Testing toxins with TIGM

Last week, the TAMU News service announced

The Texas A&M Institute for Genomic Medicine (TIGM), a leading global source for genetic discoveries, has been selected by the Defense Threat Reduction Agency (DTRA) to identify and develop new drug targets for certain toxins, viruses and bacterial pathogens. By discovering and ultimately developing strategies to eliminate the ways in which toxins and microbes hijack cells, this research has the potential to discover new vaccines and therapies to counteract the most dangerous bio-threats faced by both military personnel and civilians.

The DTRA award will be used to develop first-in-class high-throughput screening procedures for mouse stem cells involving state-of-the-art robotic equipment and pioneering screening procedures. TIGM investigators will screen more than 3,500 different genes to identify those that enable toxins and microbes to injure cells and tissues. Once candidate genes are identified, TIGM researchers will develop therapies to be tested both in tissues and pre-clinical models.

According to the press release, the award is for $12.25 M over 53 months.

More misconceptions about TIGM

Rick Finnell's email (pdf) also discusses the origins of TIGM

Your second major concern was about how the decision was made to go after this Texas Enterprise Fund award. I certainly do not know when the conversations began, as I was a faculty member brought in to give my input sometime long after the process had already started. I had my own opinions as to whether or not TAMUS should get involved and what other options might have been explored.

This might seem to be surprising, given Guy Diedrich's account during the Giroir open forum

Vice Chancellor for Federal Relations and Commercialization Guy Diedrich on Monday called claims that TIGM started in the system offices "revisionist history." He told those at the forum that proposals first came from faculty members and people in the office of former Vice President for Research Richard Ewing.

If Finnell only came in later, who was driving the formation of TIGM? Let's look at the minutes(pdf) from the BoR meeting in July 2005

Mr. White said that the Texas Institute for Genomic Medicine (TIGM) is a great example of collaboration within the System. He commented on the involvement of Dr. Bob McTeer, Chancellor; Dr. Bob Gates, President of TAMU; Dr. Dick Ewing, Vice President of for Research at TAMU; Dr. Nancy Dickey, President of the System Health Science Center (HSC); Dr. Rick Finnell, Director of the Institute of Biosciences and Technology (IBT); and Mr. Guy Diedrich, Managing Director of the Technology Commercialization Center...

Mr. Nye said that on behalf of the Board and others, he wanted to recognize that Mr. White was very instrumental in receiving the idea, getting it germinated at the state level, attracting the funds and bringing it to the university when it could have gone many other places. He commended Mr. White and said that this was a wonderful undertaking and it was appreciated.

CHANCELLOR’S REMARKS

Dr. McTeer commented that the morning before the press conference, TIGM held its organizing board meeting and Mr. White was elected as chairman. He said that this was probably the most important thing that would happen during his administration.
Dr. McTeer said that there were many people who should be commended, such as Mr. Diedrich and Mr. Doug Centilli, Congressman Kevin Brady’s Chief of Staff.

In 2006, Dr. McTeer spoke to the Texas Lyceum

Not long after TIGM was formed, I had breakfast with Alan Greenspan in Washington. He asked me what was going on in my new world. When I started explaining all this to him, he interrupted me to ask why it was that most research mice are white rather than brown. After a long moment that seemed like an hour—a place I’d been before with him—I finally said, “Mr. Chairman, It’s a conundrum.”

Pretty soon, Guy Diedrich, who had brokered the TIGM deal (and who will be on your program tomorrow) brought me another deal to sign.

The record supports Diedrich's account. The idea for TIGM didn't start with the System; it started with Regent White, who probably heard about Lexicon from his time working with the Houston Technology Center. Diedrich, working in the VPR's office at TAMU was tasked with making it happen, so the proposals originated with TAMU, not TAMUS.

Misconceptions about TIGM

The CPI has posted an email (pdf) from Rick Finnell giving his take on the TIGM story. The email was in response to comments made during Brett Giroir's open forum by Prof. Mary Meagher. Excerpts:

First, the RFA that TIGM responded to from the NIH specifically requested conventional over conditional clones. If you read the RFA, and I trust that you have since you specifically commented on this point, then you would see that the request was for a straight (conventional) knockout with a reporter in C57BL/6 ES cells. That is it. While the scientific community, of which I am a part, would have preferred that NIH invest in a conditional asset, that is NOT what the RFA requested. So TIGM was absolutely responding to the RFA.

Vision 1920 blogged about the RFA here. Our tame faculty member says Finnell is correct that the RFA expressed concerns about high-throughput generation of conditional knockouts. However,

• Finnell does not address the requirement in the RFA for a plan to go after at least 25% of the genes missed by prior gene trapping approaches. TIGM is still based on gene traps, while the RFA emphasized the need for a targeted approach.
• Meagher's comment about conditional knockouts may not be relevant to what happened during the KOMP grant process, but it is relevant to the likely demand for TIGM knockout mice going forward

Vision 1920 points out, however, that low demand is a good thing, since Giroir said TIGM loses money on producing mice from ES cells.

The fact that TIGM barely existed (I was the only TIGM member, devoting 25% of my effort at the time of the submission), we had no track record which, as you know from submitting grant proposals to NIH, weighs heavily upon the reviewers. Yes, we could pretty much guarantee a successful outcome to Francis Collins, as we were in the position to put up the 273,000 ES cell clones from the 129 OmniBank 1 gene‐trap library, up to 3000 already made Lexicon knockout mice, and the 350,000 C57 ES cell clone gene‐trap library that was under construction. But we lacked credibility as we had no reputation for shipping products to end users...

Who could have predicted that a lack of a track record was an issue when the prospect of the KOMP grant was used as the basis for its original TIGM business plan?

Finnell also suggests shenanigans:

One could speculate endlessly about the other reasons why TIGM did not get the KOMP RFA (see the attached Science article), but that is really only self‐serving and no good can come of it at this point in time. Suffice to say that the review and its outcome were highly irregular, prompting Francis Collins and his senior KOMP staff to fly to Houston to try to explain to us in person why we were not funded. I don’t know about you, but when my NIH applications are not funded, my program officer doesn’t spontaneously call me and jump on a plane to talk to me in person about it. Quite the contrary, they are usually hard to find. This was unusual. That is all I can really say.

If Collins went forward with KOMP funding to TIGM rivals despite a "highly irregular" review, perhaps he should be asked about it when he comes up for confirmation as NIH director.

Skins game

The last part of Bret Giroir's presentation was about the administrative structure of the Institute for Innovative Therapeutics. Giroir talked about how the participating components - TAMU, TAMUHSC, TEES, and AgriLife would each have primary responsibility for one of the components. In the current plan, TAMU will run TIPS, TAMUHSC will run TIGM, and TEES will run the NCTM. AgriLife will eventually have responsibility for another component, as the Institute expands into a "One Health Plus" mission, and becomes a campus bridging space between the university and the site of the planned new medical center.

The idea is that each of the System components will have "skin in the game" for all of the Institute components, with a larger share of the responsibility and revenue for the piece they run. A preliminary version of how this would work is in the strategic plan (pdf) posted on the CPI website.

The Chancellor and the CEO constituency committee should develop a model for sharing shortfalls and excess revenues across the Institution and participating components

A recommended strategy would be to have the institutional shortfalls and excess revenues assumed according to the following type of structure, using TIPS as an example. The percentage allocation should be decided upon by the Chancellor and the CEO Constituency Committee but should adhere to the principle of shared "skin in the game":

• 60% assumed by the primary owner (e.g. TAMU as primary owner of TIPS
• 20% assumed by the Institutional Partners (e.g. HSC and TEES)
20% assumed by TAMUS

The percentages presented by Giroir yesterday were different. The primary owner shares where reduced to 40%. Vision 1920 did not catch how the exact percentages were adjusted for the other components, but the plan included a way for AgriLife to have significant skin in the game even before it becomes a primary owner of a component.

The story in today's Eagle touches on the question of how much exposure is involved

"We would like to understand much better where the money is coming from and what the risks are," said Tim Hall, a professor in the College of Science.
...
"I would say the risks are incredibly* minimal," he said in an interview after the meeting. "Anything you do has risks. I can only say that we have done more financial due diligence and have more [backup] plans that I have seen at any university in my experience."

The fiscal risks are hard to estimate, as they require assumptions about the income streams of TIGM, TIPS, and NCTM. Interestingly, Giroir said he expected TIGM to continue to lose money; as a core facility it is designed to subsidize other research (currently that subsidy is to other institutions outside TAMUS). This makes the outdated technology of the TIGM knockout collection a feature, not a bug; if more labs ordered TIGM mice, it would have an even bigger deficit!

The documents posted by the CPI include a couple of different sets of fiscal estimates. In the strategic plan, which projects out to 2013, TIGM is projected to lose $2-3M/year. TIPS has two projections based on how fast imaging equipment is purchased. These show a $5M profit from a "Governor's loan" and two ETF projects in FY2009, followed by losses ranging from $2-6M/year. This does not include a hoped-for $65M deal with Xerion. The strategic plan does not have a projection for NCTM. The CPI has also posted a best/worst case analysis by Greg Anderson, the System treasurer. This shows a best case of rising profits of 1-3M/year for TIPS and $7-8M/year for NCTM by 2017. TIGM is projected to lose money in the best case scenario. The worst case scenario still shows NCTM making a $4M profit by 2014. In this scenario, long-term NCTM profits almost offset losses by TIGM and TIPS by 2017. The basis for the income projections is not clear.

*Incredibly = in(not)+credibly.

Open forum with Bret Giroir

Vision 1920 is still trying to digest nearly 3 hours of open forum where Vice Chancellor Giroir, occasionally assisted by Vice Chancellor Diedrich dazzled the faculty with the real stories behind TIGM, TIPS, NCTM, and tIIT. Dr. Giroir took us all the way back to his days at Harvard (subtly reminding those uppity faculty that he had taken courses from a better class of profs than one finds in the faculty senate or CPI) when he and his roommate snuck into a restricted area to get research jobs. He described his rise through the ranks at UTSW and his time at DARPA, and explained how everything he's doing for us here at A&M is driven by his love of science and the memories of dead children he couldn't save. He pointed out how the tIIT project is about supporting our brave men and women overseas. And about saving the world from pandemic H1N1 influenza.

It's a sign of how depraved those faculty whiners are that some still seemed skeptical at the end of this marathon.

In addition to the revelation of the meaning of Giroir's chicken, much of the discussion was about TIGM. The highlights:

• Giroir and Diedrich setting the record straight on TIGM. Shorter version: Things are great and it's not the System's fault. TIGM was a university initiative from the start, driven by the late Dick Ewing, who was VPR at the time.
• Two free mice for A&M researchers (whether A&M researchers not working on mice can sell the rights to their pair on eBay was not addressed).
• TIGM has submitted lots of grants and is now likely to get one to do screening of ES cell lines for drug discovery (?). Unlike working with mice, this can be done on a large scale.

Vision 1920 overheard some faculty potbanger saying something like "the ES knockouts are heterozygous, so they'll only see effects if haploinsufficiency has a phenotype." He also said something about RNAi.

Giroir pointed out that TIGM is a core facility and that it is currently important for research at about 200 other universities. Someone else asked for examples - what do they expect TIGM to do, collect references to papers that acknowledge them?

This is just a little bit of what happened on Monday afternoon. Vision 1920 is having a harder time reconstructing the discussion about TIPS and NCTM, and welcomes comments to help reconstruct those parts.

Umbrella, from the latin Umbra for shadow

The Eagle reports the expected announcement to go forward with tIIT.

Amid strong dissent from some faculty members, the Texas A&M University System Board of Regents took a step Friday toward creating a controversial new therapeutics research center at its flagship university.

Regents also voted to rearrange the structure of other therapeutics-related organizations within the system -- placing the organizations located throughout the system under an umbrella agency in System Chancellor Mike McKinney's office.

Vision 1920 can't imagine why faculty are concerned about some research being taken over by the System. Besides this part, we mean.

Regents asked Bennett and Pishko if they knew why faculty members were opposed to the plans. Both said they were baffled.

Pishko said that he had heard of opposition from the Council of Principal Investigators, a group representing hundreds of university researchers, but that most engineering professors supported the idea. No one from the council was involved in the center, he said.

He said he had no idea why the group opposed the plans and said he hadn't spoken to any members.

This refers to the NCTM; most faculty probably hadn't heard of the tIIT until now. According to Vision 1920's sources, the CPI asked Pishko to speak to them after the NCTM was mentioned in their resolution of no-confidence in the chancellor, but he declined. Bennett and Pishko are the engineering guys, so our confidence in them is not shaken by their failure to grasp the objections of their colleagues

"I think the concern is how this is going to be funded and that there are risks involved that have not been discussed in the open," said Deborah Bell-Pederson, a biology professor and chair of the council. She declined to comment further.
...
Fully equipped and operational, the center will cost $65 million, Giroir said, but officials initially will spend only the $50 million from the governor's office. They hope to obtain the other $15 million with revenue from research grants and partnerships brought in once the center has successfully begun attracting income and researchers, he said.

Vision 1920 is confident that potential partners and grant agencies will be happy to pony up the shortfall, plus a share of the operating costs needed after the $65M setup (TIGM was reported to cost $2M/year to run. The GMP components of NCTM are likely to cost at least that much).

Vision 1920 is sure that with another executive director at the System level, an Operations Board, and the biotech talent we already have in the System offices, tIIT will find creative ways to hide its real costs raise the money needed. For example:

• By giving tIIT staff academic appointments, personnel costs can be buried in the University budget
• "research grants and partnerships brought in once the center has successfully begun attracting income and researchers" doesn't necessarily limit the System to grants to the center, just to awards made after some future date. Staff at the Office of Technology Commercialization can identify researchers whose research is relevant, whether they think so or not.
• Costs can be foisted off on the taxpayers by having our friends in Austin make sure that ETF funds go to companies that agree to contract with tIIT.
• Now that Murano is gone, we can go back to quietly making loans like the one that went to the Athletic Dept.

Grand Unification Theory

The Eagle previews what's coming up in the Regents' meeting. One highlight:

* Establishing the Institute for Innovative Therapeutics, which will serve as a "one-stop" biopharmaceutical program to research, develop and commercialize biomedical discoveries. The new institute -- which will consist of units already within the A&M system -- will "result in a single, unified biomedical enterprise," according to board documents.

As our faithful readers already know, Vice Chancellor Dr. Brett P. "eHarmony" Giroir plans to unite TIGM, TIPS, and the NCTM in a menage a trois based on their dimensions of compatibility.

In March the Institute for Innovative Therapeutics was presented as just "An integrated biomedical institute". Vision 1920 admires whoever comes up with the names of these things. Unlike other drug discovery programs, we are only interested in innovative therapeutics. We don't just have a Center for Therapeutics Manufacturing; we have a National Center for Therapeutics Manufacturing. And each component is the foremost resource its kind. At least between North Zulch and Old Dime Box.

A better mouse trap, pt 4

Previously:

• part 1: Lexicon cuts a deal with TAMUS to create TIGM, backed by the Texas Enterprise Fund
• part 2: TIGM faces a setback as the NIH doesn't choose it for the Knockout Mouse Project
• part 3: No one could have seen this coming. TIGM vows to fight on.

In her response to Chancellor McKinney's unfavorable evaluation, then-President Murano wrote:

...a comprehensive audit of the Texas Institute for Genomic Medicine revealed many flaws with the management of that entity, which culminated in its dissolution as a 501c(3) non-profit organization. Given that the Texas A&M System had been a partner in this venture, and that it was now the recipient of its assets, the university is committed to partner with the Health Science Center in providing management oversight and significant financial resources in excess of $2 million annually to help TIGM continue to operate in spite of heavy financial losses

If Murano had taken one for the team and silently resigned when the Chancellor gave her his evaluation, then this wouldn't have come up again. As the Chancellor said yesterday:

Shakespeare said, “The past is prologue.” I believe the past can be the past if we agree to work together for the sake of the future.

But since the anti-TIGM potbangers are back, let's address the future of TIGM, with the help of our tame faculty consultant.

Despite the setback in 2006, TIGM inked several deals in 2007 to supply knockout mice to other institutions. The NIH also offered administrative supplements to grantees who would use TIGM or the competing KOMP resource. Nevertheless, the 2008 audit wrote:

TIGM has not generated enough sales to be self-sustaining and experienced a decrease in net assets of $1.5 million in fiscal year 2007. The A&M System paid $1.9 million for utility infrastructure, another $105,000 for payroll in 2008, and has committed $1.2 million to fund expenses associated with the partnership’s transition to a joint institute of TAMU and HSC.

With the worlds largest collection of gene traps, how can that be? One possible explanation is that demand for TIGM mice is not as great as anticipated. In the plan presented to the Regents (found in the Google cache), we find this:

Over 2,000 inquiries have been received from researchers through TIGM’s website since it went live in June of 2006, and over 100 colleges, universities and research institutions located in North and South America, Europe, Asia and Australia have contracted with TIGM for delivery of mouse ES cells, genetically-engineered mice and related services.

Actual sales figures are not provided in either this agenda item, the audit report, or the TIGM website. Interestingly, the KOMP blog indicates that the NIH-funded effort only hit 100 orders recently.

There are two reasons why demand might be too low to support TIGM. First, it's still expensive to do mouse research and there just aren't that many academic labs to sell to, especially during difficult funding periods. Second, RNAi technology provides a faster route to many of the same goals. RNAi is not a perfect substitute, but it's good enough in many cases.

Competition from RNAi should drive down demand for knockouts unless the prices for knockouts come down. How much can one charge, anyway? When this all started, Lexicon was charging $20-$40K plus IP restrictions. The NIH supplement information says

The NIH share will not exceed $13,125 direct costs, plus indirect costs per mutant. The applicant organization is expected to make up the difference between the funds NIH provides and the cost of the mouse. The Institution must also provide funds for cryopreservation to the NIH-funded repository that will make the mouse mutant available to the research community. This cost is estimated to be ~$2500/mouse.

This fits with the cost of getting a litter of mice from KOMP that might have a germline knockout (or not). KOMP shows the prices if you follow their order form; TIGM doesn't. ES cells are much cheaper: they're less than $700/vial at KOMP. In 2005, the NIH goal was to drive the price much lower.

At those prices, you have to sell a lot of ES cells or mice to cover a $2M/year operating budget. Thus, the Regents' agenda item says:

The worldwide mutant mouse market is over $100 million per year. With the most extensive knockout mouse library of any supplier, TIGM will be able to provide materials that are unavailable through any other source to academic and commercial entities. The sale of knockout mice to academics and non-profits will only be a break-even proposition. However, TIGM will also be able to provide knockout mice at a higher price to commercial companies for their internal research, which will provide an income stream to help support TIGM programs. TIGM personnel will work closely with the TAMUS Office of Technology Commercialization to establish the appropriate procedures for licensing genetically engineered mice to private corporations

Vision 1920's faculty consultant suspects that the $100M number is largely made up of mice sold by Jackson Labs and Charles River Labs, which, between them, sold 9 million mutant mice in 2005 for $10-200 apiece. This includes a lot of "nude mice" used in cancer research and elsewhere. Managing large volumes of small numbers of strains is very different from small volumes of very large numbers of strains.

Breaking even on academic sales may be optimistic. But the new business model seems to be based on raking in big bucks from commercial sales. Vision 1920 doesn't have the data to assess this, but notes that both KOMP and Lexicon are competitors in that market. Whatever TIGM's future, the joint venture part of the story is done. Lexicon is not part of the new TIGM; they've changed from partners to competitors. And they never delivered the bioinformatics software promised in the original agreement.

Nevertheless, in the Eagle story on the audit report, the Chancellor reiterated that TIGM is a "wonderful asset", also saying:

"The idea is great. The science is great. Could we have planned better? Absolutely. Should we have planned better? Yes," A&M System Chancellor Mike McKinney told the regents Thursday during the panel's audit committee meeting.

"It's a good idea; it's a good concept that none of us meant to mess up. But we did."

The Chancellor undoubtedly has better information than we do, so that's good enough for us. As loyal Ags, we believe that

Aggie joint ventures never lose money, they just run out of time.

A better mouse trap, pt 3

In part 1 of this series, we saw how Texas A&M seized a great opportunity to work with Lexicon Genetics. In part 2, we saw how the NIH didn't recognize TIGM's potential greatness, and chose to put the knockout mouse project elsewhere.

At least one critic is publicly saying "I told you so", but what did smarty-pants Loren Steffy actually say at the time?

If you're like me, you may be feeling a little snookered. Something doesn't seem quite right.
...
The first problem is my own skepticism. We've been hearing the economic siren song of biotech for decades, yet the grand designs have never attracted the investment they promised. It has gone to Boston and California, but not here.

That's nothing more than a hunch. If you based decisions on this argument, we'd never invest in anything that hadn't been done before.

The second problem stems from the financial round-robin among Gov. Rick Perry and a handful of Lexicon's biggest investors.

As detailed in a Chronicle story Monday, investors who as of March held 16.5 percent of Lexicon's shares have contributed some $275,000 to Perry's campaign. One of them, William McMinn, also helped guarantee a $1.1 million loan for Perry's campaign for lieutenant governor in 1998.

Perry's spokeswoman, Kathy Walt, noted in the story that Lexicon's shares had fallen since the grant was announced, and therefore investors haven't benefited from the deal.
But if the projections of jobs and a subsequent biotech boomlet pan out, those investors are going to reap the benefits.

After all, Lexicon went public at $22 a share in 2000, and it's now trading for less than $5.

The idea that campaign contributors would benefit looks even worse now. Lexicon (LXRX) closed at $1.62 when Steffy wrote his "I told you so"; it closed at $1.19 on Friday.

And in 2005, critics like Steffy couldn't have known the information in the 2008 audit report:

A business plan was requested "as soon as possible" by the TIGM Board of Directors in December 2005 and was discussed in several subsequent Board meetings as "under development." The business plan was reported as "under discussion" as late as June 2006. Two business plans were obtained by the auditors, dated November 2006 and December 2007, indicating the first formal plan was not drafted for a year after it was requested.

Interviews with A&M System Offices, TAMU and HSC employees indicate that a $50 million NIH Knock Out Mouse Project (KOMP) grant proposal that was submitted in December 2005/January 2006 was essentially the business plan for the TIGM partnership and no contingency plans were considered.

and

operating covenants were never agreed upon as required by an Economic Development agreement between the State of Texas, the A&M System, and the biotechnology company. Additionally, the biotechnology company has not provided services at each location to install bioinformatics software, load databases, and train TIGM staff as provided in the Economic Development agreement.

and

A joint management committee consisting of one senior manager and one technical staff from each party to the contract (the A&M System, TIGM and the biotechnology company) was never formed and project coordinators from these three entities were never assigned

Who could have predicted these things?

In 2006, after learning that they weren't going to get the grant, TIGM could have folded. Instead, they showed Fightin' Texas Aggie Spirit:

"Taking us on would have made it easy for [NIH] to fulfill its mission," says TIGM President Richard Finnell. Instead, he says, NIH has rejected his institute's application, potentially forcing NIH's Knockout Mouse Project (KOMP) to start from scratch and positioning TIGM as a possible competitor.
...
Despite the NIH setback, TIGM is planning to make its mark in the mouse world. "It will cost more now, but we're going to get these lines out to researchers," says Finnell. "When people think about knockout mice, they'll think about TIGM."

That's the spirit that makes Texas A&M the fine institution that it is and will alway be. In honor of the boys at TIGM, we've written a new verse for the Spirit of Aggieland:

We are the Aggies - the Aggies are we
True to our gene traps as Aggies can be
We've got to FIGHT boys
We've got to fight!
To get our biotech future right!
After they've boosted all the rest
They'll get their transgenics from the best
For we are the Aggies - the Aggies are we
We're from Texas A.M.C.

TIGM, Aggies!

To be continued...

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...

A better mouse trap

If you look around the internet, you'll find some potbangers trying to malign the outstanding work our System has been doing at the Texas Institute for Genomic Medicine. To set the record straight, let's review what happened:

Back in 1995, a company called Lexicon Genetics set up shop in the Woodlands, based on a dream of making mice that could help cure all kinds of diseases. By 1998, they were describing some of the first successes in making mice with mutations in genes that had been knocked out by a "gene trap", and soon they described a library of frozen mouse stem cell lines for the world to use.

Now, it stands to reason that in our capitalist society, someone with a better mousetrap would be allowed to make a buck on it. A review in the prestigious Nature Reviews Genetics wrote:

Sequence-based initiatives are well suited to the biotech world and therefore, predictably, Lexicon Genetics, Inc., was founded on the basis of using polyA gene trapping. More than 100,000 trap insertions in ES cells have been deposited into Lexicon Genetics 'OmniBank'... By searching the OmniBank database, clones can be identified that harbour an insertion in a particular gene, and mice derived from the trapped cell lines can be purchased at a minimum cost of US $25,000, plus additional compensation if patents are generated from work with trapped strains.

So, in 2005 Governor Perry cut a deal to let the A&M system help exploit this gold mine for the citizens of Texas.

Gov. Rick Perry today [July 16, 2005] announced a $50 million Texas Enterprise Fund grant to help create the Texas Institute for Genomic Medicine (TIGM), a pioneering research institution that will help make Texas an international focal point for medical research and foster job growth in the life science industry.
The funds are being awarded to Lexicon Genetics and the Texas A&M University System, which are forming the non-profit TIGM.

At the time, it was expected that the National Institutes of Health was looking to spend $50 million on a knockout mouse project, and TIGM would be perfectly placed to recover all of the TEF investment. Sure enough, that fall, the NIH released a Request For Applications.

• The ultimate aim of the Knockout Mouse Project is to generate a null-mutant mouse resource comprising a null mutation marked with a reporter of high utility for each gene in mouse strain C57BL/6. The purpose of this RFA is to make maximum progress toward this goal using gene targeting, transposon-mediated mutagenesis or gene trapping.
• Up to $50 million in total costs over 5 years is to be awarded through this RFA.
• It is anticipated that 1 to 4 awards will be made.
• It is anticipated that the awards will be funded in July 2006.

To be continued...