Pandemic alert

Loren Steffy takes shots at A&M again in the Houston Chronicle

Texas A&M's plan to develop a world-class medical research facility could use an injection of integrity.

In January, the state awarded A&M $50 million from the Emerging Technology Fund, which purports to benefit private-sector technology startups, for the National Center for Therapeutics Manufacturing, which plans to develop new vaccines.

Unfortunately, the infusion of taxpayer money is showing some disturbing symptoms that have been found in other state economic development deals: a web of political relationships and arrangements with financially shaky companies with ties to key decision makers in the process.

Steffy reviews material that will mostly be familiar to readers of the Vision 1920 blog. There are a few things we've missed here, though:

Bob Pearson, an Introgen director at the time of the grant and a Perry campaign contributor, is also a member of the 17-member advisory board that reviews the tech fund grants.

Introgen was founded by David Nance, a major Perry supporter who's currently on the statewide finance committee for the governor's re-election campaign. Nance, who quit Introgen just before the bankruptcy, donated $50,000 to Perry's campaign in 2005 and 2006, records show, and Perry has appointed him to three different technology committees — including the tech fund advisory panel — dating to Perry's stint as lieutenant governor.

Steffy has been a potbanger over A&M's tech vision before. He loses credibility, though with this:

“There's not a single dollar I've gotten off of any patents,” he [Giroir]said. “I never took a single dime from Xoma.”

Maybe not, but the A&M System has taken five million dimes from taxpayers, and they deserve better. The public may benefit from the NCTM's vaccine research, but it's the sort of deal that leaves taxpayers feeling sick.

5 million dimes is only $500K. The NCTM got five hundred million taxpayer dimes.

The back door goes both ways

In yesterday's Houston Chronicle, Loren Steffy writes:

The latest handout will go in part for construction of the new center, the A&M system said in a statement at the time. Public universities typically sell bonds or seek donations to finance new construction. Instead, Perry and his buddies running the A&M system used what are supposed to be economic development funds as a backdoor appropriation.

The enterprise and tech funds have been plagued by shifting definitions of their use and a lack of accountability.

No matter how you define them, though, neither fund was supposed to finance universities already supported by our tax dollars.

Chancellor McKinney has already explained how critics are just being jerks.

Vision 1920 also notes that Steffy has it wrong. TIGM has already shown that this is not about money flowing from the ETF and TEF into the university's education budget.

Redefining the R&D enterprise

In March, Vice Chancellor for Research Giroir gave a presentation to the BioHouston Breakfast forum. A pdf of his powerpoint slides is available online.

Dr. Giroir describes a vision for the future of biomedical research at the Texas A&M University System. The figure shown here, slide 11 from his talk, is perplexing, since we were not there and have no additional transcript or notes. Slide 11 appears between the sections on TIPS and the NCTM. Vision 1920 wonders if this means that our highly-ranked Poultry Science Department will be left behind, when the rest of the research enterprise is taken over by the System.

Defensive medicine

Last night we pointed out that Dr. Brett P. "eHarmony" Giroir had previous dealings with Xoma, the Berkeley-based biotech company. Nature Biotechnology wrote about what they were doing in 1998.

The pivotal phase III clinical trial of one of the last "surviving" sepsis drugs—for the treatment of meningococcal sepsis—is nearing completion. XOMA Corporation's (Berkeley, CA) Neuprex is recombinant human bactericidal/permeability-increasing protein (BPI), an endogenous neutralizer of endotoxin and, with lesser potency, an antibiotic. Some experts are cautiously optimistic about the outcome and hope that positive results will reinvigorate the sepsis field. "This field needs some excitement," says Brett Giroir, of Southwestern Medical Center in Dallas, TX, who is the principal investigator of the Neuprex trial. "If positive, this study is going to answer a lot of questions."

Neuprex was being repositioned for meningococcal sepsis after it turned out to be less effective than hoped in treating more general trauma. Xoma continued to test Neuprex against sepsis and other conditions, but Vision 1920 can't find any evidence of a final FDA approval. Xoma's current hopes are mostly pinned on an antibody drug called XOMA 052 that binds Interleukin-1 beta (whatever that is... our tame faculty consultant has been less tame of late).

Dr. Giroir was at UT-Southwestern when the Neuprex work started, but came to the Texas A&M System via the Defense Science Office at DARPA. Xoma founder Patrick Scannon also has been on DARPA advisory boards and other biodefense projects. Xoma has done biodefense work for NAIAD on vaccines against botulism toxin.

Xoma has another indirect A&M connection, noted in this 2005 news story:

Lexicon Genetics and Xoma have announced the formation of a collaboration to jointly develop and commercialise antibody drugs that could be effective in treating diet-induced obesity and enhanced insulin sensitivity.

Xoma and Introgen also have had at least one common Board member.

The suggestion that this might create a conflict of interest for Dr. Giroir is absurd:

Giroir said that Introgen is providing advice but has no contract to receive any money from the center and that Xoma's contract for helping design the center will top out at $20,000.

Murano's accusations are patently false

More from the Chancellor's extended notes (pdf)

Last time committee on IP met - she pulled out papers on XOMA & berated Guy for making deal w/co. hurting the "A&M Brand" that she was dedicated to protecting - She misread info - & did not really know how to read the data - I don't know who gave her the info [concern is valid but approach & behavior totally inappropriate]

What deal? This one from Sept. 2008:

“We are very pleased to be working with XOMA, a biotechnology company with more than 25 years of experience as a successful innovator in antibody development and manufacturing,” said Brett Giroir, M.D., vice chancellor for research for the Texas A&M System. “We expect that the project will generate new opportunities for rapid translation of biomedical discoveries into life-saving products. The collaboration also holds the promise to develop manufacturing technologies that position the state of Texas as the partner of choice for biotechnology companies in the future.”

Dr. Brett P. "eHarmony" Giroir, in case you didn't know, is the System's Vice Chancellor for Research, and a leading biodefense researcher (Try a PubMed search on 'giroir bp AND biodefense'). Dr. Giroir knows Xoma well - they hold the rights on five of his patents.

Xoma was the subject of a 2007 profile in the New York Times:

Xoma, which Dr. Scannon started in 1981, has never earned an operating profit or marketed a drug of its own. And in the quarter-century since its birth, Xoma has managed to burn through more than $700 million raised from investors and other pharmaceutical companies.
...
XOMA, which went public 20 years ago, is a case study of unfulfilled promise in the biotech business. It may also be a story that ends happily, if very belatedly, with success. The company’s management and some investors, including OrbiMed, say they are convinced that what they describe as Xoma’s dogged determination is finally making headway, or at least that its stock has room to grow.

The company’s stock has nearly doubled over the last year, hitting a 52-week high on Friday of $3.30, before closing at $3.04. Still, that is well below the stock’s record high of $32 a share, reached in both 1987 and 1991.

There's even more room to grow now; Xoma closed at $0.78/share today (down from $2.27 on the day the deal was announced).

Ad blockers pt 4

Previously:

• Part 1
• Part 2
• Part 3

Despite evidence presented that Advexin was safe, gene therapy in general was described as cursed in this 2005 Nature Biotechnology piece

"Because gene therapy has such a nasty reputation, people tried to rename it or call it 'new and improved' to free themselves of the stigma," says Michael Zasloff, an analyst with Ferris, Baker Watts of Washington, DC. "That may fool the public, but the market sees through it," he says.

Nevertheless, Nature Biotech wrote:

The first gene therapy approved in the US will most likely be Austin, Texas−based Introgen's Advexin, which delivers normally functioning p53 to cells.

Advexin was safe, and was in phase 3 trials. As noted in part 3, Introgen was planning to submit Advexin to the FDA for approval in 2004. Those plans changed...Introgen finally submitted their BLA in 2008, a few weeks after announcing a joint venture with the Texas A&M System.

This followed presentation of long-awaited phase 3 trial data at a cancer conference, which MD Anderson headlined as

Gene Therapy Increases Survival for End-Stage Head and Neck Cancer

There was some fine print

The trial showed that p53 expression in the patient's tumor before treatment is a reliable biomarker for how to treat head and neck cancer. Patients with a favorable p53 profile who received Advexin® had a median survival of 7.2 months, compared with 2.7 months for those whose tumor expressed high levels of mutant p53 before treatment. Patients with this unfavorable profile were better off taking the chemotherapy drug methotrexate, resulting in median survival of 5.9 months.

Potbangers in the biotech stock analysis community were not impressed, and predicted that Advexin would not be approved. The market agreed, and Introgen's stock plummeted.

The potbangers were right this time. The FDA told Introgen its application was "incomplete". By the end of 2008, Introgen filed for bankruptcy and David Nance had stepped down as CEO. Since then, Nance resigned from the Introgen Board and has resurfaced at a nonprofit to promote high-tech business in Texas.

David Nance says Texas could do a far better job of creating high-tech jobs and companies if the state's fiercely competitive regions and universities had a better way to work together.

Vision 1920 points out that the agreement between Introgen Technical Services and the TAMU System doesn't involve paying ITS (now renamed Vivante) anything - it's just a memorandum of understanding to apply for grants together from the Emerging Technology Fund, the Texas Enterprise Fund and the Federal Government.

So, what's the problem?

Ad blockers pt 3

Previously:

• Part 1
• Part 2

In 1993, Jack Roth's group described the adenovirus p53 vector that would become Advexin in a short paper in the journal Biotechniques. The earliest clinical trials in the gene therapy trials database with p53-carrying Adenovirus vectors started in 1995, with Jack Roth as one of the PIs. Overall, the database lists 34 US clinical trials of Adenovirus vectors carrying p53 for cancer therapy. Some of these may have involved Introgen competitors, but many were for what would become known as Advexin. A 1997 press release describes the results of one set of Phase 1 trials, and a collaboration:

Introgen Therapeutics, Inc., an Austin-based company engaged in the development of cancer therapeutics, sponsors Drs. Roth and Clayman along with 25 other clinicians and researchers at M.D. Anderson Cancer Center. Introgen and RPR Gencell, the gene therapy division of Rhone-Poulenc Rorer, are collaborating to develop and commercialize gene therapy products based on the p53 pathway and k-ras oncogene inhibition.

Adenovirus vectors fell under a cloud in 1999 when an Arizona teenager died during clinical trial involving adenovirus vectors. This was not a trial involving Introgen, but all ad vectors were suspect. Even improved vectors were cause for worries:

Gene therapy researchers at the Baylor College of Medicine in Houston, Texas, who recently reported success with the 'gutless' adenoviral vector in animals may not get to test the vector in humans.

The pharmaceutical company, Merck, which owns the licence on a technique used to produce the vector, is refusing to extend its material transfer agreement (MTA) with Baylor, saying that it does not want to be liable for any problems the vector might cause in clinical trials.

How this affected the Introgen Adenovirus projects is not clear. Phase 1 and Phase 2 trials continued, and Introgen-sponsored scientists presented safety results at meetings. In 2002, the Ad5-p53 vector was trademarked as Advexin, and Introgen was telling the world to expect an approval application in 2004 (Biodrugs 17 (3): 216-222). Also from that review:

In April 2001, Aventis Gencell and Introgen restructured their existing collaboration agreement for p53 gene therapy products. Aventis Gencell indicated that p53 research had suffered from internal competition for resources and was pulling back from its development agreement with Introgen for p53 gene therapy products.

In a 2004 review of gene therapy skepticism about the Advexin approach appeared:

Results published to date have been disappointing. Phase I trials for recurrent glioma reported only modest survival benefit and expression of adenoviral derived p53 only a short distance from the site of virus administration.¹¹⁵ Phase II/III trials for ovarian cancer failed to show treatment benefit with intraperitoneal administration of adenovirus expressing p53 with chemotherapy after debulking surgery.¹²⁰ Finally, Swisher et al published antitumour effects associated with the treatment of non-small cell lung cancer; however, no comparable control group was described in their report.¹¹⁶

That last bit is harsh. The author is not just saying the results were disappointing; he's calling the quality of the studies into question.

The potbanging would get worse.

To be continued...

Ad blockers pt 2

Prof Jack Roth and David Nance formed Introgen based on an idea for using gene therapy a cure for cancer, but like all gene therapies, they needed a way to deliver the genes to cells. That's what viruses do, and Adenovirus seemed like a good choice as a delivery vehicle, not just to Introgen, but to many in the growing field of gene therapy.

Adenoviruses are a large family of DNA viruses that infect humans and animals. They are relatively easy to manipulate by genetic engineering, they're stable, and infected cells express large amounts of the delivered gene product. Unlike retroviruses and adeno-associated viruses, Adenoviruses don't integrate their DNA into the host, which makes them less likely to cause cancer as a side effect - something that has been seen in gene therapy trials with the other delivery systems. This lack of integration is a problem for gene therapies that need long-term maintenance of the delivered gene, as is the case for genetic diseases where you want to fix lots of normal cells. But for cancer, this is not a problem. You don't care if p53 is stable in the cancer cells, because you expect p53 to kill them quickly. Unstable expression in the normal cells that also get infected is also OK; they already have their own good copies of p53.

Normal adenoviruses cause disease, but most adenoviral disease is relatively mild and most humans have already been exposed to adenoviruses. The disease-causing parts of the adenovirus can be removed by genetic engineering, and the adenoviruses can even be crippled so that they can only grow in the special cells in the lab. All these reasons led people to think that adenovirus vectors (gene delivery systems) would be safe and efficient - at least compared to the available alternatives.

So, Introgen had their anticancer magic bullet (p53) and their delivery system (modified adenovirus) back in the mid 1990s. By 1994, Introgen was starting Phase I clinical trials. The idea of p53-adenovirus anticancer gene therapy was so obviously good, the Chinese stole it! Science magazine wrote in 2006:

Introgen Therapeutics in Austin, Texas, for example, claims that SiBiono's Gendicine is similar to its own experimental product, a recombinant adenovirus containing the human p53 gene (rAd-p53).

Wei-Wei Zhang, president and CEO of San Diego-based GenWay Biotech, published the first paper on rAd-p53 while working at the University of Texas M. D. Anderson Cancer Center in Houston in 1994. He holds U.S. patents on the viral construct and related processes. M. D. Anderson negotiated a license with Introgen, which has spent more than $70 million to develop a product based on Zhang's rAd-p53, trademarked Advexin. It has been in clinical trials since 1994. The company's ongoing phase III trial using Advexin to treat head and neck cancer is under review for "accelerated approval" by FDA.

Introgen's 106-patient phase II trial in 2005 showed a 10% "tumor response rate," defined by at least 30% reduction in tumor size, in patients who received Advexin alone. Introgen Vice President Robert Sobol says phase III trials are going well.

Meanwhile, Introgen CEO David Nance claims that Gendicine is a "derivative" of his company's product. In an August 2006 filing with the U.S. Securities and Exchange Commission, Introgen claims that Gendicine infringes on a 1994 patent filed in China but concedes that "enforcement of patents in China is unpredictable, and we do not know if monetary damages could be recovered from SiBiono."

Gendicine beat Advexin to the punch in China, but Introgen still held the patents for the US and European markets. The silver lining was that Gendicine's Chinese approval in 2003 was another piece of evidence that Advexin would work.

To be continued...

Ad blockers

The potbangers keep bringing up Introgen (see the comments on this story in the Eagle, for example). So Vision 1920 will retell the tale of Introgen, even if it mans having to get faculty input again.

As noted in an earlier post, Mr. David Nance, formerly of Introgen, is a biotech expert who has been advising the Governor for years. His company, Introgen, was founded on the work of Dr. Jack Roth of M.D. Anderson

Advexin, which expresses the tumor-suppressing p53 gene, is the first gene therapy to succeed in a U.S. phase III clinical trial for cancer. Jack A. Roth, M.D., a professor in the Department of Thoracic and Cardiovascular Surgery, invented the therapy and co-founded Introgen Therapeutics, Inc., the company that makes Advexin.

“The p53 protein,” Dr. Roth said, “is called ‘the guardian of the genome’ because it protects against damage to the cell. We are all constantly exposed to agents such as sunlight or tobacco smoke that can cause gene mutations. When the gene is functioning normally, p53 can actually help facilitate repair of those mutations or eliminate the damaged cell.”

In most cancers, however, p53 is defective. The thinking behind the Advexin protocol was to take a normal p53 gene and put it into p53-defective tumor cells to cause apoptosis—death—of the cancer cells but not of normal cells. According to Dr. Roth, “When the p53-expressing adenovirus is injected directly into tumors, it causes the tumors to shrink or to stop growing. And in a few cases, there are very dramatic responses where the tumors disappear completely.”

If you can inject something directly into a tumor, why not just kill it directly instead of using this p53-whatsit to turn on a program that kills the cell? Here's why: Traditional cancer therapy is known as slash, burn, and poison. You cut out the cancer, but you might miss some and it comes back. Same if you burn it out with radiation. Chemotherapy poisons the cancer but it poisons everything else in the body at the same time; that's why chemo patients lose their hair, lose their appetites, and are prone to infections. Unless you can deliver the poison only to the cancer cells, what you want is something that's a poison to the cancer cell but not to the patient's normal cells... and that's how p53 is supposed to work.

Introgen was based on the idea that you could deliver p53 everywhere. When it hit a normal cell, nothing would happen because there was already normal p53 there. when it hit a cancer cell that lacked p53, the incoming p53 would detect that the cell had problems and tell it to commit suicide (apoptosis means programmed cell death).

To implement this strategy, Introgen needed a delivery system. Back when they started, the delivery system of choice was Adenovirus.

To be continued...

Collaborative research

The potbangers act as if the focus on commercializing research is new. Item 6 of the CPI complaint is:

Chancellor McKinney has focused the System on commercialization of the research enterprise. The System level Office of Technology Commercialization has negotiated agreements with University faculty and companies without including the University, yet it remains the University’s responsibility for certifying compliance and managing conflicts of interest related to these agreements.

But long before Mike McKinney was Chancellor, the Regents were talking about opportunities for A&M and biotechnology. From the BoR minutes from May, 2001, we have a presentation on the Texas Life Sciences Collaborative:

Dr. Wendler said that the Texas Life Sciences Collaborative is seen as a partnership between higher education, the business community and state government to focus research and commercialization of life sciences in the areas of health, agriculture and the environment.

Walter Wendler was Dean of Architecture, and was leaving Texas to become Chancellor at SIUC. He describes how Texas has unique advantages for growth in biotech. Alas,

during the legislative session, in principle, everybody was very agreeable, but when it got down to some of the details, discussions got testy.

Not to be deterred (Aggies never quit!), the governor got together a panel to figure out what to do. Wendler continues his report to the BoR:

Dr. Wendler said the hope was to get some planning funding so that through the intersession for the next two years, it would be possible to configure the public-private venture for Texas that would be unique and exploit the very special opportunities that exist in this state for biotechnology. Dr. Wendler said that was not achieved because of the state’s budget. However, he thought the Governor had given the signal. Dr. Wendler said Ms. Armstrong has been working with Mr. David Nance, President and CEO of Introgen Therapeutics, Inc., a recently gone public biotech enterprise. Dr. Wendler stated that Mr. Nance is a very knowledgeable person in the area of biotechnology and agrees that Texas is perfectly poised right now. He said some research and commercialization help is needed.

Help was on the way for Nance and Introgen, but it would be too little, too late. More on this later.

Dr. Wendler said the Governor’s office has suggested that there would be funds available to support a significant statewide assessment study. Dr. Wendler said a lot of work as been done already, but it needs to be tried at the crucible of kind of a national view of biotechnology. He said if that can be accomplished, and the support is organized over the next two years, then in the next session, he thought Governor Perry eventually would agree to the need to invest about a billion dollars over ten years. The challenge, Dr. Wendler said, is finding funds.

Funds have been found in the Emerging Technology Fund and the Enterprise Fund. But not enough.

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...

Introgen

This is the kind of thing that will help Texas A&M build the economy of the state:

June 10, 2008 -- The Texas A&M University System, Austin-based Introgen Therapeutics, Inc. and its wholly owned spinout Introgen Technical Services, Inc. (ITS) today announced formation of a far-reaching alliance to develop and produce therapeutics, vaccines and delivery systems for human and veterinary applications. The alliance will work with the biopharmaceutical industry, academic researchers and government clients, including the biodefense and public health sectors.

Newly formed ITS, whose principal function will be to provide a steady inventory stream for parent Introgen Technical Services, a biopharmaceutical firm, also will concentrate on enhancing Good Manufacturing Practices protocols at Introgen’s various sites in Texas. Initially that includes two GMP facilities in Houston and future expansions elsewhere in the state. GMP standards, based on regulations from the U.S. Food and Drug Administration, require manufacturers of drug and related products to take proactive steps to ensure maximum safety and purity of their products.

Well maybe not. I'm sure they had a good answer for this:

I thought I'd travel back in time to recount for the investing public what Introgen has been promising and repeatedly failing to deliver with respect to applying to the FDA for approval of Advexin. It is truly astonishing to see how badly this company failed to deliver on its promises, and really makes one wonder how they are able to continue raising capital to keep the whole thing afloat. It is amazing how much "credit" biotech investors are willing to extend to management teams that have done nothing to deserve any credibility.

I mean, I'm sure they asked.