Toxic Waste?

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Before testing new drugs in human beings, drug developers must first perform a series of safety tests in animals. Unfortunately, these preclinical toxicology studies are typically protected as trade secrets. In fact, many countries have laws that specifically bar drug regulators from releasing preclinical toxicology data submitted by drug developers.


Unless you take the extreme view that animal experimentation raises no ethical concerns, this represents a terrible waste of animals and a failure of researchers to enable the sacrifice of animals to enrich the bank of human knowledge. As an afterthought, it’s worth mentioning that this also comes with certain opportunity costs for human beings, since such nondisclosure potentially 1-frustrates efforts by researchers to improve their knowledge about drug safety, 2- results in duplicative expenditure of human resources.

It needn’t be this way, and the field of gene transfer shows one modest way toxicology data could be published and pooled. Since it was established, the National Gene Vector Laboratories, at Indiana University, have invited gene transfer researchers to submit summary data on toxicology studies to their database (the laboratory recently was eliminated and replaced with the National Gene Vector Biorepository– NGVB for short). As described by NGVB director Ken Cornetta and project coordinator Lorraine Matheson in Molecular Therapy (April 2009), the database is intended to provide a resource for researchers so that they can cross-reference toxicology experiments in their FDA filings and avoid duplicative studies. The authors also envision the database as a resource for grant reviewers.

The database contains 27 toxicology studies in all. This number seems small when you consider the volume of gene transfer studies pursued since the database was established. The fact that every institution that has contributed to the database is a nonprofit suggests that the private sector has not taken an interest in this worthy resource. One question I have is how many private companies have used data contained in this databank in their FDA filings (this should be easy to determine).

These questions aside, other fields should create similar resources to pool data and create opportunities for data linkage. I would go so far as to say that ethics policies should require that, at a minimum, such summary data be published on a public database. The failure to do so seem a toxic waste for animals, scientists, funders, and patients alike.  (photo credit: drp, Waste Not, 2004)

BibTeX

@Manual{stream2009-104,
    title = {Toxic Waste?},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2009,
    month = apr,
    day = 27,
    url = {https://www.translationalethics.com/2009/04/27/toxic-waste/}
}

MLA

Jonathan Kimmelman. "Toxic Waste?" Web blog post. STREAM research. 27 Apr 2009. Web. 29 Nov 2021. <https://www.translationalethics.com/2009/04/27/toxic-waste/>

APA

Jonathan Kimmelman. (2009, Apr 27). Toxic Waste? [Web log post]. Retrieved from https://www.translationalethics.com/2009/04/27/toxic-waste/


Just the FACS: Reprise on Insertional Mutagenesis

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I‘ve just returned from the annual European Society of Gene and Cell Therapy meeting in Belgium.  Lots of great material for upcoming posts. For now, I want to follow on the last posting on the leukemias in the X-SCID study.  A warning: those lacking a stomach for science geek-talk might want to skip this posting.


In the previous posting, I stated that a recent paper provided evidence that retroviral integration in the genome (“insertional mutagensis”) had triggered leukemias in the X-SCID study rather than over-expression of the corrective gene (“transgene”), the gamma c-chain (hereafter, “gc”).  This was on the basis of data in the graphic above, which used cell sorting to show that levels of gc on the surface of T-cells was within a normal range.  In Belgium, Adrian Thrasher presented similar data for the fifth leukemia.

When I first encountered this figure, it bothered me: why did the authors measure gc expression by cell surface markers (a technique called “FACS”) rather than Western or Northern blotting, or quantitative PCR, or something along these lines?  It seemed a very indirect way of seeing whether gc expression levels are in fact normal. Here are two possibilities that this figure fails to rule out:  1- gc is expressed at very high levels, but not packaged and presented on the surface of T-cells, perhaps because of insufficiency of other receptor components; 2- some gc transgene is aberrantly spliced, such that surface levels are normal, but intracellular concentrations of the alternate splicing product are abnormal.

A few years back, one team of researchers presented data indicating that gc transgene overexpression contributes to T-cell transformation. Another team claimed it was unable to reproduce this. The jury seems to still be out on whether the gc product contributed to the X-SCID leukemias, and I’m not yet convinced that the latest round of data fully exonerates the gc chain. (Graphic: figure from Salima Hacein-Bey-Abina et al, J Clinical Investigation 2008; 108: 3132-42).

BibTeX

@Manual{stream2008-123,
    title = {Just the FACS: Reprise on Insertional Mutagenesis},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2008,
    month = nov,
    day = 18,
    url = {https://www.translationalethics.com/2008/11/18/just-the-facs-reprise-on-insertional-mutagenesis/}
}

MLA

Jonathan Kimmelman. "Just the FACS: Reprise on Insertional Mutagenesis" Web blog post. STREAM research. 18 Nov 2008. Web. 29 Nov 2021. <https://www.translationalethics.com/2008/11/18/just-the-facs-reprise-on-insertional-mutagenesis/>

APA

Jonathan Kimmelman. (2008, Nov 18). Just the FACS: Reprise on Insertional Mutagenesis [Web log post]. Retrieved from https://www.translationalethics.com/2008/11/18/just-the-facs-reprise-on-insertional-mutagenesis/


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