Saturday, June 20, 2009

A better mouse trap, pt 2

The situation at the end of part 1 was summarized by Science magazine in 2006:
When the Texas Institute for Genomic Medicine (TIGM) applied to be part of a new $50 million U.S. National Institutes of Health (NIH) program to knock out as many mouse genes as possible, it seemed to be a shoo-in. Thanks to a partnership with Lexicon Genetics in The Woodlands, Texas, TIGM already has in its freezers knockouts for nearly a third of all mouse genes--twice what global knockout projects have achieved so far (see main text). "Taking us on would have made it easy for [NIH] to fulfill its mission," says TIGM President Richard Finnell.

Instead, the award went, in part, to the wrong Aggies:
NIH awarded five-year cooperative agreements totaling up to $47.2 million to two groups for the creation of the knockout mice lines. Recipients of those awards are Velocigene, a division of Regeneron Pharmaceuticals, Inc., in Tarrytown, N.Y., and a collaborative team from Children's Hospital Oakland Research Institute (CHORI) in Oakland, Calif., the School of Veterinary Medicine, University of California, Davis (UC Davis); and the Wellcome Trust Sanger Institute in Hinxton, England.

Why didn't NIH go with TIGM? Science speculates:
outside scientists were hesitant to speak on the record. But some researchers Science spoke to said IP restrictions Lexicon has imposed in the past--such as requiring labs and universities to sign away certain rights related to discoveries made using its mice--have been problematic. Under the TIGM deal, however, those restrictions are lifted, says Finnell, "so that wouldn't have been an issue."

Others say NIH is interested in more cutting-edge science than Lexicon is using to make its lines.

In hindsight, looking at the RFA, there's a hint about how Lexicon's cutting edge gene trapping technology was viewed at NIH.
It is estimated that ES cells derived from strain 129 have already been used to produce putative null gene trap mutations that represent nearly 60% of the mouse genes. However, it is widely thought that the productivity (in terms of generating mutations in previously unmutated genes) of the random gene-trap approach is diminishing and may have effectively reached a plateau, so that one or more other approaches will be needed to generate nulls in the remaining genes.

Here at Vision 1920, we didn't understand this technical mumbo-jumbo, so we made an exception to our usual rule of ignoring faculty input and asked what this means.

At the time of the RFA, Lexicon and others had already made knockouts in about 60% of the genes in the mouse genome. The money from NIH was for two purposes: to make that 60% available to researchers, and to get the other 40%. Gene trapping works by making semi-random insertions in the genome and picking out the ones that have hit genes. But you don't have a simple way to make sure every new insertion is in a gene you haven't seen before - you have to map every insertion - and after you've done this for a while, you start seeing the same old genes over and over again instead of finding new ones. The random strategy works better if things are really random, but the scientists don't know how to make them really random. It's sort of like how when you're shooting craps, you will eventually get all the numbers from 2-12, but you'll get more 7s than snake-eyes. In 2004, a letter in Nature Genetics said:
We confirm that Lexicon achieved close to 60% coverage of the genome from 200,000 OmniBank sequence tags deposited in GenBank (Fig. 1). Our analysis, supported independently by Lexicon3, indicates that the rate of trapping new genes was not linear but declined within the first 100,000 tags to a rate at which 1 new gene was added every 35 tags, comparable to the efficiency of high-throughput gene targeting methods

Our tame faculty member said this section of the RFA was kind of a Poisson pill for TIGM.

There were more signs of trouble in the RFA:
As mentioned above, the EUCOMM is using targeted gene trap technology to create a conditional resource in mouse strain 129. Therefore, to avoid duplicating existing resources or efforts, this RFA does not address the generation of additional gene trap mutations in the 129 background. However, proposals based on efficient gene trapping in the C57BL/6 strain background, either in an ES cell line or directly in mouse germ cells/embryos, will be considered.

Our boys in the Woodlands started out with a big lead. But instead of just paying for the Lexicon snowflake mice, a bunch of spoilers started their own gene trapping project. And the Europeans had a some advantages: they were public, they had EU funding backing them up, and they weren't just making the same kind of traps... they were making something called a conditional trap.

The potbangers will say that the TAMUS should have been able to see this coming. But that's 20-20 hindsight. It took Vision 1920 several hours to find this information from material that was published by 2006. And we had to compromise our principles and ask for faculty input to figure out what it meant.

In any case, the NIH decision was a dark day for TIGM. Sometimes the ref makes the wrong call.

To be continued...

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