Recently in Ethics Category

Sherley et al v Sebelius et al. The case that won't go away...to the chagrin of scientists who rely on government funding for research with human embryonic stem cells (hESCs).

The Nature News Blog reports today that scientists James Sherley and Theresa Deisher, who choose to work with adult stem cells, are appealing Judge Royce Lamberth's reluctant decision in July to shoot down a permanent injunction against federal funding for hESC research. The scientists submitted their legal brief yesterday to the US Court of Appeals for the DC Circuit. The appeals court, which ruled against Sherley et al last April (with respect to their request for a preliminary injunction), will hear oral arguments on April 23rd in this new appeal to overturn Lamberth's ruling against a permanent injunction.

But a similar decision granting federal funds for hESC research by the appeals court is not a given. The randomly selected, 3-judge panel for the April hearing will be somewhat different than the one that ruled last year, the Nature News Blog reveals. The judges for the upcoming appeals hearing will be Republican appointees Chief Judge David Sentelle, Judge Janice Rogers Brown, and Judge Karen LeCraft Henderson. The lone, common panel member is Henderson, who dissented in the previous appeals hearing by calling the government's favorable interpretation of existing law (ie, the highly ambiguous Dickey-Wicker amendment) "linguistic jujitsu."

Image of undifferentiated hESCs from http://www.nih.gov/catalyst/2007/07.01.01/page1.html. 

About one-third of cognitively normal elderly demonstrate an elevated load of beta-amyloid,* a pathologic hallmark of Alzheimer disease, in the brain, according to a newly published study from the Mayo Clinic. These data support previous observations, in which the PET-imaged brains of about a third of elderly, nondemented subjects will exhibit an abnormal accumulation of the AD-associated protein.

However, the Mayo investigators went a bit further by examining the potential association between the load of beta-amyloid, as measured with an established radiolabeled tracer (Pittsburgh compound B, or PiB) on PET images, and cognitive performance on various memory, language, attention, and visuospatial tests. As well, a relationship among brain amyloid, cognitive performance, and APOEe4 status (a well-known genetic marker for AD) was examined. What the researchers found was that poorer cognitive performance was associated with greater amyloid deposition, and that this relationship was more robust in APOEe4 carriers. Conversely the association between amyloid load and relative cognitive impairment was much weaker (ie, only "modest") in subjects who did not carry an APOEe4 allele, suggesting (the authors concluded) "that APOE isoforms modulate the harmful effects of [beta-amyloid] on cognitive function."

What any of this information means practically is very murky, however. Will some of these cognitively normal subjects with heavier amyloid burdens (and who perform less well on cognitive tests) develop AD—that is, if they live long enough? Is AD more likely in these subjects if they're APOE e4 carriers? We don't know, and obviously further longitudinal work is necessary. The Mayo authors do imply that follow-up is ongoing.

In an accompanying editorial, Buchman and Bennett commended the Mayo investigators for the size of the study (a highly respectable 408 subjects [with a median age of about 80 years]) and their "important contribution to our understanding of AD, illustrating that even among persons without dementia or [mild cognitive impairment], amyloid deposition is associated with very mild symptoms, especially among carriers of the APOE e4 allele." But "[w]hether...amyloid imaging agents will have clinical utility remains to be determined," the editorialists appropriately caution. They advise about the lack of data concerning the prognostic value of amyloid retention (presumably in any subjects, whether demented or not) and how amyloid retention may change over time. And they add that the utility of amyloid-imaging agents "will remain low in the absence of an effective amyloid modulating agent." In other words, what's the point of knowing the amyloid burden if you can't do anything to lighten the load?

A related issue, however, not explored by the editorial authors, is whether even removing amyloid in the context of cognitive impairment, is beneficial or, in fact, does more harm. Existing AD trials suggest that amyloid-modulating agents (eg, bapineuzumab) can cause brain edema—presumably due to the removal of vascular amyloid—and that they do so without improving cognition to any substantial degree overall.

Intervening earlier with anti-amyloid drugs in less cognitively impaired subjects, as proposed by some industry investigators, is a tricky move: obviously primum non nocere in persons with only mild cognitive impairment and certainly in individuals with no practical cognitive problems (regardless of their amyloid burden).

PET = positron emission tomography.

* Defined by a "global cortical PiB retention ratio" of greater than 1.50.

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

For those who are following the XMRV-CFS-Mikovits story, science blogger John Timmer at ars technica provides a decent synopsis of the crazy soap opera/Greek tragedy.

Specifically Timmer outlines a complicated narrative in reasonably comprehensible (but not outstanding*) prose. The salient points:

• the rise and fall of data linking XMRV with the dubious CFS;
• researcher Judy Mikovits's refusal to abandon the idea that XMRV is associated with CFS, despite others' data indicating XMRV contamination;
• the symbiotic nexus between Mikovits and individuals with CFS, some of whom reportedly tried to undermine any investigation debunking the link between XMRV with CFS;
• Mikovits's subsequent unethical, and possibly criminal, behavior; and
• the overall integrity of the collective, collaborative scientific process (including nods to the DHHS and the "publishing system").

* One feels that Timmer's lengthy post could be a terrific short article with some professional editorial help.
CFS = chronic fatigue syndrome; DHHS = Department of Health and Human Services; XMRV = xenotropic murine leukemia virus-related virus.

And probably rightly so, given a number of issues.

• The Harvard press release is terribly (and irresponsibly) overdramatic, emphasizing the "endocrine-disrupting" effect of bisphenol A (which is only documented in laboratory animals, to my knowledge) and the >1200% increase in urinary BPA after consuming canned soup (Progresso) for 5 days. There is no mention of absolute numbers in the attention-grabbing press release, just the astonishing percentage jump.
  
• The JAMA report, available here (courtesy of JunkScience.com), is actually published as a letter and not a more stringently peer-reviewed article.
  
• JunkScience.com takes the letter authors to task for not distinguishing between the urinary measurement of BPA (which is evidently not possible or very difficult) and that of a quickly produced metabolite. BPA is evidently rapidly processed in the body, and its "biologically inactive" metabolite (not BPA per se) was actually measured in urine, says JunkScience.com (the blog further claims that at least some of the authors should have known or do know this fact).
  
• While the percentage increase of mean urinary BPA values among canned-soup eaters is very impressive, we're talking about differences in MICROGRAMS PER LITER: 1.1 mcg/L after 5 days of fresh-soup consumption vs 20.8 mcg/L after 5 days of canned-soup consumption, for a difference of 19.7 mcg/L.*
  
• The urinary spike in BPA (or its metabolite) was probably transient, and the authors themselves acknowledge, "The effect of such intermittent elevations in urinary BPA concentration is unknown." 

So it's a non-peer-reviewed study highlighting the transient rise of urinary BPA (or really, a biologically inactive BPA metabolite) after eating canned soup, the significance of which is unknown.

* In the updated National Health and Nutrition Examination Survey, levels of BPA were detected in all subjects older than 6 years of age. Geometric means were approximately 2 mcg/L, but levels rose to 20 mcg/L (or thereabouts) in the 95th-percentile groups.

Image of can of Progresso vegetable minestrone soup from progresso.com.

The Nature News Blog and Retraction Watch provide the ongoing, head-torquing narrative of Judy Mikovits, the dubious or embattled (depending on your viewpoint) XMRV-CFS researcher who was fired in September from the Whittemore Peterson Institute in Reno, Nevada. The latest news: Mikovits was arrested last Friday in California (as a fugitive from Nevada, from what I can tell) for allegedly stealing property—eg, laboratory notebooks—from the Institute.

And while the jig certainly appears to be up for Mikovits regarding the validity of her past scientific claims about XMRV and chronic fatigue syndrome or a future career in legitimate science, to hold her without bail (especially while, elsewhere, an alleged serial pedophile is allowed out on $100,000 and no monitoring) seems terribly draconian and patently unfair.

By way of Pharmalot:

Cheng Yi Liang, 57, pleaded guilty yesterday to securities fraud and "making a false statement," after the SEC charged the former FDA chemist in March with insider trading (for background, go here). The maximum sentence for the first count is a 20-year prison term followed by a 5-year supervised release and a fine of $5 million. For count two, Liang could be imprisoned for 5 years and fined $250,000. An alternative fine could also be ordered for Liang, the plea agreement indicates: twice his gross gain or loss—or about $7.5 million by my calculation. A guilty plea also may endanger his immigration status (it is not stated in the agreement what Liang's immigration status is, however).

The plea agreement also argues that Liang's offenses are especially egregious because of the amount of money he earned through insider knowledge, the "sophisticated means" by which he earned it, and the fact that he was in a "position of public trust" as an FDA employee. Liang has evidently agreed to forfeit his $3,776,152 in gains through his TDAmeritrade and other accounts, as well as some vital real estate (eg, his residence in Gaithersburg, Maryland, and the home of his son, "A. L.").

Pharmalot also reports that Cheng Yi Liang's son, Andrew Liang, pleaded guilty last month to one count of possessing child pornography (yeesh), which was discovered in the government's investigation.

It's still not clear what tipped off the feds to the elder Liang's trading activities, but Derek Lowe's original thought about the profits Liang realized from the surprise approval of the antipsychotic iloperidone (Fanapt; Vanda Pharmaceuticals) remains highly plausible.

As demonstrated by grad student Abbie Smith at her ERV blog.

Smith's post heard 'round the Web—which is a major, career-devasting bust to researcher Judy Mikovits—shows how Mikovits clearly used the same Western blot data to describe two different experiments, both of which made the now highly dubious link between XMRV and chronic fatigue syndrome.

Although Smith acknowledges that she was not the first to recognize the identical nature of Mikovits's Western blot images (one of which was published in Science in 2009 and the other of which was presented at a recent conference in Ottawa), she should get credit for the worldwide disclosure.

Snap.

A Presidential commission, charged with investigating the US-funded VD experiments on Guatemalan prisoners and mental patients in the mid-1940s, revealed some of its shocking findings this week to the press (for background on this story, start here). The experiments, performed without subjects' consent, were discovered and reported by a Wellesley medical historian, Susan Reverby, last fall, and President Obama shortly thereafter apologized to the Guatemalan government for the unethical studies and ordered a commission to investigate them.

The commission's official report will reportedly be available in early September (tomorrow?), but a few highly disturbing details of the investigation were made available to the AP this week. Among them:

• 1300 Guatemalan soldiers, prisoners, prostitutes, or mental patients were intentionally exposed to the microbes that cause syphilis or gonorrhea
• Only about 700 (53%) of the exposed individuals received some sort of treatment (presumably penicillin*)
• 83 people in the study died, although it's not clear if death was due to intentional infection
• The research provided "no useful medical information"
• 7 women with epilepsy, residents of Guatemala's Asilo de Alienados (Asylum for the Insane), were injected with Treponema pallidum at the base of the skull, as a hopeful cure; all developed bacterial meningitis, probably as a result of unsterile technique
  
• A female patient with syphilis and an unknown terminal illness received an inoculation of gonococci in the eyes "and elsewhere"; she died 6 months later

Notorious US physician John C. Cutler, MD (right), who oversaw the PHS's Tuskegee syphilis experiment, led the American-funded human experimentation in Guatemala.

Guatemalan authorities are evidently conducting their own fact-finding investigation of the matter, but official reports have been delayed on more than one occasion. According to the AP, the Guatemalan report should be completed by November. (It should be remembered that Guatemalan authorities were complicit in the PHS experiments, according to Reverby.)

* The described rationale for the program was to determine the preventive benefit of penicillin.

Portrait of PHS physician John C. Cutler, MD, August 25, 1942, from the National Library of Medicine.

Judge Royce Lamberth, the chief judge of the US District Court for DC and the guy who originally granted a preliminary injunction against stem-cell research in the case of Sherley et al v Sibelius et al (and created a lot of havoc within the NIH and among US stem-cell researchers), has now decided that it's all okay—begrudgingly. On Wednesday, Lamberth issued his ruling on a permanent injunction that makes federal funding of research with human embryonic stem cells (hESCs) legal (go here for the Nature News Blog's story).

Lamberth's decision on a permanent injunction was evidently informed by the opinions of the US Court of Appeals for the DC Circuit, which shot down Lamberth's original, preliminary injunction last April. At the heart of Lamberth's newly revised opinion is the remaining ambiguity of "research." He concludes,

...the DC Circuit has made it abundantly clear that the term is ambiguous as a matter of law. While it may be true that by following the Court of Appeals' conclusion as to the ambiguity of "research," this Court has become a grudging partner in a bout of "linguistic jujitsu," [quoting a phrase from the Appeals Court's dissenting opinion], such is life for an antepenultimate court.

And so, for the losing plaintiffs, their option is to accept Lamberth's reluctant decision or to pursue their case to the ultimate court.*

* US District Court for DC = antepenultimate court; US Court of Appeals for the DC Circuit = penultimate court; Supreme Court = ultimate court.

Forbes dishes big dirt about former CEO and micro-manager Jeff Kindler's last frazzled days at Pfizer before his abrupt ouster last December. And former HR president Mary McLeod, who used to helicopter from her home in Delaware to Pfizer HQ in Manhatten (!), comes off looking like some kind of ridiculously entitled Iago in this Shakespearean drama. Snakes, indeed. Yeesh, makes you glad to be a low-level schlemiel.*

* Excepting those huge severance packages.