The Futile Cycle

I sometimes jokingly refer to the study of metabolic pathways as “old school” biochemistry, from the era of Hans Krebs, Melvin Calvin, and Konrad Bloch. More often than not, when you hear “biochemistry” uttered by a molecular or cellular biologist these days, they’re referring to measurements of how much proteins stick to each other, not studies of the biosynthesis of a sugar or other molecule. Really, it’s kind of a divide between biologists and chemists. When organic chemists talk about biochemistry, they still pretty much have old school biochemistry in mind, whereas biologists don’t seem to think of that too often.

Still, “old school” biochemistry is still kicking, and its study still generates great life-saving cures, like the Statins, which inhibit HMG-CoA reductase. Metabolic diseases are still some of the highest causes of death in the world, so the study of all these pathways by med students is still of great use. As an aside, Harvard, of all places, doesn’t really seem to have a biochemistry course (the closest is the “Chemistry 27″ course on topics in bio-organic chemistry). Guess they figure the students can always look it up and learn it later if they need it.

One thing I really like about medicines targeting metabolic pathways is that sometimes (and this is just sometimes), there’s something just refreshingly intuitive about the approach to those diseases. Too much cholesterol? You can keep it from being made (e.g. via statins) or you can get rid of the excess (via bile acid sequestrants, like cholestyramine). The latter method is quite interesting; though statins get all the press, bile acid sequestrants apparently also work quite well (but they’re not as easy to take as popping a statin pill). These are essentially resins that a patient swallows, which then absorb bile in the intestine. Thing is, bile is made from cholesterol, so if you remove a lot of bile, the body tries to make more from the cholesterol, thus draining the amount of cholesterol in the system. Pretty harmless.

Another really interesting application of “old school” biochemistry in medicine cropped up in the science news recently, with a 25-year study that was published in the NEJM today. See, the urea cycle processes the nitrogen in the body, breaking down proteins and removing the nitrogen parts as urea, which goes into urine. Some people, however, are born with defects in the urea cycle, which can lead to having too much nitrogen in the blood in the form of ammonia. Ever smelled ammonia? Yeah, don’t want too much of that in the blood. People fall into comas because of it.

So, what to do? How about supercharging another pathway in the body that gets rid of nitrogen atoms? One way is to hike up the synthesis of hippuric acid, which is the form in which the body gets rid of benzoic acid. Hippuric acid is just benzoic acid with a glycine molecule attached; glycine is an amino acid with one nitrogen atom in it. So, just add a bunch of benzoic acid (or sodium benzoate, which is equiavalent), and when the body tries to get rid of that, glycine will hitch a ride! It works quite well, according to the study. The other way to help is to form phenylacetylglutamine, which is phenylacetic acid stuck to a glutamine molecule (which is another amino acid). Glutamine has 2 nitrogen atoms per molecule. Even better! So just hike up the phenylacetic acid in the body, and in the race to get rid of that excess, the body will get rid of a bunch of glutamine with it. Put the two ways together, and you get a great way to reduce the ammonia levels in the blood. Pretty neat, I say!

There are a lot of prominent trials (or trials to be) involving Pharmaceutical companies right now, so here are two that have caught my eye over the past week (well, one of them was just pounded into my head over and over by the media).

From the TortsPorf Blog, Wyeth lost in a lawsuit against them in the Vermont Supreme Court in which a woman got gangrene from an accidental injection of a drug (”Phenergan”, a.k.a. promethazine) into her artery. Thing is, the drug’s label (approved by the FDA) “repeatedly and prominently warned” that gangrene is a risk if the drug is accidentally injected into an artery as opposed to a vein (alternatively, a doctor could choose to administer the drug, say, orally, which apparently works slower). A woman lost her arm because of a mistake, and so Wyeth lost the lawsuit. As Ben says, “If that’s the case, why don’t we sue gun manufacturers for every accidental death that guns cause?” I’d like to add, why don’t we sue car manufacturers for every injury sustained from not using seat belts?

Steve Nissen’s Meta-analysis of Avandia (a.k.a. rosiglitazone) is all over the news. Unfortunately, it’s being blown up to be a much bigger deal than it should be. In the Pipeline has a good overview about the caveats on the paper, from Steve Nissen himself as well as a good description about what meta-analyses are, and their inherent problems. Meanwhile, (from Pharmalot), lawyers are already holding conferences on how to sue GlaxoSmithKline. Pharmalot has a good post on the reactions to the NEJM article and the editorial that came with it, including a response editorial from the Lancet (PDF), and the various company affiliations that commenters have (e.g. Steve Haffner, who has been critical of the media frenzy, has gotten speaking fees from pharma companies in the past, and the NEJM editorialists have been paid as expert witnesses by plaintiffs’ lawyers in pharmaceutical trials). Orac has a set of links to good blog post articles on the article. The Examining Room of Dr. Charles has a good post on some unanswered questions about the methodology of the study.

There’s a very interesting article at Ars Technica on the use of CAPTCHAs in order to help computers digitize images of text. A CAPTCHA is essentially a slightly distorted image of some text (letters and numbers) that is supposed to make sure that the user of a website is a person and not just a computer program. If you try to comment on a Blogger Blog, for example, you’ll see the CAPTCHA.

What these researchers did was take the CAPTCHAs and instead of scrambling random text, they would use images of text that was difficult to digitize, and people could then help the computer. So if I had a scanned page of an original page in an old edition of Shakespeare, for example, and my computer couldn’t recognize one of the words, then they could disseminate this word’s image on the internet to ask people to figure out what the word is. So, the “useless” work that people do on a constant basis on the web can be harnessed to accomplish something real. It’s a really neat idea!

An Op-Ed in the New York Times by Mark Helprin proposes indefinite copyrights. It’s the most ridiculous proposal in the world.

Copyrights and patents are of a limited term for the public good. The time-limited monopoly that Congress gives to authors and inventors are to encourage them to produce their works through the incentive of the additional profit that the copyrights and patents give. The time limit means that ideas eventually revert to their natural state, of being reproducible by anyone, anywhere. It’s all for the public good.

Monopolistic competition (i.e. copyrighted works competing against each other) isn’t quite as good for the public as pure competition (uncopyrighted works competing against themselves). For works not under copyright, it benefits the people not only by allowing for new intellectual works to be seeded, but also by creating lower cost books through the competition of printers, who no longer gain a large profit from exclusive licensing of a copyright. Eventually, the reader would only have to pay for the physical production of a book. Just look at how inexpensive old books are! You can buy Macbeth or the King James Bible for under $6. You can download and read Mary Shelley’s Frankenstein for free on Project Gutenberg, because there are no printing costs.

But we need authors to produce these things, and if anyone could just copy what someone put all that effort into, he or she might not make it in the first place. So we give them copyrights, to allow them to make money from their work.

The author seems to think that holding a copyright indefinitely is a natural right, on the level of the right to property. The author clearly does not understand that ideas are not a protected property. Here, he says,

We have different words for art and idea because they are two different things. The flow and proportion of the elements of a work of art, its subtle engineering, even its surface glosses, combine substance and style indistinguishably in a creation for which the right of property is natural and becoming.

In the natural order of things, I have a perfect right to imitate you and anything you do; to allow otherwise would be to restrict my free will. Art and idea, I agree, are two different things; art is a subset of ideas, at least in one conception. Physical works of art are not ideas; they are the manifestations of an idea, and thus covered by property rights. I can’t take a painting from you without your consent; on the other hand, nothing should stop me from buying an imitation, because the idea of image and form structured in such a way on a canvas is free to the world. It is actually not “natural and becoming” for ideas and art to have a right of property attached. No “creation” is naturally protected under the natural rights.

The fact that art takes effort to create doesn’t mean that it’s worthy of a natural right for reproduction. Should I be restricted from reciting Martin Luthor King, Jr’s “I have a dream” speech, because he worked hard on it? Should I be forbidden from quoting G. K. Chesterton, because his quotes are so witty? No! The natural order of ideas is to be spread out and reproduced by other people, whether orally or by writing (which is just a proxy for oral speech).

The copyright is a grant from the government to an author – a gift, not a right. The copyright exists in the first place, not for the author, but for the public, because we presume that there is some societal benefit from encouraging writing and invention. That’s also why the copyright (and the patent) is of a limited time, because society draws benefit from allowing for ideas to be reproduced. Think about all the benefit that might come from a science fiction writer who find Star Trek to be a great medium for their voice. Or a social activist who thinks that using Disney characters or “Scrubs” characters would make for a more compelling medium to convince other people. Or even just for those random fans who want to draw their own comic books and write their fan fiction set in the world of Batman and Harry Potter. Can you really argue that “The Complete Works of Shakespeare (Abridged)” and “Rosencrantz and Guildenstern are Dead” are not valuable contributions to society? These would be barely possible if the copyright for Shakespeare were still extant. We give authors copyrights so that they give us these worlds and ideas, but eventually we want ideas to return to the public discourse, to go back and seed the creation of new ideas.

That is why copyrights are of a limited term.

For some reason, comments were inadvertently disabled for the last few posts, but they’re open again.

One of the most popular mathematical modeling topics in immunology is that the slow crumbling (over the course of almost a decade) of the immune system in an HIV infected patient, specifically the decline of “helper T cells” (technically known as the CD4+ lymphocytes). There are many hypotheses about how and why this happens, but each model has difficulty explaining all aspects of the disease.

Recently, in PLoS Medicine, a cool mathematical model rules out one of the hypotheses, the “runaway” theory. In that model, helper T cells, which recognize infections and activate other cells in the immune system, keep getting destroyed because each T cell gets infected, which produces more HIV, and which activates more T cells, which get infected, and so on, like a grain of sand snowballing into a giant avalanche. The mathematical model captures the essence of the immunological processes, and although (Camelot!) it is only a model, the whole point was to show that, at least based on our current understanding of the immune system, the “runaway” hypothesis would predict T cells numbers to fall very quickly (in a few months), rather than taking many years to fall.

Strangely, they do not mention Martin Nowak’s pioneering work in HIV population dynamics, which is well summarized in a review article from Bioessays (D. Wodarz, M. A. Nowak (2002), Bioessays 24, p. 1178-87). I took a great mathematical evolutionary dynamics course from him last semester, and he walked us through the logic for his phenomenological model. Essentially, he hypothesizes that any specific form of HIV is hunted down by the immune system relatively quickly and destroyed, which can be seen by the sharp drop in a patient’s viral levels shortly after infection. The human body generates very specific T and B immune cells to hunt down that version of HIV. The problem is that HIV mutates so rapidly that new forms of HIV are constantly being evolved within the patient, and over time, as the immune system tries to generate more and more different versions of T and B cells to go after each of the different cell types, the immune system just stops being able to keep up with the evolutionary rate of the HIV virus. Eventually, the HIV just mutates fast enough that all the different versions, together, overwhelm the immune system and cause AIDS. Using some experimental estimates, Nowak actually simulated his model on a computer, and found that it reproduces the time course of the disease, the slow drop in helper T cell levels, and so on.

I find it interesting that even after all these years, people are still “discovering” this mechanism for HIV, who seem to be unfamiliar with Nowak’s work. These physicists from 2006, for example, seem to just reproduce Nowak’s work, and don’t cite him at all. Note that Nowak came up with his model in the mid-1990s, so it’s been almost ten years, and still his model gets missed!

(via Greg Mankiw’s blog, Edward Glaeser, a quite well-known Harvard professor of economics, has a wonderfully written piece on environmentalism, and how to implement environmental policies well. He talks about various hidden costs and downsides to certain environmentalist policies that can undermine the good intentions of the movement to stop global warming, such as the ineffectiveness of emissions standards as they are implemented today, the counter-productiveness of conserving suburban greenspace (urban development is one of his specialties), and the problems of the patent system in encouraging environmental innovation.

I’m a big fan of Ed Glaeser’s work, and I found him quite entertaining as a professor. Sometimes he might come off as an arrogant, aristocratic know-it-all, but he’s also absolutely brilliant and witty.

This will be a small rant.

Why don’t journals put abstracts into the RSS feeds of their table of contents? The abstracts are open to the public anyway, and it would make their feeds much more useful. Because Nature, PNAS, and other journals don’t include their full abstracts, I’m regularly subjected to the overflow of windows:

I never really understood this, but for whatever reason, some people really think of vitamins as kind of a be-all-end-all cure for all sorts of health issues – and many times, this is how they are marketed. I think it might have started with Linus Pauling and his bogus Vitamin C obsession, but the strange idea that large doses of vitamins will prevent all sorts of cancers and metabolic diseases seems to have caught on very strongly in a variety of weird parts of the country, especially the New Age, alternative medicine crowd. I think that might have something to do with the perceived high price of drugs, the popular hysteria about “artificial chemicals” and their effects on the body, and a distinct anti-corporation distrust of the pharmaceuticals industry and mainstream medicine.

(As an aside, I myself have noticed that Asians seem to be very partial to the “supplement craze”; maybe it has a lot to do with their centuries-long fascination of bogus health remedies and bodily “balance”, as with the Daoists? But Europe does have some past with that kind of thought, such as the balance of the bodily humors idea of Galen. So why does Daoism still have such a great hold on Asian popular thinking, while the humors theory lies in the wasteland of discarded thought? Is it because of the Enlightenment that took hold in the West?)

Anyway, vitamins probably aren’t really a cure for anything except, well, vitamin deficiency, and finally more and more studies are coming out debunking the “New Age-y” obsession with vitamins and multivitamins. It doesn’t seem that there’s much science at all to support any of the vast claims that supplement manufacturers claim.

The Journal of Visualized Experiments (i.e. JoVE) is yet another biological procedure video sharing site, except that JoVE videos are reviewed by an editorial board and seems to have much more high level content.

There’s a whole spout of online procedure and methodology sites on the web now, from the comparatively “venerable” OpenWetWare and Protocol Online to the above entrant and LabAction. There are also journals dedicated to this topic, including Cold Spring Harbor Protocols and Nature Methods and Plant Methods.

It’s taken a while, but finally it seems that biologists are using the internet for more than just the online BLAST searches!