By Kevin E. Noonan —

After a thorough review by a peer-review panel of the scientific data presented in a report published in its pages five years ago, the journal Nature announced on June 14, 2007 that, although representation of the data in one figure was flawed, the underlying conclusions were scientifically valid.  These conclusions were accompanied this week by a Corrigendum (or correction) published in the journal by the reports’ authors, identifying and acknowledging the mistakes but reasserting their conclusion that multipotent adult progenitor cells, or MAPCs, could be found in mouse bone marrow (see Jiang et al., "Pluripotency of mesenchymal stem cells derived from adult marrow").

The report comes as a sort of vindication for Dr. Catherine Verfaillie, the principal investigator in the study who is now at the Catholic University of Leuven in Belgium.  Dr. Verfaille has maintained all along that the basic conclusions of the work are sound, but has also acknowledged that there were flaws in how the paper was published (see "Limitations on The Usefulness of Adult Stem Cells").

Specifically, the paper identifies as unreliable one figure (Figure 1b), a fluorescence-activated cell sorting (FACS) plot.  This data was unreliable, according to the Corrigendum, because the intensity of staining was 10-fold lower than expected, and the proper controls were not included.  However, the authors provide a corrected Figure, and affirmatively state that they have been able to reproduce the work and obtain a reliable result.

These events may breathe additional life into efforts to develop pluripotent human stem cells from adult tissues.  One important reason that human embryonic stem cells have remained a primary focus of stem cell research even in the face of governmental efforts to suppress (or at least limit) their use for religious and "moral" reasons, is that stem cells from the inner cell mass of the blastocyst have been the only truly pluripotent cells known.  The Verfaille work, if truly reproducible, provides another, less controversial avenue for developing human pluripotent stem cells.  This line of investigation has the additional advantages that MAPCs could be derived from a patient’s own tissues, and thus avoid potential immunological complications to using human stem cells therapeutically.  Since the Bush administration is steadfast (or just plain stubborn) in its opposition to human embryonic stem cells (having used two of its only three vetoes against bills that would expand the scope of human ES cell lines approved for federally-funded research), any chance that stem cell science will advance in the U.S. is dependent on finding other sources.  These include alternative funding sources, such as the California initiative (see "Stem Cells a Go! in California") and other states and private foundations.  They once again include alternative stem cell sources, such as Dr. Verfaille’s MAPCs.  Perhaps these developments will blunt the negative effects that federal funding restrictions have had on the progress of stem cell science in this country.  Such an outcome would be beneficial both to science and the economy, and may help to reverse the "stem cell brain drain" the Bush Administration’s policies have had over the past seven years.

For additional information on this and related topics, please see:

• "Can Fibroblasts Solve The Problems with Human Embryonic Stem Cells?" June 15, 2007
• "Massachusetts to Invest $1 Billion on Medical and Science Research," May 10, 2007
• "It’s Time to Stop the Hypocrisy over Stem Cell Patents – Part II," April 26, 2007
• "It’s Time to Stop the Hypocrisy over Stem Cell Patents – Part I," April 17, 2007
• "WARF Stem Cell Patent Claims Rejected in Re-examination," April 3, 2007
• "NIH Chief Dissents on Federal Stem Cell Funding Ban," March 20, 2007
• "Stem Cells a Go! in California," February 28, 2007
• "Limitations on the Usefulness of Adult Stem Cells," February, 28, 2007

    By Kevin E. Noonan —

The U.S. faces a potential crisis over the failure of the Food and Drug Administration (FDA) to properly oversee quality assurance for drugs produced by foreign generic drug companies.  The risks of the current situation, detailed in an earlier post (see "The Effect of Foreign Generics on The U.S. Drug Supply – Part I"), will only become greater as the foreign generic drug industry expands in countries like China and India and the number of generic drugs (and perhaps even branded drugs) made as either finished drug products or active pharmaceutical ingredient continues to increase.  The potential for a genuine catastrophe is high.

What such a catastrophe might look like has been foreshadowed not once, but several times with regard not to active pharmaceutical ingredients but rather ancillary compounds used for preparing drug formulations.  As detailed in a June 17, 2007 article by Walt Bogdanich in The New York Times, there have already been several instances of the preservative glycerin, used in the preparation of liquid drug products like cough medicines and fever remedies for children, being contaminated with diethylene glycol, a toxic component of antifreeze.

Although "certified" as being pharmaceutical grade, the glycerin used to prepare antifever medicine for children in Haiti in 1995-96 caused the deaths of at least 88 children.  One of the difficulties in dealing with the crisis was that it took time to identify the glycerin as the source of the problem, and during that delay more children became ill and died.  The contaminated glycerin was ultimately traced to a Chinese government-run chemical company, Sinochem International Chemical Company, but in following the trail back to this Chinese company, FDA investigators found political and commercial interests aligned to thwart identification of those responsible and, as it turns out, prevent the catastrophe from recurring ten years later.

According to Mr. Bogdanich’s article, FDA investigators were motivated to get involved because even in the 1990’s the U.S. was importing pharmaceutical-grade glycerin and other compounds used in drug-making.  The investigators found that the immediate source of the glycerin was a German broker, but the records were unclear, and indeed that broker had contracted with other brokers to distribute what turned out to be additional barrels of adulterated glycerin.  The obfuscation of the commercial records was not merely sloppy record-keeping, however.  According to the FDA, the European traders were merely conforming to the practice of "neutralization," which prevented the end (or even intermediate) purchaser from being able to deal directly with the source and thus "eliminate the middle man."  Neutralization was a commercial practice these "middlemen" used to protect their business interests, but it had as a deadly consequence destruction of the identity of the adulterated glycerin source.

This problem was exacerbated in China, where Sinochem was the source but not the producer of the adulterated glycerin.  And Sinochem was completely uncooperative, although the FDA merely asked for a list of glycerin producers.  The company initially refused to identify the glycerin source for the same reason the European traders did:  to prevent foreign purchasers from bypassing Sinochem (and thus the Chinese government) and deal directly with the producers; this practice was banned under the centrally-planned Chinese Communist government.  Sinochem continued to refuse to cooperate even when the public health-related reasons for the inquiry were revealed.  Indeed, when questioned later, Sinochem officials maintained that the glycerin they sold was safe, and suggested any contamination occurred as the glycerin passed through the European supply chain.

Ultimately, after much delay, Sinochem identified the producer as the Tianhong Fine Chemicals Factory, located in northeastern China in the city of Dalian.  Amazingly, however, Sinochem refused to provide an address for the company, but gave the FDA investigators only a telephone number.  This led to a dead end, since the company official (when the investigators were finally able to contact him) denied there was any contamination in his plant.  But since he also refused to give the investigators the factory’s address, this line of inquiry came to an end.  (Years later, when an FDA investigator did visit the Dalian plant, the factory was no longer making glycerin, and all records of glycerin production were gone.)

Following the Haitian incident, and the FDA’s frustrations in its investigation, a number of groups including the World Health Organization and the American Medical Association recommended changes in how these chemicals are regulated worldwide, including certificates of analysis clearly showing the drug source.  However, none of these recommendations have been implemented, and eleven children were dying in India of diethylene glycol poisoning even as the AMA’s recommendations were being promulgated in its Journal.  A similar incident of diethylene glycol contamination of purportedly "pharmaceutical grade" glycerin occurred last September in Panama, killing at least 40 children according to an FDA report released last month.

And these are not isolated incidents:  over the past twenty years there have been at least five other occurrences of mass poisonings, in places like Bangladesh, Nigeria, Argentina, and India.

Despite these incidents, the absence of an international body with the authority to cross borders in pursuit of the purveyors of adulterated chemicals, and having the power to address the problem at the source and punish those responsible, precludes any global solution to the problem.  Any smug assurance in America that "it can’t happen here" should have been shattered by recent reports that low-cost toothpaste in several East coast discount stores was found to be contaminated with diethylene glycol, sourced from China and made subject to a recall of tens of thousands of toothpaste tubes.  This instance was especially troubling since the contaminated toothpaste was found in branded products that were purportedly counterfeit, having been traced to South American companies where the branded company has no manufacturing facilities.  It seems that not only can’t the FDA prevent such adulterated chemicals from contaminating products in America, but our customs officials can’t distinguish actual from counterfeit products.  These inabilities, due in part from lack of funding in view of the current Administration’s funding priorities, condemn the American people, at present, to far less protection in their foodstuffs, drugs, and cosmetic products than they have been accustomed to, and to which they are entitled.