Doc Bushwell's Chimpanzee Refuge

Monday, August 29, 2005

Hurakan or Yahweh?

As a Midwesterner-by-birth, and Midwesterner-at-heart, tornadoes epitomize the Big, Bad Storm for me. The flat terrain of the region where I grew up afforded excellent views of roiling squall lines as they marched across the prairie. This was exciting, in that negative-ion charged kind of way, but also frightening, because occasionally, the monster thunderstorms would drop a twister from their wall clouds. Although we were driven to our basement twice when I was a kid, whatever tornado passed nearby did no more damage than uprooting a few big maple trees in our yard, ripping some shingles off the house and barn roofs, and flattening the neighbor's silo like an accordion. Still, these storms made an impression on my psyche, and I experience recurring dreams in which I try to make my way to shelter as the storm approaches. In some of these dreams, I am back on the family farm and attempting to round up the passle of semi-feral cats so that I can take them to safety. Maybe that dream imagery was a harbinger of my current duties in my workplace. Curiously, I wake up refreshed after these dreams.

Tornadoes are devastating storms to be sure, and the big ones like the Great Plains twisters cause significant loss of life and property damage. The Xenia (Ohio) tornado and the storm system which spawned it and other funnel clouds are prime examples. Yet, their destructiveness seems more concentrated compared to a powerful hurricane, such as the one which is battering Louisiana, Mississippi and Alabama as I write this.

Although I'm familiar with tornadoes, and fortunately with passing familiarity since I have not experienced direct hits on my various homes, I encountered a hurricane only once, and I was mightily impressed. Leaving our kids with their maternal grandmother, my husband and I traveled to Chatham, MA over Labor Day weekend, 1996, to attend a wedding and otherwise enjoy the company of a bunch of longtime friends who were re-uniting for the event. Hurricane Eduardo was brewing to the south that weekend, and worked itself up to a Category 4 storm as it approached the Outer Banks of the Carolinas. Then the bugger took a turn and began to make a beeline toward New England. Its track took dead aim at Chatham which is nestled in the elbow of Cape Cod.

Our friends' wedding, both ceremony and reception, took place at a nice resort on the coast. During the ceremony, the outriders of Eduardo streaked across the sky. As the reception was well underway, we periodically dropped by the resort's bar with its television and well informed bartenders to get updates on the storm. The guests became increasingly nervous. Many opted to leave early and drive back to Boston. We were staying in a glass walled suite of a little bed and breakfast. I was torn between getting stuck in that fishbowl (our proprietor assured us of shelter in her house) or mired in traffic on Rt. 6. My husband, a.k.a. "The Weather Yenta," checked out the radar and predicted the cooler waters offshore would weaken the storm, and that the jet stream would push the eye eastward. So we decided to stay put, and with that decision, proceeded to imbibe plenty of good red wine. Later, we joined a number of guests from the wedding at a local restaurant for a New England version of a hurricane party.

Sure enough, Eduardo diminished to barely a category 1, and its eye passed closer to Nantucket, thus reinforcing my husband's insufferable amateur meterological predilections. However, if the winds and rain which hit late that night and the next morning were characteristic of a category 1 storm, or even a strong tropical depression, I cannot fathom the experience of hurricanes in the category 3 through 5 range. Tornadoes arrive and are gone in a flash. Wimpy Eduardo was bad enough for a much longer period. The prospect of howling winds of 100+ mph for hours is horrific. Fortunately, hurricanes of that magnitude are rare along the northern Atlantic seaboard and in New England although historically, some big ones have hit these regions, as noted in the National Hurricane Center's historical archives.

In a fit of perimenopausal insomnia, I woke up around two o' clock this morning. I turned on the television and began channel flipping in an effort to find something mindnumbing enough to lull me back to sleep. Electronic Ambien, if you will. Out of curiosity, I checked out the talking heads on Fox News, CNN, and MSNBC. The televised news coverage of the hurricane struck me as ghoulish. Maybe it was just me, but I discerned a perverse "Oh, wow! Maybe New Orleans will be sunk!" tone in the reports. It was like the yammering newscasters wanted this monsterfucker of a storm to smack into the Big Easy and drown it in a toxic flood despite protestations, e.g. "terrible tragedy," to the contrary. More egregious was the MSNBC newscaster's repeated use of "storm of biblical proportions." My insomnia addled brain was taken aback: "Biblical proportions? What the fuck?" I recall he tossed in a few "apocalyptic's," too. Maybe I am oversensitized by the depressing developments pertaining to "intelligent design" as a proposed part of "education" in this country, and for hate-spurting commentary like that of Pat Robertson. Well, OK, so maybe assassinations of particularly noxious heads of state and icky dictators might be a more cost-effective means of meddling in foreign nations' affairs, but did Robertson actually have to articulate this for crapssake? In any case, I immediately read sub-text into the phrase, "storm of biblical proportions" which was bearing down on New Orleans. Yeah, buddy! Let that big mothafukkah of a storm hit those libertines and faggots and drown 'em all. That's what Jesus wants! And you'll turn into a pillar of salt if you stop on I-10 to turn around and look.

Eventually, I felt drowsiness encroaching on my ill-defined outrage , so I shut off the tube, and went to sleep. This morning, I checked out the MSNBC web site, and there it was: "storm of biblical proportions." A couple of hours later, the phrase was absent from the web site. I can only hope there were objections raised to it. Why inject religion into this, and on an MSNBC broadcast/web site to boot? If this were some Christian cable network, it would be less grating, although I wouldn't be watching such. But the use of the phrase solidifies my paranoia regarding the collusion of the American Idiot mainstream media (thank you, Billie Joe Armstrong) and "certain special interest groups."

The word "hurricane" derives from Hurakan, the Mayan creation god who also presided over thunderstorms, hurricanes, and whirlwinds. It is understandable that ancient, pre-technological mankind interpreted natural disasters as anger of the gods. Unfortunately, it would appear that there are those of the 21st century who do as well.

Monday, August 22, 2005

Poison Pill

Big Pharma stocks plopped into the dumper today like so many fecal pellets, thanks to the Vioxx debacle. Back in the day, that is, when I was a young sprout fresh out of my post-doc, Merck was the place to be if pharmaceutical research was your gig. How the mighty "America's Most Admired Company" has fallen. Roy Vagelos must be spinning in wait, Dr. Vagelos is still alive. Well, he must be quite pained by what happened to his former company.

The idea behind the specific cyclooxygenase-2 (COX-2) inhibitors was a good one: target the enzyme suspected as being a prime mediator of inflammation, and leave its close relative, COX-1, which helps the stomach/gut lining stay happy and healthy, alone. In theory, this specific inhibition would spare the gut from ulceration and other nasty stuff which the less specific non-steroidal antiinflammatory drugs (NSAIDs) like ibuprofen can cause in some patients. There was a lot of nice biochemistry done on the COX-2 and COX-1 enzymes and their inhibitors. This research gave me that "ain't it cool?" tingly feeling, and also inspired me to think along the same mechanistic lines for a viral enzyme which was my research raison d’être for a few years. Several companies raced to the clinic with their COX-2 inhibitors, among them the aforementioned Merck.

New drugs are subjected to extensive clinical trials. Among the Vioxx trials were the VIGOR and APPROVe Phase III clinical studies. During the VIGOR clinical trial, in which Vioxx was compared to naproxen ("Alleve" is a brand of this OTC drug), there were indications that there was a four fold higher risk of heart attacks for the Vioxx treated patients enrolled in this clinical trial (0.4% of the Vioxx-treated vs 0.1% of the naproxen treated patients). Merck development scientists/clinicians believed that this was because of naproxen's cardioprotective effects although allegedly, there were rumblings via internal e-mails that Vioxx might be the cause. However, the APPROVe trial, which was designed to see if Vioxx would help prevent development of colon cancer, showed an increased risk of atherothrombotic ("clotting") events against control groups who were not taking naproxen. At that point, Merck could not dismiss the findings, and had to pull the drug.

The big question is...did Merck withhold negative results during the clinical trials? If this is the case, and there are indications that it is, Merck is going to have to pay the Litigation Piper. Withholding or suppressing clinical trial results is reprehensible. Gilmartin's (the former CEO) resignation speaks volumes.

Equally reprehensible were Merck's marketing tactics. Vioxx was originally targetted for a smaller group of patients, but was pushed aggressively by Merck for a much larger demographic. This demographic included patients with compromised cardiovascular health which made them more suseptible to the mechanism based toxicity of Vioxx. Also, keep in mind that not every physician is as skilled in pharmacology as he or she should be when whipping out those Rx pads. Some MD's may rely solely on pharma sales reps' information when they should also be keeping up with the medical literature. There's plenty of blame to go around.

Another problem was Merck's push to the FDA for "fast-tracking" Vioxx. This process is descibed more fully here. Its original intent was to move ahead new drugs directed toward unmet medical needs and for catasrophic diseases like AIDS or cancer. Whether Vioxx qualifies for this status is questionable to my bench monkey mind. Certainly, there were other drugs which, although not ideal, were taking care of inflammatory disease. Plus, diseases like osteoarthritis are chronic, and patients will be taking the drug for a long period of time, years perhaps, and safety is of the utmost concern. It would seem careful, extensive clinical trials to ensure safety would be in order, not fast tracking as appropriate for HIV and HCV antivirals or oncologics where adverse effects are more acceptable risks.

Hopefully, the whole fiasco will effect a sea change in pharma and in the FDA. In my opinion, one of the worst developments for the pharma industry was the event of direct to consumer (DTC) advertising for drugs. DTC marketing for Rx drugs is bad for the patient, bad for the physician and bad for the pharma company. There is a movement away from this. One big pharma has voluntarily imposed a 1 year moratorium on DTC ads for a year after a new drug is launched. Maybe others will follow suit.

Here is a truism: all drugs are poison - whether they help you or kill you is a matter of dosage. No drug is absolutely safe. The consumer must be well informed when it comes to medication, but given the level of scientific illiteracy in this country, I'm not optimistic that will ever happen. Elimination of DTC ads, more independent reviews of clinical trials (the FDA is a staggeringly bloated bureaucracy, so independent reviews will need to be conducted outside the agency), and better education of prescribing physicians (and not solely by pharma sales reps) would be positive steps.

That said, tort law reform is well overdue. There are drugs taken off the market which some patients desperately need. For the few percent, and tragically, this may be a fatal few percent, who experience adverse effects, there are many, the majority even, who do not, and for whom the drug is valuable. Then comes the hard decision: is the drug taken off the market because of exhaustive litigation? There are fewer and fewer obstetricians and anesthesiologists practicing due to soaring malpractice premiums which are driven by litigation.

Christ on celecoxib, I have a headache just thinking about all this. I think I'll go take...a pill.


Some answers to questions from "not up on this:"

What is Aleve? a NSAID?

Yes, Aleve is naproxen sodium, a non-steroidal antiinflammatory drug. It is a non-specific inhibitor of both cyclooxygenases, COX-1 and COX-2. These enzymes are both needed to make prostaglandins, an important class of biomolecules involved in all sorts of signaling processes in the body.

Does taking Advil also protect the heart for someone who can stomach it?

Where does Celebrex fit in this? Isn't it a NSAID too? Why or how is it diffrent than say Advil?

I'm going to address these questions by providing a bit of background on the balance of prostaglandins which activate platelets, and thus can cause them to stick together (clotting), and those which have antiplatelet properties (anti-clotting). For a straightforward explanation of platelets and what they do, check out this little article.

The prostaglandin which signals platelets to clump up and form a clot (this appropriately occurs when you get wounded) is called thromboxane A2 (TxA2). Platelets carry the COX-1 isoform which makes TxA2. Now COX-2, the other cyclooxygenase isoform, was long believed to be only upregulated as a response to biomolecules which induce inflammation. This inducible COX-2 was thought to be present only in cells which mediate inflammation, and thus was part of the impetus to seek COX-2 inhibitors to treat inflammatory diseases. However, it turns out that COX-2 is present in many tissues, including the vascular endothelium (this is the inner layer of cells lining blood vessels and has direct contact with blood). One of its key products is prostacyclin, or PGI2. PGI2 acts to prevent platelet aggregation. So, TxA2 and PGI2 levels are normally balanced to keep platelets in homeostasis. This is illustrated in the figure above in the upper left hand corner, e.g. the "normal" balance.

Any drug which inhibits cyclooxygenase can alter this balance. Low dose aspirin selectively inhibits COX-1 which decreases the level of the pro-clotting TxA2, and thus achieves an antithrombotic (anticlotting) effect (upper right hand panel; low levels of TxA2 = antithrombotic). Thus, low dose aspirin is recommended to prevent clotting. Now NSAIDs like naproxen and ibuprofen inhibit both COX-1 and COX-2. Thus, the levels of proclotting TxA2 and and the anticlotting/antithrombotic PGI2 are decreased. Because naproxen and ibuprofen also reduce PGI2, their cardioprotective effect may not be as good as that of low dose aspirin. The selective COX-2 inhibitors like Vioxx and Celebrex (also a selective COX-2 inhibitor like Vioxx; Bextra is another drug in this class) only decrease the "good" anticlotting PGI2 while leaving TxA2 levels alone. This selects for a pro-thrombotic/proclotting state (bottom right panel), and thus may increase the risk of heart attacks due to blood clots.

Bottom line: low dose aspirin appears to be the best bet for decreasing the risk of inappropriate clot formation, and Advil and Aleve are less so. It's likely that the risk for clot formation is a class effect in the COX-2 inhibitors. However, other vascular modulators may contribute to increased risk of thrombosis, and underlying disease in the patients being treated with these drugs must be considered, e.g., someone with distinct cardiovascular risk factors is probably not a good candidate to take this specific class of drugs.

Figure taken from F. Krotz et al. (2005) "Selective COX-2 Inihibitors and Risk of Myocardial Infarction," Journal of Vascular Research, 42: 312-324.
Doc Bushwell's Fun With Science Glossary
Isoform: Multiple molecular forms of a given protein (or iso enzymes or isozymes if they are enzymes). Isoforms can usually be separated by electrophoresis or some other separation technique. They exist because of multiple gene loci or multiple alleles (also called allelomorphs / allelozymes or allozymes) or subunit interaction or secondary changes - such as post-translational modification. Definition courtesy of Glossary of Terms Used in Molecular Genetics.

post-translational modification. After a protein has been synthesized via the process of translation, e.g. DNA => RNA is transcription then RNA => protein is translation, other enzymes can come along and add embellishments to the protein. These may include addition of sugar moieties (glycosylation) or phosphate groups (phosphorylation) among others. Definition courtesy of what resides in Doc Bushwell's memory banks.

Tuesday, August 09, 2005

Pink and blue matter

So my elder kid is off in Boston for summer school at the World's Greatest University. Don't be impressed. If a high school student has a B average, seems motivated, and the parents are willing to fork over tuition, the W.G.U, more appropriately known as the World's Greediest University, is quite happy to take him or her in like Flint.

Over the Fourth of July weekend, my son traveled by train to visit dear old Mumsy and Pops. On the day of his return trip, I knew we were cutting it close when I decided to offer a lunchtime sacrifice of animal flesh to the patriotic altar of the Weber grill. I figured if my kid and spouse left a half hour before the departure time, all would be well since the Amtrak site said the train was running 6 minutes late. They took off. Not long after his father delivered him at the station, I received a call from my son, who said he didn't have much time to talk since the battery was low on his cell phone. He was unable to find the notice for his train on either the monitor or the board. I advised him to go talk to the ticket agent, and then...the connection cut out. I hoped for the best, and over the course of the evening, I tracked the train which he allegedly boarded. The arrival time for the train on which he might, or might not, have traveled, came and went, followed shortly by a call from a concerned adult in Cambridge who was awaiting his return. I assumed he caught the next train, which was running an hour late. In spite of this rational assumption, I nonetheless was freaking out with motherly worry: "Why didn't he use a pay phone and call me!!??" Finally, a good three hours after he was supposed to arrive in Boston, he called and all was well. Nonetheless, winding down from worried mother mode was slow, so I didn't go to sleep until the wee hours of the morning, and was thus semi-wiped out for the duration of the next day.

Lesson learned by the kid: make sure the cell phone is charged before a trip and have some spare change in the old pocket.

Now my otherwise intelligent son's lack of attention to contigency plans or other means of ordered thinking simply may be due to adolescence, but his thought process also hints of the differential functioning of the male and female mind. Although my friend, Pete, may be better known in the Boston region for his athletic prowess (placed 23rd in the U.S. Men's Olympic Marathon Trials five years ago), he is an accomplished fellow in other areas, including his vocation which is scientifically oriented. He also has a propensity for wry observations of people and life. When comparing the ways in which men and women organize their memories, Pete said something to this effect: women's minds are like Rolodexes with everything in their place which can be quickly accessed, whereas men's minds are like an Etch-a-Sketch: capable of holding a great deal of detail but prone to erasure.

I have often quoted Pete's droll observation because I think it is true in that men and women process information differently. What I find fascinating is that although men and women take divergent paths at problem solving, they arrive at the same conclusions whether by Rolodex or Etch-a-Sketch. Having survived the past couple of decades or so, I recall the rampant feminist-inspired orthodoxy which held that most male and female human behaviors, aside from those directed toward mating, were culturally ingrained. However, as a budding scientist in the 70's, I had my doubts as to the politically correct sociological canon. This was solidified when I became a card-carrying scientist (I keep the card in my wallet) and became involved in the study of steroid biochemistry. I knew that the gonads and adrenals contained the requisite steroidogenic enzymes to produce hormones like our old friends, the progestins, estrogens, androgens, and corticoids, but I learned that the brain also has a set of of steroidogenic enzymes which synthesize steroids in situ. These steroids exert either non-genomic effects or genomic effects in the brain.

Neuroactive steroids, also called neurosteroids, act at the non-genomic level, meaning that they do not influence gene transcription. Their roles in the CNS are not completely elucidated but a signficant amount of research has ensued since their discovery in 1981. A good, albeit fairly technical, review article entitled "Neurosteroids and Psychiatric Disorders" by C.E. Marx describes the various neurosteroids, their interactions with receptors in the brain, and how they may modulate neurotransmitter function. Neurosteroids distinguish themselves from their gonadal and adrenal brethren by interaction with a different class of receptors called ligand-gated ion channels. Here's a neat little animation representing such a receptor: Ion channel at work! In this movie, the grey blob which attaches itself to the receptor (from the right) is the ligand. When it binds, the channel opens up and lets ions pass through to the other side of the cell. This causes a response, namely altering the excitability of the nerve cells. Thus neurosteroids which bind to these channels can exert effects in a timeframe of seconds.

The brain also contains another class of proteins to which steroids bind called nuclear hormone receptors (NHR). When steroids bind to their NHR partners, they act at the genomic level, meaning that they can "turn on" gene expression. In a simple model, a steroid, like testosterone or estrone, diffuses into the cell, then binds to the NHR. The activated NHR then relocates, or translocates as cell biologists like to say, to the cell's nucleus where it, along with other protein partners, sits down on a segment of DNA and turns on a gene which then goes on to express a particular protein. Here's a cartoon of the androgen receptor and its protein partners which illustrates how this funcitons. Note that it's quite different than the ion channel example above. In contrast to the rapid effects of the ligand-gated ion channels, NHR-induced changes at the genomic level take place over a much longer period of time, e.g. hours to days.

With the knowledge that steroids bind to these two major receptor classes in the brain, and exert a wide range of effects, it comes as no surprise that men's and women's brains appear to have different neural architecture and processing. These observations have been greatly aided by the advent of more precise imaging techniques. PET scans and MRI have allowed neuroscientists to gaze into the living human brain. Jill Goldstein, a principal investigator at the WGU's Medical School, used imaging technology to study brain function in schizophrenics and healthy patients. Her pioneering work revealed sex-based differences in the etiology of the disease as well as differences in control male and female subjects. Among Goldstein et al.'s findings for healthy male and female brains were the following:

  • The frontal cortex, where many higher cognitive functions occur, is bulkier in women than in men.

  • The limbic cortex, involved with emotional response, is bigger in women's brains.

  • The parietal cortex, which is associated with spatial perception, is larger in men's brains.

  • The amygdala, that part of the brain which is associated with heightened emotional arousal, is larger in the male brain.

  • The larger versus smaller comparisons are proportional, i.e., the size of a sub-structure is considered in comparison to overall volume of each brain. Typically, the proportionate size of a part of the brain is thought to correspond to its importance to the organism. Primates are visual animals, so the brain sub-structures associated with vision tend to be larger. Olfactory-oriented animals, like dogs or rats for example, have larger sub-structures associated with the sense of smell. Thus, the differences in the sizes of human male and female brain sub-structures suggests that hormones may play a role in shaping these areas. It is believed that hormones in the pre-natal environment assist in differentiation of the fetal brain. In laboratory animals, those areas with high densities of steroid NHR's during brain development correspond to the same regions which diverge in men's and women's brains. It is likely that the differences in the male and female brain are intrinsic, and present from birth.

    This is only the tip of the neural iceberg with regard to the complexity of research directed at the human male and female brain function. Since this is a blog, and I tend to be too wordy as it is, I'm not going to attempt to write a scholarly review. I have a copy of an accessible-to-the-layman article from the May 2005 issue of Scientific American entitled "His Brain, Her Brain" by Larry Cahill. If you're interested in obtaining this for further reading, please let me know.

    As with any research directed toward human biology and behavior, misinterpretation abounds. Enter Lawrence Summers, the current president of the W.G.U.

    Summers is a controversial president. He caused a ruckus in those hallowed ivy halls by his notion that the undergrad curriculum should be overhauled to reflect modern times, supporting the expansion of the Harvard campus across the Charles into Boston, and twitting Cornel West so much that West was driven to join the faculty in Einsteinville. The first two of these are commendable; the latter one, well, I have yet to see West "keepin' it real," as a putative intellectual role model for the minority students in the Einsteinville regional public school system. That's no surprise since he surely didn't hang out in the 'hood in the far more diverse Cambridge Public Schools, and evidently preferred to associate with Ivory Tower types or Famous People of Color. But I digress...

    Larry Summers truly stirred the pot early this year at a conference on women and minorities in science and engineering. When contemplating the small number of women at the elite levels of the field, he speculated that perhaps the reason women are underrepresented is that their innate ability in math and science is less than that of men. As one might imagine, the shit hit the fan upon those remarks, which Summers flailingly noted were supposed to be controversial. Here is the transcript of Larry Summer's fateful speech. As predictable as the screams of outrage were, so were the "Oh, this is an overreaction" responses. Interestingly, none of the "overreaction" responses came from women scientists and engineers.

    The chilly atmosphere for women scientists, particularly at the senior level, is well recognized within the W.G.U. Although I am not a liberty to name them, I personally know two women scientists on the faculty who have attested this to me, and they were among a significant group to protest Summer's remarks. So, it wasn't just the women's studies humanities types who were outraged. It hit much closer to home.

    The much beleaguered Larry Summers was correct in his observation that there are differences in men's and women's brains, but he really needed to do his homework on this complex research area before that speech. Women's and men's scores for tests of general intelligence are equivalent. Now test scores in math suggest that guys have a bit of an edge, and with men's ability to tap into spatial reasoning, something that really boosts mathematical understanding, maybe there's something to this. However, there are women and girls who possess this enhanced spatial reasoning component. Me , for example. I can mentally twirl three dimensional objects around in my little noggin, which has certainly helped me envision molecules in three dimensions. Who knows? Maybe my parietal lobe was slightly "androgenized" when pre-I was in utero. Also, there's evidence that women and men arrive at equivalent mathematical solutions using different neural networks.

    Even if men have a slight edge in mathematics, which might barely register as statistically significant, environment acts as a huge multiplier of very small differences, i.e., boys are encouraged to excel at math whereas girls are not, or were not. I say "were" because the younger generation of women increasingly embraces math, and consequently, any gap between boys and girls in standardized math scores is rapidly closing. Anecdotally, my son's AP calculus class was divided almost equally between young men and women, something one did not see when I was a teenager.

    As different as men and women are morphologically and behaviorally, it's little wonder that our respective brain structures show variation. Heck, I regard men as a separate species. I have worked in a predominantly male field for years now (there are more young women in the discipline these days, but as one rises throught the ranks, you see fewer old broads), and by and large, I truly appreciate the male mind although at times I find you guys baffling. Rolodex or la difference!