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Tuschl II siRNA Assay
Knock-down of nuclear envelope protein Lamin. Elbashir, Harborth et al. Nature May 24 2001. This assay was proposed by Klaus Weber.

Citations Frequencies for Tuschl and Bass - not the total answer

On February 28th we published an article assessing the relative importance of the three seminal papers relating to the Tuschl I and Tuschl II inventions based upon citation frequency - referencing by other journal papers - of these papers (see here). In many cases comparing citation frequencies between different papers is like comparing apples to oranges. For example, important methodology papers tend to be referenced many more times than other types of papers presenting basic research that can be conceptually important to an inventive methodology paper.

Comparing the seminal papers for Tuschl I and Tuschl II, on the other hand, is like comparing apples to apples because they are dealing with the very same methodology in the process of discovery of what has become known as “short interfering RNA” or “siRNA” - terms coined by Thomas Tuschl in the seminal Tuschl II papers.

It seems reasonable that differences in citation frequencies of the seminal Tuschl I paper (listed below) and the two seminal Tuschl II papers (also listed below) reflect the relative importance of these papers in disclosing the method of siRNA-mediated gene silencing. Note the high number of times these papers were referenced by other papers (data taken from Google Scholar).

Seminal Tuschl I and Tuschl II papers (these can be found in the left sidebar):

March 31, 2000 (Tuschl I paper) - Zamore, PD; Tuschl, T; Sharp, PA; Bartel, DP Cell 101:25-33. – 1878 citations

Jan. 15, 2001 (Tuschl IIA paper) - Elbashir, S; Lendeckel, W; Tuschl, T Genes & Development 15:188-200 (2001). – 2483 citations

May 26, 2001 (Tuschl IIB paper) - Sayda Elbashir, Winfried Lendeckel, Thomas Tuschl et al., Nature 411:494-498. This second Tuschl II paper described for the first time gene silencing by siRNA in mammalian/human cells. – 6308 citations

Comparing the Tuschl I & II papers to the Brenda Bass’ papers in the same time period is not quite apples to apples because she is not disclosing methodology for siRNA-mediated gene silencing. In two cases, the minireviews published on April 28th, 2000, (in which she was invited to comment on the Tuschl I paper) and on May 28th, 2001 (in which she was invited to comment on the Tuschl IIB paper) she is providing insightful views about the significance of these Tuschl I and II papers. However, in her April 28, 2000, paper she speculated on the role of RNAse III in producing dsRNA fragments that became known as siRNA. Under Dr. Bass’ May 28 Nature paper published in the same issue of Nature as the Tuschl IIB paper, I have quoted four statements (below) made by Dr. Bass about the findings published in the Tuschl IIB paper. Note the number of times Dr. Bass’ papers were referenced by other papers (taken from Google Scholar). These numbers, though lower than the Tuschl inventive papers, are impressive in their own right.

Brenda Bass’ key papers in 2000-2001 (the minireview published on April 28, 2000, commenting on the Tuschl I paper is in the left sidebar)

April 28, 2000 - Bass, B. “Double-Stranded RNA as a Template for Gene Silencing” Minireview in Cell 101: 235–238. – 355 citations

Sep. 15, 2000 - Domeier, ME; Morse, PE; Knight, SW; Portereiko,M; Bass, BL; Mango, SE “A Link Between RNA Interference and Nonsense-Mediated Decay in Caenorhabditis elegans” Science 289: 1928-1930. – 126 citations

Sep. 28, 2000 - Katrina A. Lehmann and Brenda L. Bass Double-Stranded RNA Adenosine Deaminases ADAR1 and ADAR2 Have Overlapping Specificities Biochemistry” 39: 12875-12884. 68 citations

Sep. 21, 2001 - Knight, SW; Bass, BL “A Role for the RNase III Enzyme DCR-1 in RNA Interference and Germ Line Development in Caenorhabditis elegans” Science 293(5538): 2269–2271. – 479 citations

The minireview by Dr. Bass that accompanied the Tuschl IIB paper in Nature

May 24, 2001 - Bass, B. RNA Interference: The Sort Answer Nature 411: 428-429. - 81 citations

“On page 494 of this issue (the Tuschl IIB paper), Tuschl and colleagues describe research that paves the way for successful RNAi in mammalian cells.”

“Importantly, Tuschl and co-workers went on to show that siRNAs are not only effective at targeting the transgene luciferase, but also at targeting naturally occurring, endogenous genes.”

“And, as Tuschl and colleagues show, even in mammalian cells, siRNAs are effective at concentrations that are several orders of magnitude below the concentrations typically used in antisense experiments.”

“…the new study shows that one way dsRNA pathways can co-exist is to require different lengths of dsRNA. This is good news for cells — and for researchers.”

As stated at the top, citations are likely to be higher for papers describing valuable methodology. The two Tuschl II papers reduced to practice the best mode for siRNA-mediated RNA interference. Tomorrow I will look at more of Dr. Bass’ papers, but it’s crystal clear that the Tuschl II papers had a huge impact on subsequent research on gene silencing compared to Dr. Bass’ papers (not to say that Dr. Bass’ papers where not insightful).

Determination of Dr. Bass’ role in the invention of siRNA-mediated gene silencing will hinge on what she disclosed to the Tuschl I and Tuschl II inventors. Speculation and obviousness can be damaging prior art for an invention, but a secret may not be.

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What is siRNA?
Elbashir etal. (left sidebar): "Double-stranded RNA (dsRNA) induces sequence-specific posttranscriptional gene silencing in many organisms by a process known as RNA interference (RNAi) ... 21- and 22-nt RNA fragments are the sequence-specific mediators of RNAi. The short interfering RNAs (siRNAs) are generated by an RNase III–like processing reaction from long dsRNA. Chemically synthesized siRNA duplexes with overhanging 3' ends mediate efficient target RNA cleavage ..." and "... (these) 21-nucleotide siRNA duplexes specifically suppress expression of endogenous and heterologous genes in different mammalian cell(s)..."
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