the numbers of women using assistive reproductive technology doubled from 1996 to 2002. At least half of their pregnancies culminated in multiple births (twins or more), which are at high risk of premature delivery.


This is really a bizarre conclusion based on an incomplete read of the available data with several misleading and factually incorrect statements. First I'd point out, that our infant mortality rates are not being compared to the poorest third world countries, in his own article he says we're comparable to Malta and Slovakia, we're not exactly talking about Mozambique here in which his dysentery argument would actually be valid. So, in warning us away from and apples to oranges comparison, he makes an egregious apples to oranges comparison.

Next I'd like to point out this map:



from this previous post. Here's how I originally wrote about the problem.

Infant mortality rate (deaths per 1000 live births) by state 2000-2002. To put the numbers in perspective, Mississippi, with its stunning rate of 10.5 deaths per 1000 live births (or 1 in 100), has more than double the infant mortality rate of Massachusetts at 4.8, and places it somewhere between Macedonia and Uruguay on an international scale.

...

When you compare states with the highest infant mortality rates (Alabama, Arkansas, Delaware, Georgia, Louisiana, Michigan, Mississippi, North Carolina, South Carolina and Tennessee all have rates of 8 deaths per 1000 live births or greater), and the states with the lowest infant mortality rates (California, Maine, Massachusetts, Minnesota, New Hampshire, Oregon, Washington, and Utah all have rates of infant mortality in the range of 4.8- 5.5 deaths per 1000 births) you see that a certain portion of America actually enjoys comparable or lower infant mortality than the combined average for the EU or countries like Great Britain and the Netherlands.

...

Source: National Center for Health Statistics. Health, United States, 2004 With Chartbook on Trends in the Health of Americans. Hyattsville, Maryland: 2004.


Now, think about this. The states in our country with the highest infant mortality have the highest birth rates, the highest teen pregnancy rates, the poorest hospitals, the highest rates of venereal diseases, and the highest poverty rates. Dr. Singhavi argues that it's not these problems, it's not the absence of equality in health care, it's not the poor overall health of these citizens, it's fertility treatments! It's neonatal intensive care! Hmmm, not likely, these are things far more available in rich states and for rich people with insurance.

Beware inversions people, they lead to sloppy, sloppy thinking. This is very poor analysis from Dr. Singhavi.

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Wednesday, February 28, 2007

Hey you, stop trying to improve on nature
One of the funny things about Buck's post on the latest homenoschooling on Wife Swap is the discussion of the raw food types. One thing to remember when dealing with any type of woo, as Orac would call it, is that the purpose of most people's crazy beliefs about diet, medicine whatever, are attempts to create control in their life. People like alternative medicine, not because it respects the body and is natural, these are rationalizations. People like it because there is always an alternative medicine you can take, every day, for any reason. Largely because they're harmless, this is ok. If you did this with real medications you would probably end up dead or sick. Same with the raw food guy in this show. When confronted by the other parent who challenged the wackiness of a world view that includes eating raw chicken, what did he do? He ran to the kitchen and started eating. It's about a feeling of control, that's all, and to some degree that's ok, people need coping mechanisms to deal with stress, and if they end up being a little wacky, that's fine (eating raw chicken might not be).

If a system of "alternative" medicine were legitimately interested in preserving health rather than just selling worthless supplements, one of the first elements of its practice would be to do nothing if nothing is wrong. This new paper in JAMA makes this point nicely. It is entitled "Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention" and is a meta-analysis of nearly 400 studies on antioxidants like selenium, beta-carotene and vitamins A, C, and E. Their findings? Dosing yourself with beta carotene, vitamin A, and vitamin E may increase your mortality, while selenium and vitamin C are at best harmless.

For the most part your body knows what it's doing and can and should be left alone. A normal diet will provide you with all the nutrition you need, and it's very unlikely you need to supplement with some exceptions like folic acid in women of childbearing age, B12 in vegans and old people or if one has an underlying condition like anemia which requires supplementation. So, a simple way to determine if something is quackery is if you're healthy, do they still suggest treatment?

Again, most of these interventions are mostly harmless and merely relieve the sucker of money they soon would have parted with anyway. But it's a sure sign of a bad medical practitioner if they want to do anything to a helthy person to "make them better".

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Monday, February 19, 2007

Autism, SNP arrays and Neurexin 1
Hail genomic medicine! Researchers have used massive genetic screens to identify a gene with a major link to autism in Nature Genetics AOP (BBC article here).

Here's the abstract:

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,168 families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12–p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.


Autism is complicated though and even in twin studies there isn't a 100% correlation (it's 60-90%) suggesting that even if you did have one or more genes that contribute to the disorder you're still not guaranteed to get it (this is called incomplete penetrance of a trait). This suggests environmental factors, early childhood events, something in gestation etc., that might be additionally required for the disorder to present.

Autism actually has an interesting history in terms of its suspected causes. First described by Leo Kanner, the suspected causes followed a pretty predictable course for psychiatric disorders of children. What I mean is that of course, first the parents are blamed for the disorder (specifically the mother). This was the fault of Bruno Bettelheim who coined the term "refridgerator mother" to describe the emotionally distant mothers who must have caused the problem. Luckily this view eventually fell into disfavor, but there are still plenty of idiotic theories as to the causes, like vaccines. I won't say mercury, because after mercury was removed from vaccines the rate of autism continued to increase, and the anti-vaccination wackos have persisted in attacking vaccination as a cause of autism. Autism has also had a major uptick in frequency in the last few decades, but this is more likely to be due to increased ability to recognize the full spectrum of autistic disorders and inclusion of kids with "autistic traits" into the definition. Right now the current frequency of autistic disorders is estimated at about 1:150.

Now, the researchers of The Autism Genome Project Consortium have made a major advance in understanding autism through the discovery of genes frequently linked to the disorder. They did this by analyzing DNA from about 1400 families in an attempt to statistically link single-nucleotide polymorphisms (SNPs, pronounced snips, meaning a single nucleotide deviating from norm in the genome) to the autism spectrum disorder. They do this using SNP gene arrays made by a company called Affymetrix, who make most of the popular "arrays" for rapid analysis of thousands of genes by their level of expression or by analysis of polymorphisms. These arrays consist of a solid surface with various known DNA sequences that are spotted into specific positions. The samples of genomic DNA are then loaded onto these arrays (and hybridize by Watson-Crick base pairing) and then are probed for the presence of these single base mutations. This allows researchers to evaluate the entire genome of an individual very rapidly. It also generates an enormous amount of data, an enormous amount of cost, and an enormous amount of time interpreting the output. So you can imagine with 1400 families being tested, this is a truly phenomenal undertaking.

Their results? They were able to link many copy number variations (CNVs - repetitions or deletions of between 10,000 - 5 million bp of DNA on chromosomes) in various regions of the chromosomes, with the presence of autism in individuals. The full set of CNVs is quite large and it's not clear which genes they contain and increase the copy number of, but one in particular set off their alarms when they detected a deletion of an exon in the neurexin 1 gene that was associated with autism in one pair of individuals. While this isn't a completely solid finding since it was such a small sample, the interaction of neurexins with other genes implicated in autism disorders and the presence of this mutation in two affected individuals (and absolutely no controls) is suggestive of an important piece of information in the autism puzzle.

This is pretty amazing stuff, and while massive informatics like this isn't my specialty, I can appreciate what an amazing feat this is.

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Bad news for adult stem cells
One of the most promising types of adult stem cells, the MAPC or Multipotent Adult Progenitor Cell, originally discovered by Catherine Verfaillie's group and published in nature, has fallen on hard times according to NewScientist.

The results proved hard to repeat, and for more than six months from late 2003 even Verfaillie's own group was unable to isolate the cells. When New Scientist looked more closely, we found that six plots from the Nature paper and its supplementary information were duplicated in a second paper, published at about the same time in Experimental Hematology (vol 30, p 896), even though they were supposed to refer to different cells, taken from different mice. The plots described "marker" molecules on the surface of the cells, supposedly characteristic of MAPCs.

...

After New Scientist questioned the results, a panel of experts reviewed the data. Verfaillie, now at the Catholic University of Leuven (KUL) in Belgium, has since written to the two journals informing them of problems with data within the two papers, stating: "It was [the experts'] consensus opinion that the data were flawed and should not be relied upon as accurate representation of MAPC marker profiles."

The flaws she refers to do not relate to the duplications in the papers. These duplications, Verfaillie told New Scientist, were a simple mix-up. She stands by the claim that MAPCs can develop into most of the body’s tissues, and argues that later papers have described reliable methods for identifying them. In her most recent paper, Verfaillie and Irving Weissman, a stem cell biologist at Stanford University in California, showed that MAPCs can give rise to all the cell types found in blood, but it is still unclear whether MAPCs are as versatile as she claimed in the original Nature paper.


This is bad news. When these cells initially came out I remember we did try to get them. First we were told that the culture conditions were too difficult, then that there were intellectual property problems etc., excuses excuses. When we asked to come study it, they hemmed and hawed and said the cells really could only be successfully cultured in their lab and they were very finicky. Eventually we just gave up. However, the issue of repeating the results with MAPCs has become critical as her group continues to publish on them without other labs adopting the technology, and they simply should not be allowed to publish another paper on these cells until another lab can replicate at least some of these results or use them for new applications.

Now we have word of data being duplicated by her group in more than one paper (a no-no in science) and that other labs have had the same experiences in terms of difficulty acquiring and growing the cell. I'm really thinking the usefulness of these cells is essentially unproven. Even the papers they've continued to publish such as this one from J Exp Med on the hematopoietic potential of these cells are much less impressive than the initial results. In this case, they showed that MAPCs might supposedly be a hematopoietic stem cell progenitor (ha ha) because when you put thousands of them in a lethally-irradiated mouse, some of them were able to reconstitute their hematopoietic system. This claim is pretty specious considering thousands more MAPCs had to be used compared to HSC (of which under 10 cells can rescue the blood supply of a lethally-irradiated mouse).

Big trouble in adult stem cell land for sure. Now if I were Charles Krauthammer or some other New Atlantis/First Things/right wing fundamentalist writer, I'd suggest it's because the study of adult stem cells is so corrupting and foul that people who research them can't be trusted. However, not being a total idiot, I'd just point out that in all fields you occasionally encounter difficulties replicating results, the rare liar etc. We'll see how this pans out, I'd be really shocked if there were a fabrication here, but there's definitely some back-pedaling from this group and the whole "mix-up" excuse for data duplication? That's a poor excuse.

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Monday, February 12, 2007

Dr Weird


If only science were this much fun.

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Professionalism
I should have blogged on this NEJM article last week when the WaPo and several other newspapers picked it up. It's a study of the ethical behavior of doctors with regards to referrals, and whether or not they'll allow their personal morality to interfere with their job.

I'll admit I'm disappointed by the results.

A total of 1144 of 1820 physicians (63%) responded to our survey. On the basis of our results, we estimate that most physicians believe that it is ethically permissible for doctors to explain their moral objections to patients (63%). Most also believe that physicians are obligated to present all options (86%) and to refer the patient to another clinician who does not object to the requested procedure (71%). Physicians who were male, those who were religious, and those who had personal objections to morally controversial clinical practices were less likely to report that doctors must disclose information about or refer patients for medical procedures to which the physician objected on moral grounds (multivariate odds ratios, 0.3 to 0.5).


I think the moral of the story is that you should avoid male and religious doctors. They will make paternalistic decisions that are not in your best interests about your medical care, and they really should just eat shit and die for being so morally sanctimonious. I mean really, you're a professional! Do your job! Since when did it become ok to get a career when you know doing your job correctly will interfere with your moral code? And it's not like you couldn't still be a doctor. Just go into psych, or pathology, or derm, or orthopedics, there are dozens of specialties that would avoid such "moral" conflicts. While the survey was a cross-section across specialties the authors unfortunately did not provide information that would suggest that the doctors who responded incorrectly had decided on specialties that would remove such conflicts from their daily practice. It's hard to tell if this is a real problem if the majority of the docs who said they would withhold information and referrals were those involved in primary care or specialties like OB/Gyn. Either way, it's a sad sign, and taken on its own suggests that you should ask your doctor questions about their moral codes before allowing them to treat you. It's a sad day for medicine as a profession when 14% of doctors feel like they can impose their morality on patients, and a full 29% won't give referrals for things they personally object to.

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PhD in dishonesty
The NYT has an article on a Liberty University (aka fake commuter college) professor who got his PhD in paleontology from the University of Rhode Island only to use it to promote creationism.

His subject was the abundance and spread of mosasaurs, marine reptiles that, as he wrote, vanished at the end of the Cretaceous era about 65 million years ago. The work is "impeccable," said David E. Fastovsky, a paleontologist and professor of geosciences at the university who was Dr. Ross's dissertation adviser. "He was working within a strictly scientific framework, a conventional scientific framework."

But Dr. Ross is hardly a conventional paleontologist. He is a "young earth creationist" - he believes that the Bible is a literally true account of the creation of the universe, and that the earth is at most 10,000 years old.

For him, Dr. Ross said, the methods and theories of paleontology are one "paradigm" for studying the past, and Scripture is another. In the paleontological paradigm, he said, the dates in his dissertation are entirely appropriate. The fact that as a young earth creationist he has a different view just means, he said, "that I am separating the different paradigms."



Now, I read this and think, can't they rescind a PhD? If the PhD was gained by fraud, essentially the student parroted what he was expected to, and then subsequently used the degree to attack science for religious reasons, isn't this dishonest and immoral? I would treat this the same as someone who acquires an MD just to promote quack remedies. This is fundamentally dishonest. He acquired a degree in a scientific field to give his creationist BS a patina of legitimacy that it does not deserve. This guy thinks that science that is based on data and fact is just a "paradigm". I think this quote summed it up ok.

...Dr. Dini said in an interview, adding, "Scientists do not base their acceptance or rejection of theories on religion, and someone who does should not be able to become a scientist."


I think that's about right. It would be one thing if he was a evangelical Christian and got this degree and continued to pursue paleontology from the so-called paradigm of using actual data to justify conclusions. But that's not what he and the other creationists described in the article are doing. Instead, they're undermining science by training false experts for the denialist goals of sowing confusion in an established scientific field. It is fundamentally dishonest, and unethical, and PhD programs who suspect their students will engage in such behavior simply shouldn't let them graduate.

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Monday, February 05, 2007

Chris Mooney on Restoring Science
Chris Mooney and Alan Sokol write an Op-ed for the LA times on restoring scientific integrity in government. Those of you who don't know Mooney, he's the guy who wrote the Republican War On Science.

I think this is a pretty sound essay on returning scientific integrity to the federal government, and interestingly, he starts out his essay describing how before the Republican majority took over in 1994, it appeared the post-modernist left was the true danger to science.

n the 1990s, conservatives such as Dinesh D'Souza, Gertrude Himmelfarb and Roger Kimball wrote best-selling jeremiads attacking postmodernist academics who, they insisted, were taking over American universities and subverting the standards of scholarship. Although much exaggerated, this contained a grain of truth. Some self-described leftist academics did seem determined to reduce the real world to mere "discourse." No worldview, they insisted, could be considered objectively more valid or factual than any other. Even the findings of science were described as reflecting societal conditions and struggles for power and dominance rather than something true about the nature of the world.

One of us — Sokal — was sufficiently disturbed by these trends to try an unorthodox experiment: write a parody of postmodern science criticism to see whether a trendy academic journal would accept it as a serious scholarly article. Asserting up front that "physical 'reality' [note the scare quotes]... is at bottom a social and linguistic construct," Sokal averred that the latest conceptions of quantum gravity support deconstructive literary theory, Lacanian psychoanalysis, "postmodernist epistemology" and, of course, progressive politics. The cultural-studies journal Social Text ate it up.


I remember encountering that crap in college, as a physics major, it was very tiresome in your humanities courses to encounter post-modernism and be told science wasn't real. How is post-modernism doing these days by the way?

Anyway, their solutions to our current problems seem reasonable, and they rightly hit on the necessary step to re-institutionalize science as a part of effective policy-making.

TO ADDRESS this new crisis over the relationship between science and politics, we propose a combination of political activism and institutional reform. Congress needs to establish safeguards to protect the integrity of scientific information in Washington — strong whistle-blower protections for scientists who work in government agencies would be a good start.

We also need a strengthening of the government scientific advisory apparatus, starting with the revival of the Office of Technology Assessment. And we need congressional committees to continue with their investigations of cases of science abuse within the Bush administration, in order to learn what other reforms are necessary.

At the same time, journalists and citizens must renounce a lazy "on the one hand, on the other hand" approach and start analyzing critically the quality of the evidence. For, in the end, all of us — conservative or liberal, believer or atheist — must share the same real world. Antibiotic-resistant bacteria do not spare deniers of evolution, and global climate change will not spare any of us. As physicist Richard Feynman wrote in connection with the space shuttle Challenger disaster, "nature cannot be fooled."


Truly, the recovery of the OTA would be a great first step. We can only hope that if the Republicans try to disband it again we won't let it go without a fight.

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Friday, February 02, 2007

IPCC report
The Report(PDF) is now available.

Perhaps we should take some of that good Exxon money Buck mentioned and totally sell out for like, 10,000 dollars. That would be awesome.

I will try to read it thoroughly, I think some of the data they've included speaks for itself.

First of all, the so-called Hockey-stick figures showing the relative increases in greenhouse gas emissions due to human emissions compared to ten thousand years of data from proxy measurements:



Then there is the global mean temperature increases (the measure of global warming), sea-level increases, and snow cover decreases over the last 150 years or so.



The projections of temperature increases are pretty depressing.



Finally, the projections of global mean surface temperature according to the human response to the crisis. Different models are based on different responses to curbing global greenhouse gas emissions, so far, despite attempts to confuse the graph by denialists like Pat Michaels, these models have held up. From what I understand we tend to travel along the blue-line.



The last and most-depressing statement from the report I'll mention?

Both past and future anthropogenic carbon dioxide emissions will continue to contribute to warming and sea level rise for more than a millennium, due to the timescales required for removal of this gas from the atmosphere.


Time to get off our asses and do something about this. Luckily some Democrats have expressed an interest. For a better understanding of the science involved, I'd direct everybody to the Real Climate discussion on the IPCC report. This is just a summary right now, but the final full report will be available in April.

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Thursday, January 25, 2007

Too much complexity!
Science this week has an interesting paper, interesting in that it gives me a headache and I wish life would find simpler solutions to problems. It doesn't though. I think I'm going to take the creationist route soon though and just blame everything on a fickle creator who existed solely to deceive and atagonize molecular biologists.

Anyway, in biology there is what is called the "Central Dogma of Molecular Biology" and it has to do with the way information is stored, propogated, and used to express a phenotype in a cell. The most basic expression of this "Dogma" (one based on evidence at least) is that DNA is the heritable information in a cell, it is transcribed to make RNA, and then is translated into protein. DNA, in this simple explanation, is merely a storage medium. RNA is then a messenger and enabler shuttling materials between the genomic information storage space and the molecular assembler known as the ribosome. Each 3 base pairs of the messenger RNA (mRNA) correspond to a single amino acid, the basic building blocks of proteins. The 64 different potential codons correspond to 20 amino acids (multiple codons correspond to the same amino acid), and are shuttled in on transfer RNAs (tRNA) that then are assembled by the ribosome into a chain based the coding sequence of the mRNA sequence. Protein is the ultimate goal of this information transfer, and is responsible for carrying out all the responsibilities of the cell.

This is what you learn in highschool, and it seems a little complicated but reasonable. You may ask questions at the time, like why do we have 64 codons when there are only 20 amino acids? If only it ended there. Here is an image from the Wikipedia article showing a more accurate representation of the current state of knowledge of how information is transferred in biological systems.



This image is already inaccurate because RNA-Dependent RNA polymerase activity has been found to be associated within higher eukaryotes (c. elegans) and siRNA, so it's already off. Still, you can see how complicated the "dogma" has become. You have viruses going every which way, plants doing weird stuff, crazy lab experiments bypassing RNA etc.

This week in Science, the picture becomes even more complicated. Researchers have found that in humans, the multi-drug resistance gene (MDR-1) is sensitive to single nucleotide polymorphisms (that means changes in a single DNA base pair), that are "synonymous" which means that the mutation doesn't lead to a change in the protein sequence. So you have 64 codons, which correspond to 20 amino acids and are responsible for assembling the primary sequence of a protein. But now we're learning that when one codon in the mRNA is exchanged for another codon that corresponds to the exact same amino acid, the protein function can be drastically altered. This is pretty extraordinary.

Evidence from within the paper suggests that the "mutated" protein assumes a different conformation despite having an identical primary sequence as the "wild-type" protein. Clearly something interesting is happening at the ribosome in response to different codons, and the evidence is that the kinetics of translation is altered, such that the presence of the synonymous codon leads to a greater or shorter time of passage of the RNA through the ribosome, thus altering the kinetics of protein folding as the amino acids exit the ribosome. The increased or decreased times through the ribosome may lead to protein conformations which would not otherwise be energetically favored.

It is questionable whether this is a mechanism that evolved to create greater complexity of expression in cells, or whether this is some kind of emergent property of a complex system. Either way, this is an interesting result which does a lot to explain the so called "preferred" codon usage in higher animals, which is the observation that codons that encode the same amino acid are present at differing frequencies in various animals, which would suggest some advantage for using one codon over another, despite being synonymous. And the reason why I bring up the Central Dogma of Molecular Biology in a discussion of this isn't because there's a new pathway of information transfer. Rather, this paper suggests that in addition to transporting sequence information from DNA to protein, the mRNA codon preference encodes a piece of kinetic information which can ultimately alter phenotype. The evidence is clear that the raw amino acid sequence is not responsible for these changes in the MDR-1 phenotype. There's a new angle to explore and it's entirely possible that both rare and common codons have specific usages that ultimately may effect the phenotype of cells, the pathogenesis of genetic diseases, as well as creating an unexpected source of variation between individuals.

Also the parthenogenic stem cells paper that was published online about a month ago is out. We blogged about it previously.

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Tuesday, January 16, 2007

Sciblogging Anthology
Coturnix has posted the results of his Science-blogging anthology. A pretty impressive effort for sure. He managed to get nominations for best scienceblog writing over the last year, peer review them, rank them, and publish them through Lulu all in about 3 weeks. It's available for download or purchase at lulu.com

Good job man!

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Friday, January 12, 2007

Important Science
There's some good stuff being published this week in Nature and Science of broad appeal.

First a pair of papers, including one from recent Nobel laureate Andrew Fire, on siRNA and the existence of an RNA-dependent RNA polymerase (RdRP) activity with RNAi effects. Now, to make sense of that sentence. RNAi refers to the use of RNA molecules to inhibit translation of RNA into protein, either by destruction of the message (exact binding of siRNA to a sequence leads to the cutting of mRNAs), or by blocking translation (inexact binding of miRNAs to mRNA appears to prevent proteins from being translated from the mRNA message).

These papers are proposing at the very least a modification of the siRNA dogma, that is the siRNA binds to the mRNA because of its complementary sequence and leads to enzymatic cutting of the mRNA - thus destroying the transcript. Instead it lends support to an alternative hypothesis that there seemed to be evidence for for quite some time, that the siRNA binding to transcript leads to the formation of more short complementary RNA molecules, or secondary siRNAs, that increase the efficacy of the siRNA effect. The initial siRNA might not be responsible for digestion of the mRNA at all, and instead may just be a signal for RdRP to create the secondary siRNAs responsible for functional RNAi.

The second big news I like is that researchers have reported in Nature the discovery of a glucose sensor in the liver. This seems like an obvious thing for the body to have, but the fact that we only just found it shows how difficult it's been to discover. For the most part glucose concentration in the blood is thought to be controlled by insulin, but this represents a direct target of glucose in the liver that when activated by glucose controls genes involved in liver glucose metabolism and cholesterol homeostasis. It also may represent a new target for therapy not just for diabetes (Type II or adult diabetes more likely) but for also for cholesterol control.

Finally, Nature reports on the fate decisions in the early embryo and the histone modifications determine general fates of cells in the 4-cell stage. This is interesting because it represents a fairly new field called epigenetics - that is the study of modifications to DNA that transmits information without changing the DNA code itself. Therefore a gene might be active or inactive, not because of a promoter sequence that would ordinarily allow transcription, but because of small chemical changes to the DNA or the histone proteins that DNA is wrapped around. These authors show which modifications of histones are determining cell fates after the first two divisions of cells in a mammalian embryo, it's pretty amazing and reflects a distinct and powerful layer of control of gene expression above the genetic code that is critical from the very start of development.

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Tuesday, December 19, 2006

Good news ladies
Previously we wrote about an advance on generating embryonic stem (ES) cell-like cells from men by isolating spermatagonial stem cells from testes. These cells were powerful, and appeared to do most of what ES cells would do, at least in mice.

Now bona fide ES cells can be derived using oocytes to create parthenogenic embryonic stem cells (or pES cells). Here's the abstract from the Science article:

Genetically matched pluripotent embryonic stem cells generated via nuclear transfer (ntES cells) or parthenogenesis (pES cells) are a potential source of histocompatible cells and tissues for transplantation. Following parthenogenetic activation of murine oocytes and interruption of meiosis I or II, we have isolated and genotyped pES cells and characterized those that carry the full complement of major histocompatibility complex (MHC) antigens of the oocyte donor. Differentiated tissues from these pES cells engraft in immunocompetent MHC-matched mouse recipients, demonstrating that selected pES cells can serve as a source of histocompatible tissues for transplantation.


So, basically what the researchers did is freeze the cells destined to become mature oocytes (or eggs) in meiosis, which is the division of a diploid (in humans it's 2 x 23 chromosomes) cell that ultimately results in halving of the genetic material to create a haploid cell (once copy of each of the 23 chromosomes). The problem is that it's more complicated because of exchange of genetic material between chromatids could generate homozygosities where heterozygosities existed before, but the researchers accounted for this by subsequently screening the cell lines they generated for the correct Major Histocompatibility Complex (MHC) genotype. Apparently natural killer cells can also detect the absence of a MHC complex in what is known as "hybrid resistance" so a homozygosity generated in this process could potentially be detrimental for the recipient.

I realize that's complicated, but here I'll state it more simply. The researchers have figured out a way to make embryonic stem cells that are immunologically compatible to the woman who donates the oocyte, and additionally are nearly genetically identical. Because of recombination in meiosis, a heterozygous locus may become homozygous, but at least no new genes will be introduced that the body would then attack as foreign.

This is cool for many reasons. If this can be generalized to humans, which is likely, this means that women can have embryonic stem cells made that are highly-genetically matched to them, and immunologically compatible for the generation of replacement tissues. Initially I think treatments for diabetes - pancreatic islet cells - will follow, as well as hematopoietic stem cells for bone marrow transplant, and possibly liver and other tissues. Also, many lines can be generated and banked based on MHC profile.

The second reason it's cool is because it bypasses the idiotic religious belief some people have that life begins by some sperm-magic at conception. Not only does life not begin since it is continuous, but the whole sperm-magic thing is so tiresome. If they object to this procedure it can't be because a conception has been terminated, they'll have to come up with a new dogma to attack this.

Sadly, women won't be able to use this to bypass men altogether and just reproduce themselves (although I think they could if they figured out how to fuse two eggs and induce them to enter embryogenesis), since it would be the ultimate form of inbreeding. Pretty much any dangerous recessive gene you have would have the potential for becoming homozygous, and generating genetic disorders in the offspring. But for tissue generation? This is really cool.

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