Monday, February 1, 2010

Clutching at Straws, Whitehead Attempts to Force Unwitting Scientist to Testify

According to recent court filings, the Whitehead is facing stiff opposition in getting a scientist to play a role in their defense in the Tuschl case.

The scientist in question is Brenda Bass from the University of Utah. In April 2000, she speculated in a review article that the small RNAs reported in the scientific publication underlying the Tuschl I patent application had been generated by an RNase III enzyme. Since RNase III enzymes are known to leave 3’ overhangs, the defense wants to use this speculative review article as proof that 3’ overhangs had been common wisdom in the gene silencing field at that time. This is designed to substantiate their claim that small RNAs 3’ overhangs were already implicit in Tuschl-I.

While I take my hat off to her remarkably prescient insights, the relevant remarks were clearly only speculations. Even if those speculations came from a well-respected scientist, most speculations in review articles do not turn out to be true to the same extent and for these reasons such speculations are generally not adopted as gospel in a scientific field, or by ‘those in the art’.

Maybe the Whitehead should start looking in the notebooks of Zamore, Bartel, and Sharp, or any other scientist for that matter, whether, since it was apparently so obvious, they were already in the know about the 3’ overhangs at the time (April 2000). This may be better than trying to annoy another person to become involved in a legal action. It essentially inconveniences her for being an insightful scientist.

If Whitehead is now alarmed that Dr. Bass does not really like to play according to their tune, then they really seem to be clutching at straws and continue to alienate the scientific community in their quest to lay claim on what belongs to the inventors of Tuschl II. And as a technicality, even if (unlikely) the judge could be convinced of this review article to have made 3' overhangs common wisdom, then given the filing dates it is still likely that Tuschl would be able to show that he first conceived of the overhangs before the April 2000 date.

Partly responsible for the alarm could be the fact that Max Planck and Alnylam are seeking, in addition to the permanent injunction, treble damages from the Whitehead and UMass for willfully conspiring to undermine the interests of Max Planck and Alnylam. If the $1.1B price tag for Sirna Therapeutics is any guide, it could get quite expensive. I just cannot get my head around Whitehead's eagerness to side with UMass, who along with their licensees Sirna/Merck and RXi seem to be the only financial beneficiaries should Tuschl I emerge as the fundamental RNAi trigger patent. In fact, Whitehead would even suffer financial harm by doing so, if it is true that Whitehead, MIT, and Max Planck would share equally in the combined Tuschl I-II royalties as per the Therapeutic Agreement. The only reason provided by them and Alnylam/Max Planck seem to be the political damage that siding with Max Planck instead of fellow UMass would entail. Clearly, there must be more to this than meets the eye.

Excerpt from the review:

Does PTGS by dsRNA Involve an RNase III–Like Enzyme?

Although the identity of the RNAi nuclease has not been determined, the characteristics of the short 21–25 nucleotide RNA pieces suggest they were generated by RNase III or a highly related enzyme (see [16] and [1], and references therein). RNase III is the only characterized nuclease known to cleave dsRNA at specific sites to generate dsRNA fragments of discrete sizes. For RNase III to stably bind a dsRNA, it must be at least two helical-turns in length, consistent with the observation that RNAi and transgene-induced silencing yield stable fragments of 22 base pairs. RNase III can produce fragments <22 class="apple-converted-space"> Figure 1, fragments less than 21–23 base pairs would not have been observed in the recent experiments because they would not remain stably bound to the enzyme and thus would be more accessible to degradation by other cellular nucleases.

Given the similarities between the cleavage products of RNase III and the RNAi nuclease, I have incorporated properties of the RNase III enzymes into the model of Figure 1. For example, RNase III makes staggered cuts that leave 3′ overhangs of two base pairs, as shown for the 23-mers of Figure 1. If RNAi involves an RNase III-like enzyme, it might explain why the small RNAs observed by Zamore and Tuschl range from 21–23 nucleotides. The initial cleavage might produce dsRNAs comprised of sense and antisense 23-mers, but the 3′ overhangs would be more accessible to single-strand–specific nucleases present in the extract, and trimmed to 21 and 22 nucleotide pieces. Zamore and Tuschl observe that cleavage of the dsRNA, unlike mRNA cleavage, does not absolutely require ATP. However, dsRNA cleavage is faster in the presence of ATP, and without ATP the pieces are predominantly the longer 23-mers. Certainly this is a clue to the role of ATP in this in vitro reaction, but at present its meaning is unclear.

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By Dirk Haussecker. All rights reserved.

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