Saturday, July 02, 2005

The Interface of Physics, Chemistry, and Biology

Probably the greatest discoveries of the 21st century will occur at the interfaces between traditional disciplines.  Those who are considering a research-oriented career would do well to consider what kind of problems they want to work on, then obtain an education that readies them to attack those problems.  This differs from the old-fashioned approach.  Traditionally, one would decide which discipline applied most directly to the problems of interest, then studied that discipline.  

There is a nice illustration of this in the June 23, 2005 NEJM: How Ebola Virus Infects Cells. (Subscription required for full text.)  Scientists have known for years that there is a complex mechanism that permits viruses to enter cells and infect them, bypassing the usual defenses.  The mechanisms vary for different viruses.  This is a matter of great interest, for obvious reasons.  We would like very much to be able to stop viruses from entering human cells.

In How Ebola Virus Infects Cells, Dr. Kawaoka describes the precise mechanism for breaching the cell membrane, as outlined in a recent paper by Chandran et al. 1:
Chandran et al. propose a third triggering mechanism (Figure 1). They discovered that proteolysis by two endosomal cysteine proteases, cathepsin B and cathepsin L (which are active in a low-pH range), renders a conformational change in the surface glycoprotein of Ebola virus. They showed that glycoprotein-mediated infection is substantially reduced in cells lacking these proteases; that cathepsin B and cathepsin L can individually cleave Ebola virus GP1 to yield an approximately 18-kD N-terminal fragment, which is further digested by cathepsin B; that the extent of viral infectivity mediated by glycoprotein is correlated with the efficiency of the production of the 18-kD fragment; and that selective inhibitors of cathepsin B and of both cathepsin B and cathepsin L block viral infection in cultured cells (Figure 1). Their model therefore predicts that after the internalization of Ebola virus into the endosomes of cells, the C terminus of the viral GP1 is removed by cathepsin B, cathepsin L, or both in the endosome, leaving the 18-kD N-terminal fragment. Subsequent digestion of this fragment by cathepsin B initiates membrane fusion by GP2, the still-intact fusion domain of the glycoprotein molecule.
In order to understand this, one must understand the physics of hydrophobic/lipophilic interactions, the nature of the conformational changes in protein folding, and the effects of pH upon enzyme activity.  One also must have a good understanding of the types of bioactive molecules present at the site of entry.  This means that one must have a grasp of physics, chemistry, and molecular biology in order to understand virology.  

Many well-informed persons are worried about the potential health impact of climate change.  Some of the more predicable ones should not be too difficult to control:
Dengue, schistosomiasis, and Rift Valley fever are only three examples of major human diseases that can be expected to be influenced by global climate change. There are experimental vaccines for dengue and Rift Valley fever, and drugs for treatment of schistosomiasis. We can combat all three diseases with environmental sanitation and health education. In spite of these measures, we have not been successful in controlling them and we can expect local and world changes in temperature and rainfall to make their control more difficult.

Fortunately, the changes will happen gradually and if we act now, we have time to learn more about the epidemiology and ecology of the vector-borne and zoonotic diseases. We also have time to devise better control and prevention strategies. These studies will require interdisciplinary research. The trend today in graduate education and in university and government research is to specialization, and in infectious diseases the trend is to specialization at the molecular level. This trend is laudable to a point; many of our solutions will require understanding at the molecular level. However, this particular problem will also require training in more general and interdisciplinary fields including field ecology, general medicine, epidemiology, forestry and botany, entomology, climatology, and zoology to name a few.
The mechanisms are explained in that article, and in this one:
But it won't be a gradually warming world that triggers future health crises, says Patz, a scientist based at the UW-Madison Center for Sustainability and the Global Environment. It will be a dramatic increase in severe weather events - major storms, heat waves, flooding - triggered by a shifting global climate that will wreak most of the human health havoc.

"Averages don't kill people - it is the extremes," Patz explains.

The issue, Patz says, is how are we going to adapt? If we don't do something to mitigate the potential human health effects of climate change, the world, beginning at the local and regional level, will begin to experience climate-related catastrophe. [...]

Strong El Nino events, for example, tend to trigger heavier rainfall in the American southwest, setting the stage for rodent population booms and increased risk of exposure to hanta virus, a sometimes deadly disease transmitted through rodent urine and droppings.
There will be some advance warning for some of these problems, and some are problems that we have some capacity to combat.  Some will come with no warning, and there may be some for which we have no effective defense.  

It is interesting to speculate about what effects this will have on the economy.  Specifically, will it be feasible to continue the trend of globalization, if any given cargo container could bring the next epidemic to our shores?  Of course, any of you could speculate about that as well as I.

1 Chandran K, Sullivan NJ, Felbor U, Whelan SP, Cunningham JM. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science (in press). (Available at http://www.sciencemag.org

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Wednesday, June 29, 2005

I Just Love This Stuff

One of the older antibiotics known is tetracycline.  Long used as a treatment for syphilis, chlamydia, mycoplasma, intestinal protozoa, cholera, and acne; it is old enough now that a lot of organisms have developed resistance to its effects.  

From Cecil's Textbook of Medicine:
C. psittaci is susceptible to tetracyclines and macrolides but resistant to sulfonamides. Tetracycline has had the greatest clinical use. Psittacosis is the most gratifying of all chlamydial diseases to treat. Defervescence and marked symptomatic relief of systemic signs occur within 24 to 48 hours after starting tetracycline 500 mg four times a day or doxycycline 100 mg twice a day. Treatment should be continued for 10 to 21 days.
"The most gratifying of all chlamydial diseases to treat"?  Frankly, I never though of treating infections as gratifying, but I suppose it is.

Tetracycline is named for the four carbon rings.  Early in the history of pharmacology, it was common to name medicines and classes of medicine according to their chemical structure.  Now it is much more common to name drugs according to their mechanism of action.  
tetracycline chemical structure - chemfinder.cambrigesoft.com
Tetracycline works by binding to ribosomes inside bacterial cells.  The binding is specific to the ribosomes in bacteria; the ribosomes in mammalian cells do not interact significantly with tetracycline.   The binding to ribosomes interferes with protein synthesis.  Tetracycline gets into bacterial cells via an active transport mechanism in the bacterial cell membrane.  Because the ribosomes of mammalian cells are not affected by tetracycline, and mammalian cell membranes prevent tetracycline from entering the cells, tetracycline is harmless to mammals.  In fact, it would not be expected to have any direct effect in mammals, except perhaps to cause allergic reactions. (Harrison's Online, chapter 118).

But things are not always what they seem.  In medicine, there always are surprises.  

Now comes a report that a variant of tetracycline may have a role in the treatment of osteoarthritis (OA).  This is completely unrelated to its action as an antibiotic.  

Doxycycline, as you can see, it related closely to tetracycline; it even has the four carbon rings.

doxycycline chemical structure -- chemfinder.cambridgesoft.com

Effects of doxycycline on progression of osteoarthritis: Results of a randomized, placebo-controlled, double-blind trial
Kenneth D. Brandt 1 *, Steven A. Mazzuca 1, Barry P. Katz 1, Kathleen A. Lane 1, Kenneth A. Buckwalter 1, David E. Yocum 2, Frederick Wolfe 3, Thomas J. Schnitzer 4, Larry W. Moreland 5, Susan Manzi 6, John D. Bradley 1, Leena Sharma 4, Chester V. Oddis 6, Steven T. Hugenberg 1, Louis W. Heck 5

Arthritis & Rheumatism
Volume 52, Issue 7 , Pages 2015 - 2025
Published Online: 28 Jun 2005


To confirm preclinical data suggesting that doxycycline can slow the progression of osteoarthritis (OA). The primary outcome measure was joint space narrowing (JSN) in the medial tibiofemoral compartment.

In this placebo-controlled trial, obese women (n = 431) ages 45-64 years with unilateral radiographic knee OA were randomly assigned to receive 30 months of treatment with 100 mg doxycycline or placebo twice a day. Tibiofemoral JSN was measured manually in fluoroscopically standardized radiographic examinations performed at baseline, 16 months, and 30 months. Severity of joint pain was recorded at 6-month intervals.

Seventy-one percent of all randomized subjects completed the trial. Radiographs were obtained from 85% of all randomized subjects at 30 months. Adherence to the dosing regimen was 91.8% among subjects who completed the study per protocol. After 16 months of treatment, the mean ± SD loss of joint space width in the index knee in the doxycycline group was 40% less than that in the placebo group (0.15 ± 0.42 mm versus 0.24 ± 0.54 mm); after 30 months, it was 33% less (0.30 ± 0.60 mm versus 0.45 ± 0.70 mm). Doxycycline did not reduce the mean severity of joint pain, although pain scores in both treatment groups were low at baseline and remained low throughout the trial, suggesting the presence of a floor effect. However, the frequency of followup visits at which the subject reported a 20% increase in pain in the index knee, relative to the previous visit, was reduced among those receiving doxycycline. In contrast, doxycycline did not have an effect on either JSN or pain in the contralateral knee. In both treatment groups, subjects who reported a 20% increase in knee pain at the majority of their followup visits had more rapid JSN than those whose pain did not increase.

Doxycycline slowed the rate of JSN in knees with established OA. Its lack of effect on JSN in the contralateral knee suggests that pathogenetic mechanisms in that joint were different from those in the index knee.
So doxycycline, a tetracycline-class antibiotic, slows the progression of joint-space narrowing in patients with OA.  In addition, the treated patients had less pain, albeit by only one of the measures.  These patients had OA in one knee but not the other.  The doxycycline had no effect in the OA-free knee.  

To put it mildly, these findings are both unexpected, and difficult to explain, at least for a non-rheumatologist.  It turns out that laboratory experiments had shown an effect in decreasing the rate of destruction of cartilage.  Those experiments had been done with animals, and with isolated human tissue.  Non-rheumatologists would not ordinarily read those journals.

The most obvious significance of this study is that we may be able to develop a treatment for OA that actually alters the progression of the illness.  Current treatments alleviate symptoms, but do not stop the progression of joint damage.  Finding a way to slow the progression would be a significant advance.

One potential problem is that giving antibiotics to the large population of persons with OA, over a long period of time, would promote the development of antibiotic-resistant organisms.  Ideally, we would find a new molecular entity that has no use as an antibiotic, but which retains the anti-arthritic effect of doxycycline.  That would be a multi-billion dollar drug, so long as it did not kill anyone.

The unexpected dual use of doxycycline, however, is not why I find this so interesting.  I think that it is evidence that there is some kind of organizing principle in pathophysiology that the medical profession simply does not understand.  There probably is some kind of abstract, complex mathematical formula that unifies the antibiotic effect of tetracyclines with the antiarthritic effect.  This would be the medical equivalent of the unified field theory that physicists have been gnawing at in the post-Einstein decades.  Of course, physics is relatively simple, compared to pathophysiology.  If the greatest minds in physics have not been able to solve the "simple" physics problem, the likelihood that a solution will be found for the corresponding physiological problem is not great.

On the other hand, if we could figure this thing out, in would open new avenues for drug development.  It would be worth a lot of money.  It also would give fits to the proponents of Intelligent Design.

On a clinical level, there is an important lesson here.  From time to time, patients return to the doctor's office after having been started on a new drug.  They report that something unexpected happened, and are told "that can't happen."  It is important for physicians to recognize that, in some cases, that it can and does happen.  We just don't understand it.

All knowledge comes from observations.  If an observation does not fit the theory, we should not assume automatically that the observation is wrong.  It may be that the theory is wrong, or that we are working with an incomplete theory.

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Tuesday, June 28, 2005

U.S. aid for Africa is up, but short of Bush claim

In the debates during the 2004 Presidential campaign, Mr. Bush made a number of factual errors.  Now his command of information is being challenged again.  Likewise, during the presidential campaign, polls showed that many Americans were misinformed about crucial political topics; this has become apparent once more.
U.S. aid for Africa is up, but short of Bush claim
27 Jun 2005 21:17:09 GMT

WASHINGTON, June 27 (Reuters) - U.S. aid to Africa has increased 56 percent over the last four years, but has not tripled as President George W. Bush claimed earlier this month, according to a report on Monday by the Washington-based Brookings Institution.

Excluding food and security assistance, U.S. aid to Sub-Saharan Africa rose just 33 percent in real dollar terms, according the report made public a week before a Group of Eight summit in Scotland where aid to Africa will be discussed. [...]

In nominal dollar terms, total U.S. aid to Sub-Saharan Africa increased to $3.39 billion, the last completed fiscal year of the Bush administration, the report said. This compares to $2.34 billion in fiscal 2000, the last full budget year of the Clinton administration.

[Susan] Rice said more than 53 percent of the total increase between 2000 and 2004 consisted of emergency food aid.

"(Food aid) is important, obviously, and meet the need that varies from year to year, depending on circumstances on the ground, but it is not development assistance and the sorts of assistance that enables countries to embark on a path of sustainable assistance," she said.

"It is important for life-saving but from a development point of view it is a Band-Aid," she added, calling the upcoming G8 summit a "historic opportunity" for the U.S to take the lead on increasing aid to the world's poorest continent.
Live 8 challenged by U.S. perception of generosity
27 Jun 2005 13:49:57 GMT
By Mark Egan

NEW YORK, June 27 (Reuters) - Buddy, we gave already.

Live 8 concert organizers want to spur a global groundswell of support for African debt relief, but experts say the biggest challenge in the United States is changing entrenched perceptions that it is the world's most generous country.

Polls over the last decade show most Americans believe 10 percent of the federal budget is spent on humanitarian and economic aid for the world's poor and that America gives more than any other country.

But the world's richest economy actually spends just over one half of 1 percent of its budget on aid to the world's poor, less per capita than every other wealthy nation.
Regarding the first item, it will be interesting to see if the US media pick this up. If so, will the Administration be challenged regarding the misinformation?  Regarding the second item, some will point out that US citizens contribute a great deal via private channels.  That is true, but even if that is taken into account, the US foreign aid still lags behind other wealthy nations.
But even when private giving is counted, American aid on a per-capita basis ranks 19th out of 21 rich countries, according to Foreign Policy magazine's 2004 Ranking the Rich survey.
The Foreign Policy report that the author refers to can be seen here.  Japan is the one nation on the list that ranks lower than the US.  They point out that the rationale for such aid is twofold.  Most obviously, there is an humanitarian reason for the aid.  Secondly, development aid can reduce the potential for global health problems [e.g. bird flu], as well as various kinds of violence [e.g. terrorism].  

In an effort to be fair and balanced, I should point out that FP's Ranking the Rich report also includes what they call a Commitment to Development Index.  The CDI is calculated via a ranking of direct aid and the value of trade, technology, security, environmental standards, and overseas investment, as well as including a rating of immigration policy.  According to the CDI, the US ranks seventh out of twenty-one.

click for link to original source

The asterisk next to Norway indicates that their score was adjusted due to a negative value in the trade category.  

Personally, I find it hard to fault the US public for being misinformed, since most of them don't read blogs.  However, I do fault our educational system, which is increasingly focused on rote learning as opposed to critical thinking.  I also think our President should take responsibility for his error and make a public announcement of the correct information.  Although some persons might hold that against him, those with critical thinking skills would respect him for it.  Or, at least, disrespect him less.

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Sunday, June 26, 2005

Physician Involvement in Military Interrogation

The New England Journal of Medicine has an open-access article: Bloche MG and Marks JH. Doctors and Interrogators at Guantanamo Bay. N Engl J Med 2005:353(1);6-8 (PDF-593KB). Mr. Marks is a barrister at Matrix Chambers, London, and Greenwall Fellow in Bioethics at Georgetown University Law Center and the Bloomberg School of Public Health.  In lieu of an abstract, they posted the following:
Notice: Because of current public interest in this topic, this Perspective and its accompanying audio interview were published early at www.nejm.org on June 22, 2005. The article will appear in the July 7 issue of the Journal.
As supplementary material, the audio file of an interview with Mr. Marks is here, a 3.3MB MP3.

Early-publication articles at NEJM are almost always worth reading.  In this post, I review the contents of the article briefly, then discuss a recent report by Physicians for Human Rights, then some commentary from the Blogosphere.  I conclude with some thoughts about the ethical issues raised by the NEJM article and the PHR report.

I've written about this subject before (1 2 3).  In fact, the third post was the one that led me to change the background color of The Corpus Callosum to black for about six months.  Why write a fourth post?  The more recent NEJM article provides some new information.  Also, some of the source material I used in those posts is not openly available, but the latest article is.

Mr. Marks and Dr. Bloche document the involvement of psychologists and psychiatrists in Behavioral Science Consultation Teams, known somewhat disarmingly as "Biscuit teams."  The authors focus on two issues.  One, the BSCTs had access to health information that had been collected for the purposes of health care.  Although the Army's policies (source cited in article, here) stress that detainees do not have any right to privacy, and should not be given an expectation of privacy.  Mr. Marks points out that it generally is considered appropriate for health care providers to breach confidentiality, if there is a credible threat to the safety of another person (the Duty to Warn).  However, he draws a distinction between that exception to the general practice of confidentiality, and the complete abandonment of all privacy, which was/is routine at Guantanamo Bay.  He points out that the military's own guidelines dictate that health care providers should not abandon the ethical principles that guide their professional conduct.

The authors provide a link to a military policy document that describes the confidentiality policy.  That policy states explicitly that:
Medical personnel may not, however, become active participants in the collection of information, and may not be tasked in any way for the collection of such information.
They were able to find evidence that the BSCTs in some cases did attend interrogations, and that they helped develop plans for interrogations.  They were, in fact, tasked to develop psychological profiles and to consult with interrogators about how those profiles could be used to extract information from the detainees.  Incidentally, one of the psychologists was mentioned in a Time Magazine article (premium content) as "Maj. L" (Major John Leso).

The NEJM article provides evidence that military health care providers violated the ethical principles that govern their respective professional societies, and that they violated the military's own policy.  At least, they violated one of the military's policies.  They may have acted in accord with other policies that contradict the policy that is openly available.  We actually don't have any way of knowing all of the policies that may have been drafted to cover this situation.

The situation is much more clear with regard to International policies, as well as those put forth by the US State Department.  An organization known as Physicians for Human Rights published an extensive report on the use of extraordinary interrogation methods by US forces: Break Them Down: The Systematic Use of Psychological Torture by US Forces (PDF - 2.5MB).  An excerpt (page 119):
A strong indication of the US interpretation of legal restrictions on torture and cruel, inhuman, and degrading treatment over many years can be found in the annual Country Reports on Human Rights Practices by the US State Department. These reports describe the status of internationally recognized human rights in nearly all countries outside the US. In the 2005 report’s section on torture and other cruel, inhuman, or degrading treatment or punishment, the US government has consistently referred to the use of isolation, sleep deprivation, “humiliations such as public nakedness,” and “being forced to stand-up and sit-down to the point of collapse.”785 The report criticizes Egypt, for example, as having a “systematic pattern of torture”786 and points to stripping prisoners naked and blindfolding them and the use of threats, including threats of rape.787 With respect to Iran, the report criticizes the use of sleep deprivation, “prolonged solitary confinement with sensory deprivation,” and threats of execution.788 The report condemns Libya for threats of attack by dogs and calls them acts of torture.789 Other countries, including North Korea,790 Jordan,791 Pakistan,792 Saudi Arabia,793 and Syria794 are chastised in the report for similar violations of human rights.795 It is evident that these very techniques were approved and systematically used by the United States as methods of interrogation in the “war on terror.”
Break Them Down is an extensively researched document, consisting of 131 pages, containing 846 footnotes.  It includes a review of legal decisions pertaining to psychological torture, and seems, at least to this non-legal-expert, to prove that modern legal thought is contrary to such torture.  The footnotes show where most of the pertinent information of the subject can be found.  This includes references to documents that the US government has used to try to justify the use of torture.  This starts on page 72 of the text, which is the 76th page of the PDF.  They quote Sec. Rumsfeld's oroborusotic statement that:
“The Combatant Commanders shall . . . treat them [detainees] humanely and, to the extent appropriate and consistent with military necessity, in a manner consistent with the principles of the Geneva Conventions of 1949.”  [emphasis added] 
The problem with that statement is that the Geneva Conventions state explicitly that military necessity is not a valid rationale for deviating from the dictates of the Conventions.  Therefore, the set of actions, that would be consistent with the Conventions except for military necessity, is empty.  Therefore, Mr. Rumsfeld's statement is brilliantly meaningless.

Blogosphere commentary on this subject appears to be limited.  MNObserver posting at Power Liberal comments upon the Pentagon's indignant response to the allegations:
Nevermind the fact that Dr. Miles is a medical ethicist. Nevermind that he once spent months working with torture victims in southeast Asia in the 1970s as medical director of the American Refugee Committee, and knows torture when he sees it. Nevermind that he still volunteers at the Center for Victims of Torture in Minneapolis. Nevermind that interrogators themselves have said the military doctors' role was to advise them and their fellow interrogators on ways of increasing psychological duress on detainees. Dr. Miles told an inconvenient truth, and watch what is going to happen to him as he publishes his book asking more questions and revealing more inconvenient truths.
Dr. Miles is a US Senator, by the way.  MNObserver was posting after having read a bit up on Norwegianity.  Body and Soul has two pertinent posts.  First is a compare-and contrast exercise with the NEJM article and a contemporaneous NYT article.  Jeanne is troubled by her impression that the NYT article was so much less critical of the practices of the BSCTs:
Conduct contrary to the laws of war is a bit more serious than a vague ethical dilemma, but this is so typical of the corporate press, which, even when it reports on abuses, manages to dance around the direct responsibility of high level officials for that abuse.
Three days later, she reminds us that June 26 is the anniversary of the UN Convention against Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment.  Transparent Grid recalls that the way the BSCTs exploited a prisoner's phobias is reminiscent of Orwell's 1984.  HealthLawProf Blog comments on the NEJM article, concluding:
This article, and the others that follow it, should hopefully help generate some greater discussion about  how we are treating our prisoners abroad and bring about much needed change in policies. 
I think it is sad that they are assuming that more articles will follow.  Neil Lewis, writing at arthur, comments on the issue, titling his post Hippocrates Betrayed.  Moses, posting on Yowling From the Fencepost, comments about the involvement of physicians, rather pointedly:
I am sure it is only to make sure interrogators are modulating the comfort levels of detainees accurately and safely so they don't suffer permanent injury or die.
The attention drawn to this issue has led to calls for an investigation, but the White House is not interested.
White House spokesman Scott McClellan countered that "the Department of Defense has taken these issues head-on and addressed them."

"They continue to look into allegations of abuse. People are being held to account, and we think that's the way to go about this," McClellan said when asked whether the White House would support creation of an independent commission as proposed by Democrats.
The question not asked is this: Given that the health care professionals were specifically tasked for involvement, have any of them, or those who gave them the task, been held to account?

There are many ethical issues raised by the reports of health care professionals participating in interrogations.  Some of these are specific issues that health care professionals should think about: the privacy of medical information, and appropriateness of health care providers adopting a military role.  

For those who would consider participating in a Biscuit Team, there is another issue to think about: the mentors who taught you your profession did so with the expectation that you would use that knowledge and those skills to advance the well-being of patients.  Although there is not a moral obligation to restrict yourself in that way, there is a moral obligation to at least think about the fact that you are betraying those who got you where you are today.

I can anticipate that some readers will be tempted to comment that the exceptional circumstances posed by the Global and Perpetual War On Terror (GAPWOT) would justify deviation from the usual ethical principles governing interrogation methods.  Before you do, however, consider this: the GAPWOT extends to every corner of the globe, and it will never end.  Therefore, the circumstances are not exceptional.  The GAPWOT is the new normal.  The set of things that are both normal and exceptional is empty.  Furthermore, making exceptions to ethical principles is a kind of ethical relativism.  While ethical relativism is not itself objectionable, a detailed analysis is necessary to justify and delimit such deviations.  And once you become an ethical relativist, there is no turning back.

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