publication date: Jan. 29, 2016

Slamming the Door

How Al Gilman Taught Texas a Lesson in Science 

 

This series re-examines the concurrent controversies at the Cancer Prevention and Research Institute of Texas and MD Anderson Cancer Center. This examination is possible in part because of new insight provided by Alfred Gilman, the Nobel laureate who served as the first scientific director of the state institution that distributes $300 million a year. Gilman died on Dec. 23, 2015.

 

Part I:

The Hazard of Promising

 

Alfred Gilman’s approach to distributing public funds wasn’t particularly difficult to understand: he wanted to pay for the best science available. Period.

The pot of money entrusted to Gilman was vast. In 2007, Texas voters approved the largest investment in cancer research outside the federal government: $3 billion, to be spent over 10 years. By way of comparison, NCI grants going to Texas researchers and institutions added up to $240 million a year. CPRIT more than doubled that money. Only Texans were eligible to apply.

Gilman accepted the CPRIT job at age 68, because he thought that it would be a significant contribution to a major research effort, and a nice way to finish out a long career.

Gilman shared the 1994 Nobel Prize in Physiology or Medicine with Martin Rodbell for discoveries involving G-proteins, and served as the dean of the UT Southwestern medical school.

Since his life’s research work was fundamental and not specifically focused on cancer, he needed to get to know more cancer people. His first call was to a friend—Phillip Sharp, a Nobel laureate himself and an institute professor at the Massachusetts Institute of Technology Koch Institute for Integrative Cancer Research.

Together, Gilman and Sharp recruited members of the CPRIT scientific council. Most of them were people Gilman didn’t know. The members were the sort of people who could only be associated with a bona fide scientific peer review.

Planeloads of academics would come to Texas to review CPRIT scientific grants. Scientists who reviewed research proposals for the state-funded institute would later tell me that they had never served on a better peer review committee. For the first two-and-a-half years, the system worked smoothly.

There were no separate study sections for specific areas of research. The review committees were broadly constituted: basic, translational, clinical. There were no quotas for cancer type or research approach. There were no quotas based on geography. There were no quotas for science versus commercialization. The state law mandated that up to 10 percent of the funds were to be spent for evidence-based cancer prevention programs. The rest went to peer-reviewed science, including grants to companies, which were reviewed for both scientific quality and commercial potential.

Gilman walked into his office fully realizing that the job of CPRIT Chief Scientific Officer would entail working around bureaucratic absurdity and Texas-sized egos. But even being a seasoned academic politician, he could never have predicted that he would ultimately end up turning whistleblower in the name of defending of peer-reviewed science.

A year before his death from pancreatic cancer, Gilman sat down with me and provided a detailed account of his epic battle to protect public money from what he described as an arrogantly conceived, sloppily executed incursion. The stories of the ungluing of CPRIT and controversies at MD Anderson Cancer Center developed concurrently.

Some of these events have been described in The Cancer Letter before, but news stories seek to capture events as they unfold. Stepping back and enriching the narrative with greater insight can yield rich detail—and produce a different picture. My goal here is to present this material systematically, with the benefit of historical perspective—while incorporating Gilman’s insight.

 

 

Gilman had the demeanor of a curmudgeonly professor.

If he felt like presenting a six-pack of Budweiser to a student as a reward for the right answer, he did so. At one point, he compared his scientific council to World War II generals—on the Allied side, of course. A conversation with him was never brief and it was always a hoot.

At CPRIT, Gilman ended up fighting a war on many fronts.

There were attacks from a state legislator, who was seeking more research funds for his part of the state.

A number of institutions were objecting to the fact that UT Southwestern, the institution with which Gilman once helped run and where he kept office while at CPRIT, was getting more funds than anyone else.

The 11-member oversight committee provided no shield from political meddling. Indeed, Gilman used to say that only one of its 11 members knew that cancer was spelled with a “c.” (That wise man would be Joseph Bailes, an oncologist.)

And, finally, there was a proposal for a $20 million biotech incubator that was going to be located at MD Anderson Cancer Center.

Through this proposal—and the role of Lynda Chin, a senior scientist and wife of that institution’s president, Ronald DePinho—the problems at CPRIT merged with controversies over interactions between MD Anderson leadership and private industry. Gilman’s resignation brought these controversies to the attention of scientists and the public.

“I built something I am proud of, and now it’s being taken apart,” Gilman said to me at the time. “I can’t work for people who are pushing their own interests at the expense of the interests of cancer patients.”

Gilman was disappointed but not surprised.

“A wise and experienced friend said to me: ‘This is always the way it works when you put a large amount of public money on the table. The vultures and the hyenas lie low for two or three years to see how the system really works. And then they come in for their feast.’”

The controversy made enough of an impact to inspire a cartoon by Nick Anderson, which appeared in the Houston Chronicle, and is reprinted above.

Gilman was wary of anything called “a moonshot.” The metaphors of war and space travel were deceptive, he said.

“We have been guided by a few simple principles,” Gilman and Sharp wrote in an opinion piece in the Houston Chronicle after they departed from CPRIT. “We were truthful about the complexity of cancer.

“To find cures, we must ponder dynamic cellular systems containing huge numbers of parts whose behaviors are governed by rules that have evolved over millions of years. We don’t understand these systems in nearly enough detail to explain why and how they become dysfunctional. Progress in treating cancer requires rare and penetrating insights into deep pools of ignorance and translation of these insights into new therapies. It’s pointless to push money at a problem—no matter how important it may be—if you lack insight for finding a solution.

“Texans deserve to hear the truth about cancer. They must understand that miracles will not happen in a short time. Progress will not be made by those who simply proclaim without explanation that they can do better than hundreds of skillfully staffed and well-financed pharmaceutical and biotechnology companies. Real progress requires the concerted high-quality efforts of basic, translational and clinical investigators from the academic community collaborating with counterparts from the private sector when appropriate.”

Gilman believed that the only way to save CPRIT was to knock it down—to walk out the door, followed by the world’s premier scientists, and slamming said door as loudly as possible. Nothing less than that could create the urgency for Texas to re-create a clean peer-review system. Those who followed Gilman out still believe that this was the right thing to do.

His successor at CPRIT, Margaret Kripke, said in an interview that she basically reconstituted the review system Gilman had constructed (The Cancer Letter, Jan 6).

“I’m not sure resignation was necessary,” Dan Fontaine, executive chief of staff at MD Anderson, said to me recently. “I’m not sure it required a resignation; I’m certainly not sure it required resignation of others. I think there could have been other avenues that would not have stirred the controversy, but at the same time that’s the benefit of hindsight.

“Regardless of what the circumstances are, there’s no question that CPRIT is in a very good place today and doing exactly what the voters wanted them to do. Secondarily, I think that the debate about the role of academic institutions and commercialization has not gone away. I think, as you well know, there’s always going to be some differences in opinion about that,” said Fontaine. An attorney, Fontaine is not an MD Anderson faculty member.

The MD Anderson project that contributed to the controversy went on without CPRIT support.

“I do believe, quite frankly, that when you look at the fact that there is a pipeline of some very promising therapeutics that we are moving through the Institute for Applied Cancer Science—there have been some spectacular strategic partnerships that we have put together with the pharmaceutical world because we have the capabilities of the Institute for Applied Cancer Science—I really think that four years hence, our commitment to bridging that gap between the discoveries in the academic world and products in the commercial world, which is what the Institute for Applied Cancer Science was designed to do. I think history is on our side on this one,” Fontaine said.

“I think it’s being proven out that we are on the right path. And I’m not sure that Dr. Gilman’s resignation had anything to do with that at all, or the resignations of any of the scientific board. We went on without the CPRIT grant, and while I think all of the benefits of the Institute of Applied Cancer Science are yet to come, certainly there’s some early successes in what we have been trying to do, partnered with our strategic industry ventures department, to really put together ways of accelerating discoveries into therapeutics and diagnostics.”

Last year, Chin left MD Anderson to become the UT System’s associate vice chancellor for health transformation and chief innovation officer for health affairs, based in Austin, and there are no plans to replace her as the scientific director of the cancer center’s Institute for Applied Cancer Science, Fontaine said.

 

 

By design and policy, the scientists who guided Gilman were from outside Texas.

This was an effort to keep intrastate academic rivalries from influencing the review process. Every member of every study section was from out of state as well.

With this set of conflicts managed, Gilman believed it was reasonable for him to run the review process from an office on the UT Southwestern campus in Dallas. He felt it was critical to remain in an academic environment. Besides, he was recused from the actual decisions about funding. These recommendations came from the study sections and the Scientific Review Council. Gilman had no vote, nor did he voice opinions about grants, save for reiterating what insiders called his mantra: “We want the best science.”

The office in the medical school administration building was rented by CPRIT for his use. This was a nondescript place—just large enough for Gilman and an administrative assistant. There was also a small conference room with a videoconferencing hookup, which was used for monthly meetings of the Scientific Review Council.

Gilman was an academic’s academic. A friend once joked that he is likely the only person ever named after a textbook. His father, Alfred Gilman, a well-known professor of pharmacology, was a co-author of the classic textbook The Pharmacological Basis of Therapeutics. The younger Gilman’s middle name was chosen in honor of the book’s other co-author, Louis Goodman.

Throughout his career, Gilman had never worked anywhere other than a biomedical research campus, including three medical schools and the National Institutes of Health.

By staying on campus, he could attend seminars and meet with long-time friends in their offices or at the faculty club.

 

 

CPRIT’s main office in Austin, a place Gilman rarely graced with his presence, seemed to have evolved a culture that was foreign to Gilman. The place was full of people whose stock in trade was politics.

It could be a tribute to Gilman that for the first two-and-a-half years of CPRIT’s existence, I had little interaction with CPRIT. The peer review committees met, the place hummed along, and there was nothing for me to do, as a journalist. After things changed, my job was to pry the truth, or at least a coherent lie, out of bureaucrats who seemed to have three speeds: lying, stonewalling and an eagerness to please, in the hopes that I would go away. Some of these bureaucrats spoke as though they were on a mission from God to rid Texas from the scourge that is cancer.

Geographically isolated from the bureaucrats, Gilman drew on the expertise of top-tier cancer experts, the sort of people who would never let their names be associated with whitewashing a politically fixed giveaway of public funds in Texas or any place else.

They were:

• Clara Bloomfield, the William G. Pace III Professor of Cancer Research at Ohio State University.

• Sanjiv Sam Gambhir, the Virginia and D.K. Ludwig Professor in the department of radiology and bioengineering, chair of the department of radiology, director of the Molecular Imaging Program, and director of the Canary Center for Cancer Early Detection at Stanford University.

• Tyler Jacks, the David H. Koch Professor in the department of biology and director of the David H. Koch Institute for Integrative Cancer Research at MIT.

• William Kaelin, professor of medicine in the department of medical oncology at Harvard University and the Dana-Farber Cancer Institute.

• Richard Kolodner, professor of medicine and member of the Ludwig Institute for Cancer Research at the University of California, San Diego.

• Charles Sherr, chair of tumor cell biology, co-director of the Molecular Oncology Program, and Herrick Foundation Chair at St. Jude Children’s Research Hospital.

• Everett Vokes, the John E. Ultmann Professor of Medicine and Radiation Oncology, and chair of the department of medicine at the University of Chicago Medical Center. (Vokes replaced David Johnson, who was impressed with CPRIT after brief service on the council, and was ultimately recruited from Vanderbilt to become chair of Internal Medicine at UT Southwestern.)

“Al knew many of us, although some better than others. In fact, as far as I’m concerned, he tried to recruit me to UTSW as a department chair many years ago,” Sherr said to me recently. “As a council member, I was asked to appoint a review committee. Al said, just get 15 solid scientists who deeply understand cancer biology—the only caveats were that all must come from institutions outside of Texas and that no more than two of them could come from a single institution. I called 16 friends, of whom all but one agreed to serve on the Basic Science Review Committee that I would chair.

“Among the seven council members, we drafted over 100 scientists as CPRIT reviewers. We paid little attention to being politically correct—we just tried to get the very best people involved. Still, on this basis alone, my committee had national representation, and a virtually equal number of men and women. Despite the work, I think that CPRIT received some 850 applications at the get-go, and although we had to figure out how to parse them between committees at our very first meeting, the review process soon evolved to be very effective. Everyone wanted to ensure that the proposals got a fair reading, and council members ‘traded’ applications so that reviewers with appropriate expertise would be available. This was an adventure—the rules of the game were established on the fly.”

 

 

Gilman and his advisors weren’t the sort of people who promise the cure. They had seen the sad results of overpromising, overstating and overselling. The best science was the only thing they could promise responsibly. It was possible and desirable that some of the basic knowledge bought with Texas taxpayers’ money would lead to development of new therapies, but there could be no guarantees.

From his first day at CPRIT, Gilman urged state officials and politicians not to promise too much. To him, such promises were classic buffoonery, which people resort to in order to generate support and short-term infusions of cash. Basic science would be included in CPRIT’s portfolio. You have to accept that you are building a foundation of knowledge from which great things will spring. Alas, you can’t tell exactly when and where this is going to occur.

This doesn’t mean that basic science produces no returns. Just ask an elderly person what her life expectancy was when she was born. She will have greatly exceeded it, and that’s at least in part due to advances in medicine that have been driven by fundamental understanding.

When people started to discuss cancer as an engineering problem, Gilman cringed. Engineering is a study of systems created by man, which presumably can be understood by man. Biology was created by evolution over hundreds of millions of years. The rules are incredibly complicated and dynamic.

Biology demands humility. Every time you think you understand it, something new comes along and hits you in the face.

Copyright (c) 2018 The Cancer Letter Inc.