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 his…no 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 or class action? 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.

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 Etch-a-Sketch…viva la difference!

    Big Tick and Ugly Deer

    Although I still pine for my former home in the Boston area, I am consoled by the relative proximity of The City, the Big Apple, the place where, if you can make it there, you can make it anywhere, that is to say, New York City. A visit to NYC satisfies me when I’m jonesing for a fix of the urban. It’s an easy day trip by train from the central part of the Gaaah-dun State, the neighboring butt of many New Yorkers’ jokes and overall contempt, but the source of many home-grown, Jersey Fresh comedians’ shtick. I guess you have to possess a good sense of humor to live in Hoboken.

    The NJ Transit, PATH and Amtrak trains rumble through some outstanding examples of urban blight. The branch of the NJ Transit system with which I am most familiar makes its way through what epitomized the Garden State in my Midwestern-imprinted mind for a long time: abandoned warehouses, empty, cratered parking lots, grim housing projects, and contaminated marshlands which harbor schools of three-eyed fish. However, the Garden State is appropriately named if one ventures to my little corner of the state. Here are bucolic stretches of farmlands and horsey estates, older villages, pockets of McMansions hemmed in by zoning laws, and woods full of tall trees characteristic of the mid-Atlantic hardwood forest.

    The township where I live cherishes and protects its green space, and my immediate neighborhood is surrounded by woods. A preserve and an arboretum are within a mile of my digs. Looking out from my deck, I face a copse of trees whose lacework of leaves, bark and underbrush screen the sight of the other units in the small development. Sweet gums, tulip trees, and maples line the woods’ edge. I especially enjoy these surroundings during my early morning perambulations. Currently, these bouts of low key exercise are composed of a lot of walking interspersed with fits of jogging, the intervals of which increase weekly as my fitness slowly but surely returns. Wood thrushes call out in flute-like tones as the sky brightens, and occasionally, screech owls will hoot as they settle down for the day. I’ve spotted wild turkeys out foraging for their breakfast.

    It’s tempting to set forth and blaze a trail in these woods, rather than confining myself to asphalt and grass. Back in the Boston area, there are 50 miles of well tended trails around Lincoln and Concord. These trails meander through woods and meadows in conservation land and private property where owners have granted permission for the trails’ establishment and maintenance. These were created through the auspices of the Lincoln Land Conservation Trust, and are popular among local long distance runners, who are appreciative of such forgiving surfaces.

    Here in Einsteinville, the Autumn Hill Reservation and Herrontown Woods have trails, but they are not as well maintained as the Lincoln, MA system. There is an extensive trail system around the Institute for Advanced Study, but I have yet to check this out. Hopefully, they are more akin to the Lincoln system. Stay tuned.

    It’s frustrating to see these trail-free expanses of woods along my route, especially since the sparse undergrowth beneath the dense tree canopy would make it appear that creating trails wouldn’t be so difficult. However, property owners around here are a possessive bunch as evidenced by the blaring yellow or orange flyers which announce “Posted: Private Property. No trespassing!” tacked to the tree trunks of the along the perimeter of their land. Thus potential lowlife bushwackers are warned, and it seems unlikely that the owners would be willing to let runners and hikers careen through their property. It is not only the gaudy flyers which give me pause when I consider spontaneous trailblazing, but also the sinister devil deer which lurk in the forest.

    Yes, I fear the Bambis of Central Jersey. Well, maybe I loathe them. Or fear and loathe them. I admit that I like them as a tenderloin draped in a cognac-based sauce, centered on a fine plate, and with a glass of the old kroovy-like Cab. Sauv. on the side or ground up into “deer balls” then simmered in a ketchup and Welch’s Concord grape jelly concoction in a slow cooker. This is a Wisconsin delicacy if ever there was one, and is best washed down with Augsburger Dark.

    With the encroachment of humans into their territory, and with no four legged predators to keep their numbers in check, the deer have made hay with their population in Einsteinville, which now stands in the 1100-1300 range in an area estimated to adequately support only 300 of their number. The swollen herd has caused deer-meets-car incidents to increase. Back in Cambridge, I avoided clueless Ivied-out students who wandered out on the streets as I wended my way around Harvard Square. Here I needn’t drive in the Ivy students’ habitat, but the roads in the township and surrounding countryside take me smack dab into deer territory. My side-of-the-road rapid scanning perception clicks into high paranoid gear as I drive along the Jersey backroads. In a year plus of living here, I’ve had some close calls, that deer-in-the-headlights scenario, but thankfully, the beasts kept their burning demon eyes at the side of the road instead of directly in front of my car’s path. Still, the presence of visible deer in my peripheral vision causes me to flinch and slow down defensively in anticipation of the animal flinging itself in front of my Mini-Cooper.

    The deer-car crashes are bad enough, but there is something more insidious which the devil deer bring to the community, and far less obvious, until one starts gathering epidemiological anecdotes from folks in the borough and the township. My elder kid brought home a tidbit of such information gleaned in his high school biology class. His teacher asked the students who among them had contracted Lyme disease, and to raise their hands if they had been infected. My son, still less than 18 months removed from an urban, deerless setting, was one of two out of twenty students in the class who had not contracted the disease. Although we moved from an area of the country where Lyme disease is endemic, deer don’t roam freely through the streets of Cambridge, so that part of Middlesex County, MA, is considered low risk for Lyme disease. The wildlife population of the People’s Republic boasts skunks, rats, and the odd drunk or junkie here and there, but no Ixodes scapularis lurk on these mammals. Maybe other virulent organisms stake their claim in Cambridge, for example, Larry Summers, but no deer ticks abound along Massachusetts Avenue. I was incredulous at my son’s news.

    I’m not the only one who has noted the drawbacks of the backyard deer and their eight-legged pals. One of the side effects of living in towns which host Ivy League universities is the presence of Famous People. Yes, there are a number of Famous People who live around here. One of them is Paul Krugman, who is a professor in the Dept. of Economics at Princeton, and a columnist for the New York Times. I like Krugman’s writings. He’s intelligent as hell, and has a sharp, sometimes biting, sense of humor. As a Famous Person here in Einsteinville, he has something to say about deer:

    Oh, Deer

    SYNOPSIS: When you’re stuck on the computer all day the pesky deer can be your only friends

    A troop of about a dozen deer just tromped through the snow in our backyard – a fairly common sight in Princeton (lately I’ve been seeing this group daily) but still a welcome break when you’re slaving away at the computer.

    But I’m tormented. I know rationally that deer are a huge nuisance, and even a menace: most of our neighbors have had Lyme disease. I support culling; I think it’s irresponsible to feed them.

    But they’re so adorable …

    Originally published on the Official Paul Krugman Site, 2.18.03 from the Unofficial Paul Krugman website.

    Professor Krugman speaks to me. Yes, I admit it. I think the damned things are adorable, too, and really quite graceful except perhaps when launched upon the hood of a vehicle. The critters seem well adapted to their suburban/ex-urban environment, and with no cougars, wolves or even Princeton Tigers to feast upon them, their numbers do not abate. The township’s approach to this has been to contract with a culling service. These guys are sharp shooters with guns and with bows as their weapons. By taking on a quasi-lupine role, they attempt to reduce the deer population.

    Not surprisingly, the deer herd culling service contract caused a hue and cry among Einsteinville’s precious set, including Famous People, who raised objections to the deer herd culling endeavor. One of these Famous People is the accomplished writer, Joyce Carol Oates. Now I recognize that Ms. Oates is a literary lioness of the late 20th and early 21st centuries. In the interest of Educating Myself in contemporary American literature, I made valiant attempts to enjoy her work, but personal tastes led me to other novelists, a couple of whom are noted in my profile. Ms. Kingsolver and Ms. Divakaruni both appear to be hale and hearty women, but for all her formidable intellectualism, Ms. Oates’ physical appearance, when extrapolated to an animal totem, recalls nothing other than…a deer. I am not the only one who discerns a connection between the great authoress and this critter.

    Oates writes of her studio (from Joyce Carol Oates: In the studio, the American Poetry Review, Jul/Aug 2003)

    It’s a room much longer than it is wide, extending from the courtyard of our partly glass-walled house in suburban/rural Hopewell Township, New Jersey (approximately three miles from the high-decibel intensity of Princeton) into an area of pine trees, holly bushes and Korean dogwood through which deer, singly, or does-with-fawns, or small herds, are always drifting. Like the rest of the house my study has a good deal of glass: my immediate study area, where my desk is located, is brightly lighted during the day by seven windows and a skylight.

    With reference to Oates’ essay from which the quote above was taken, Melissa Pritchard, who counts Oates as friend, mentor and confidante, confirms the deer metaphor:

    I think of Joyce Carol Oates as a deer, fleet and superbly alert yet always slightly startled by the world, slightly wary, lovely as only swiftness of movement and movement’s fluid grace can be, lovely without guile or selfish intent – and her writing, both act and art, like running, too, in running’s constant motion, with its eternal impulse to grace of movement and gift of expression, from this, the embodiment of eloquence comes. I am struck by quality of permeability in her as well, absorbing everything, censoring nothing, responding sensitively, empathetically, bravely, and again, if I return to the image of the deer, that agile, surefooted creature arrowing between heaven and earth, aware on all possible levels, subearthly, earthly, celestially, cellularly. She is courageous, unafraid of truths brutal or brilliant, horrifying or divine. And within this deerlike grace unafraid, resides an untrammeled spirit, eternally questing, upheld by the muscled spring of the leg, the pumping of the arms, the breath that sustains, in attunement, in harmony with, the tensile, mercurial mind.

    Clearly, Oates identifies with the deer. This is further reinforced by her belief that Princeton exudes “high-decibel intensity.” She must indeed be an exquisitely sensitive creature if she describes this sleepy little borough like that. Frankly, given how habituated her Odocoilean pals are to the town, I’m surprised we don’t find them queueing up at Thomas Sweet for ice cream or the MacCarter Theatre for a play . The beasts seem far better habituated to the high-decibel life than does the doe-eyed novelist.

    Ms. Oates, along with others, argue that the hunters might bag a university student jogging along the trails around the Institute for Advanced Study, and that the community is not given ample warning when the shootings are to take place. My own observation of prominently displayed signs posted around the local preservations, advising that shooters would be out and about during certain months, serves as ample warning to me to take my perambulations to the canal path during said time. Another argument is that stray bullets can travel up to a mile. One would hope that the term “sharpshooter” implies someone who’s a better shot than Bernie with a few Budweisers in his belly, but yeah, I can see that as a cause for concern. Net and bolt traps garnered protest among various animal rights activists, including another Famous Person, ethicist and university professor (also Oates’ friend), Peter Singer, who said he would prefer a “more humane” method of reducing the herd.

    Even though I am callous former agrarian, I would give a nod to the Famous People’s objections were it not for Oates’ publicized protest against township laws which forbid feeding the damn deer. Yes, humans feeding the deer. It may be a “right” to do what you will in your own domain, but cripes, why act as enablers to the deer’s burgeoning population? I can only imagine how the City of Cambridge would react if Alan Dershowitz decided to set out food for the local alley rats.

    As Krugman notes, actively aiding and abetting the pesky, albeit adorable, deer is objectionable. Fortunately, the New Jersey courts upheld the ban. Oates’ protest to the matter certainly implies that she was feeding the animals. To me, her argument against culling loses some steam since she’s interfering with the animals’ natural lifestyle by setting out deer chow for them: crumbs for a starving man and all that.

    Given the aforementioned Peter Singer’s philosophical bent on animal rights, it’s perfectly consistent that he would take umbrage at the deer being shot or trapped with nets then “bolted.” Captive bolt guns, the same devices employed to kill animals in slaughterhouses, are similarly used to kill the deer after capture. Singer, also on the Princeton faculty, is famous, and infamous, for his statement: “Killing a defective infant is not morally equivalent to killing a person. Sometimes it is not wrong at all.” He argues against speciesism with a convincingly pragmatic tone, that is, the life of a human is not necessarily more important than that of say, a mouse, but considers the value of each life on an individual basis. Check out the FAQ section on his web site. His answers to the questions posited are indeed thought-provoking.

    Although my views on animal rights certainly are skewed toward species bias, with humans coming out on top, I am simultaneously intrigued and repulsed by Professor Singer’s philosophical writings. High on the repulsion list is his review of Dutch biologist Midas Dekker’s book, Dearest Pet: On Bestiality. Singer writes that bestiality ought to be illegal only because the act has potential to cause pain and suffering to the animal. For example, porking a chicken invariably results in the hen’s death due to internal injury. However, Singer implies in the review that if no harm is done, then why not engage in bestiality? After all, we are as much animals as any other, and to cast horror and shame on the practice of fucking non-human mammals, as long as one doesn’t hurt them, is rank speciesism. Again, my human bias runs rampant here. There are many objections to this practice, not the least of which is that a less-than-articulate animal, like a cow or a sheep, cannot give consent to an eager and tumescent farm lad. Zoonoses and the “Ewwwww!” factor also spring to mind. But, hey, there’s something for everyone. Why else deck out cows in lingerie?

    Yes, I am a speciesist. As a human animal evolved to be an opportunistic ominvore, I eat meat, and I wear leather as the occasion dictates, typically just in the guise of shoes with no leather S&M wear in my closet, since I am a dominatrix only in spirit, and a timid one at that. I don’t fuck with non-human animals. I respect others’ dietary choices with regard to lacto-ovo-vegetarianism or veganism if presented with reasons of health, dislike of the taste and texture of flesh, or the desire to leave smaller environmental footprint as in the case of veganism. But the rationale of “not eating anything with a face” leaves me cold. That, dear reader, is pure and flagrant kingdomism, i.e. Kingdom Animalia, Kingdom Plantae. As a former student of plant physiology, I can tell you that plants and animals, although very different in many respects, share common features at the molecular level. Plants, albeit non-sentient as far as we know, cf. Day of the Triffids, are as vibrantly alive as any animal. To be truly consistent with my views of the common themes of life at the molecular level, and to avoid kingdomism, I’d have to become a Jain. That’s too rigorous a lifestyle for me to adopt, so I may as well eat animal flesh, which has on occasion included venison.

    It’s less the deer versus vehicle issue that troubles me, statisically speaking, than the high rate of Lyme disease infection in the Garden State. The bug which causes the infection is Borrelia burgdorferi. It’s a wiley bacterium since it must evade the host defense systems in order to colonize mammalian tissues. It does this by shifting around its protein expression by differential regulation of its genetic complement. Crafty little bugger. Here’s an excellent summary of Borrelia, the tick vector and lifecycle, symptoms of the disease, and much more in the online Textbook of Bacteriology written by Kenneth Todar, Dept. of Bacteriology, at the University of Wisconsin-Madison. Quick intervention with doxycycline, the current antibiotic of choice, is in order after a suspected tick bite. The trouble is, in the absence of the characteristic “bull’s eye” rash, which only occurs in 60-80% of the bite victims, the symptoms of early stage infection mimic a lot of other infections. Joint pain and neurological symptoms occur in late stage infection, and this is where things can be potentially nasty. It’s an unsettling disease. A look at the Center for Disease Control’s map of Lyme incidence by county shows a lot of deep blue in this region. In the interest of full public health disclosure, the incidences of gonorrhea and clamydia infections are higher in Mercer County, but Lyme is third. Mammals other than deer, like the white footed mouse, and birds carry the tick, but these hoofed critters are prime suspects since adult ticks preferentially feed upon white tailed deer. Quoted from K. Todar’s article:

    A relationship has been observed between the abundance of deer and the abundance of deer ticks in some parts United States. Reducing and managing deer populations in geographic areas where Lyme disease occurs may reduce tick abundance.

    In the interest of “fairness,” here is the Mercer County Deer Alliance web site which has not been updated for two years. The deer advocates support non-lethal means of reducing the population, and in fact, the culling contractor instituted a pilot program in which the does are brought down with tranquilizer guns, then tagged with a device which releases a deer contraceptive. So the deer can boink all they wish, and not reproduce. This is a pretty nifty idea, but it is more costly than lethal culling. The other tactic is to control the ticks themselves. These ticks like brush, so removing such is an option, but undoubtedly, those who wish to leave the Bambis be will also strenuously object to pesticides liberally applied to the woods.

    When I was a kid, I remember how sad I was when Bambi’s mother was killed by the hunter in the Disney movie. Oh, fawns, cartoon characters or breathing, long limbed beasties, seemed so cute then. Now, when I spot a real-life doe, buck or fawn, I not only see a graceful creature, but a walking bundle of zoonosis. And I would cheer raucously should I again view Bambi’s mother’s cinematic demise. Goddamn devil deer.

    Doc Bushwell’s Let’s Have Fun with Science Glossary:

    zoonosis, pl.zoonoses: a disease in animals which can be transmitted to humans.

    A placeholder

    I’m somewhat wired this evening with a number of thoughts pinging around my cerebral cortex, not unlike a BB let loose in a corrugated steel shed. A friend was just diagnosed with glioblastoma, possibly stage II, and is scheduled for surgery in just a few hours. He has been otherwise quite fit and healthy, but noticed some odd cognitive disjoints. A scan in the MRI revealed the brain tumor. Scary stuff. The prognosis for gliomas isn’t exactly rosy.

    In the 18th or even 19th century, by all rights I would be a wizened old grandmother or even long dead, but in the early 21st century, I mentally view myself as not terribly different in many ways than “me” in my late 20s/early 30s. It is thus a rude shock to find that it is more difficult to regain fitness than it was 20, or even 10 years ago, that the results of my blood tests are not as pristine and perfect as they once were, and I am sometimes taken aback when I see a dowdy matron, crowned aplenty with salt n’ pepper curls, in the mirror’s reflection. But being an old broad has its perks, no doubt about that. Still, the news of my friend gives me pause as mortality taps me on the shoulder during my merry march toward cronehood.

    The placeholder, just to whet the appetites of the two or three individuals who might drop by the chimp refuge, is for the following which will be blogged in the near future:

    Joyce Carol Oates, Paul Krugman, Odocoileus virginiana, Ixodes scapularis and a garden trowel. Circle the four which belong together.

    Pink and blue matter: some bonobic observations of men’s and women’s brains.

    I want to be Steve

    This essay, “How Quantum Physics Can Teach Biologists About Evolution,”appeared in this morning’s New York Times, and reminded me of this nifty endeavor, Project Steve, described as:

    …the National Center for Science Education’s (NCSE) “Project Steve” is a tongue-in-cheek parody of a long-standing creationist tradition of amassing lists of “scientists who doubt evolution” or “scientists who dissent from Darwinism.”

    Only about 1% of scientists are named Steve, or variants thereof like Stephen (Project Steve was named such in honor of the late Stephen Jay Gould) yet thousands of “Steves” have signed on in support of eaching evolution in public schools. [Note added in proof; OK, not “thousands” but around 500 or so “Steves” have signed on; but “thousands” has a nice ring to it.] Unfortunately, I am neither a Stephanie nor a Stefania, so I am not qualified to become a NCSE Steve but I can still get the T-shirt!

    One of the FAQ’s of the Project Steve site discusses the noticeable lack of biologists on the creationists’ lists. Of the creationist oriented scientists I have encountered over the years, or perhaps I should further qualify, those scientists who discounted evolution and adhered to the “creation in 6 days” myth, none were biologists or biochemists. Typically they were chemists of the more physical type or “computer scientists” although I think that “scientist” is a loose term for these techocratically hued IT nerds. One guy, a chemist, had written in his various organic chem. texts, “This book belongs to God,” and various bellicose verses taken from the Old Testament. This fellow was a real lord-love-a-duck fundie curiosity.

    Check out the National Center for Science Education. I’ll link it to the Refuge. It’s an in-depth resource for defense of teaching evolution in public schools.

    The essay in the NYT makes a good point. Most of us practicing scientists have our heads buried in our real work at the bench, and thus the alarm calls warning us of creationist encroachment in our schools are muffled. The concept of theory is often misconstrued by the layman, thus adding niggling doubt to those observing the debate. But the facts remain, evolution is consistent with science, and there are no data supporting “intelligent design” or a whip it up in 6 days Earth. We need to raise our heads from the bench, or onerous midyear reviews if we are scientific management, a.k.a. feline guidance assistants, and speak in one voice. “Evolution! It’s not just a theory. It’s good science!”

    On a related note, my younger kid, a performing-arts-drama-queen type, kicked butt on the science section of her standardized state middle school exam. Well, yes, it was just a standardized test, but as I have told her many times, regardless of what one chooses as a vocation, a solid understanding of science and math serves one well in this world,and that includes coursework on evolution.

    Big Fat Golden Goose Eggs (also to be found on Cognitive Emesis)

    Several thunderstorms of Midwestern caliber recently passed through the Land o’ Ten Thousand Superfund sites, a.k.a. The Gaaah-dun State, which assured that the Saturday morning air, though laden with dripping moisture, was a darned site more bearable than the cloacal conditions in benighted regions of South Florida, at least as described by the Chief Cognitive Emetic. I hauled my jiggling ass out for an early perambulation with the extra motivation of having obtained a good glimpse of my posterior, ballooning toward barnlike proportions, in the expansive mirrors of a friend’s bathroom during a recent visit post-vino.

    I know what I need to do to reverse the trend toward buttocks of agricultural outbuilding size. An EFD (Every Fucking Day) plan of lurching bipedal locomotion, and just saying “no” to gorfy junk scattered about at departmental meetings as well as too copious amounts of good food, seem to be the ticket toward decreased adiposity, but only with consistency of these practices over a goodly amount of time. The requirement for this endeavor got me to thinking about the Fattists, oft the brunt of flowery and simultaneously scatological verbosity on this very site, and their rampant braying that the obesity epidemic is a false alarm created by collusion of the medical community and greedy Big Pharma. These ruminations, as inspired by the Campos camp, causes me to come clean and confess the reality of my situation:

    I am not the amorphously shaped, menopausal drudge as described above. In truth, I am a reprehensibly wealthy research minion of the pharmaceutical industry. I giggle with glee, digging deep with the heels of my Manolo Blahniks, as I tread up the backs of blue-haired Medicare ladies whilst clambering to my late model Porsche Carrera. There, I rip open my tidy white lab coat, revealing my bosom straining the weft of a snug Juicy T-shirt, legs akimbo beneath my little Prada skirt. I then pull my mane of hair loose from its sensible ponytail. My mouth forms a little pout as I run over various patients and Canadian-bound consumers in search of the bargain basement prescription, on my route to my pied-a-terre in Tribeca. This makes for an ever so bumpy ride after all. I yearn to upgrade my other residence, an all too modest 6 bedroom cottage tucked away in the Hamptons, but that will only come if I, in league with my sinister colleagues, bring forth multiple medications for the obese or even barely overweight. Thus, I am motivated, no, make that hungry to discover the Magic Fat pill which will do a damn slight bit of good, cause multitudes of side effects, but will put reams and reams of dead Presidents in my Gucci pocketbook.

    Well, perhaps I have slightly exaggerated my appearance and my financial situation. “Dowdy matron” suits me just fine, and as for my salary, I can’t complain but in this affluent neck of the woods, I ain’t among the rich. But unfortunately, I know all too well that the industry is pursuing drugs for obesity, but not for the reasons that the Fattists claim. Big Pharma has not concocted the obesity epidemic with their partners in crime, the medical establishment, but rather, in its typical voracious fashion, seized upon the trend toward decreased physical activity and burgeoning gullets as a large (pun intended) market opportunity.

    Although we bench monkeys would like to think that good science drives discovery research, and in fact this is not an uncommon event, the pecuniary creatures in market analysis have in the past decade or more, increasingly worked their wiles earlier and earlier in the stages in the drug discovery process. “Good science” is not always first and foremost in marketing’s greedy mindset. Consequently, many pharma companies have research efforts directed toward obesity. Woe to those who do not. Other than the niche-directed biotech boutiques, to remain “competitive,” obesity targets must be on the research docket {Aside: “targets” meaning discreet biochemical entities such as enzymes and receptors which have potential to be affected pharmacologically.} Now, in terms of pure science, I have to admit there’s a certain degree of “Ah ha!” coolness to some of the targets related to obesity. The “Ah ha!” factor is an especially seductive influence in a scientist’s work. Hours of tedium are whittled away in experiments for that moment of discovery. I suspect that little spurts of dopamine are released at those moments, tickling the reward centers of the brain, and thereby making the process addictive. For example, interesting enzymes involved with fatty acid metabolism and certain GPCRs, which appear to regulate satiety, represent potential, and challenging, targets. {Second aside: GPCRs = G-protein coupled receptors; remember this, my comrades in emesis, since I may very well use this term again in subsequent verbal vomitus.} But those of us grizzled old veterans, as tempted by the “Ah ha!” factor as we might be, know the pitfalls of bringing forward drugs for chronic indications, and certainly obesity falls into the latter category.

    For drugs that treat chronic conditions, for example, high blood pressure or arthritis, the safety of the meds is of great concern. The patient takes these drugs daily for months or years, more likely, so adverse side effects are not particularly tolerable, in contrast to a cancer patient who bears the brunt of cytotoxic chemicals coursing through his or her system in the effort to drive back tumor growth although a thought-trend in oncology is to approach cancer as a chronic state. Unfortunately, with the rush to market certain cox-2 inhibitors, safety and proper direction of the drug toward its intended patient group, went out the window. The Vioxx debacle, in my opinion, was a wake-up call to both the pharma industry and the FDA, but that’s the subject for another screed. Drugs cost a fucktacular amount of money to bring to market, and the proper trials to determine efficacy and long term safety of a potential obesity drug (let’s not forget Fen-phen; I’m sure Wyeth would like to forget it) will add significantly to this cost. All in the name of what? A 10-20% weight loss versus placebo?

    One Friday evening at the local watering hole, a group of us shlub scientists were lamenting the research efforts directed toward obesity. One of the sr. chemists working on an obesity target, himself a moderately portly fellow who was scarfing down pizza and drinking beer like the rest of us, opined that his intellectual blood, sweat and tears were being spilled on a hypothetical pill which a 300 pound person would swallow, only to lose a walloping ten pounds as a result, then sue the manufacturer when his or her stools take on the ballistic strength of an AK-47 or when once pliant skin becomes an infected, arid wasteland due to some pharmacologically induced fuckup in fat metabolism. All of us gathered around that pub table recognized that yes, there exists a population of the morbidly obese who quite likely have some genetic variant predisposing them to the condition, but this population of folks does not exactly represent a billion dollar market. To a person, we investigators each believed that diet and exercise are first line treatments for most garden-variety obesity.

    So to the Fattists who believe that the pharma industry wants you to be fat, well, to an extent you are right since your obesity shines like a golden egg to the devils in pharma marketing. However, let me assure you, many of us who actually try to discover drugs wish you’d just walk, bike, swim or run more, and eat less, so we can direct our attention and our “Ah ha!” cravings toward drugs to treat cancer, infectious disease, immune disorders, neurological disease, and such.

    Sailing in uncharted waters (from June 26, 2005)

    Although I am nearly braindead this evening as the result of a long drive from Cambridge MA to Princeton NJ, I am compelled to plaster my first ever yammerings in my brand new little piece of blogdom.

    Blogs cause shivers to trill and skitter along my spine like nervous, neural-sheathed shrews. Blogs are inherently so public, and although I consider myself a gregarious sort, my tendency is to nurture and to guard my own, and others’, privacy. But such scruples be damned! It’s the Golden Age of Self-Absorption so…

    Avast, ye scum! Monsters be here!