No Brain Study Grant : Cuts Wound Biomedical Researchers

When they began, they would later say, they were simply stumbling in the dark, as usual.

But the crack team of five young research scientists here at the New York University Medical Center knew that the brain in a fetus or newborn will regenerate if damaged, while the brain in an adult will not.

If they could understand what causes that difference, and trick mature cells into acting like new ones, the scientists reasoned they might find ways to treat everything from cerebral palsy and birth defects to spinal cord injuries, strokes, Alzheimer’s disease and brain tumors.

Funding Recommended

Needing more than $400,000 a year for the five-year research project, they submitted a 155-page grant proposal in mid-1984 to the National Institutes of Health. An NIH review committee gave them a high rating and recommended funding. The NYU team celebrated, and excitedly began preliminary planning while waiting for official notice of their grant.

But the notice never came. Instead, last Jan. 16, the team learned that the Reagan Administration intended to cut 1,500 of the 6,500 grants NIH had planned to hand out this year--including theirs. There would be no inquiry into how the brain develops and repairs itself.

The NYU experience is just one telling example of the impact the Administration’s budget plans may have on the burgeoning field of basic biomedical research, which faces cuts this year of $280 million.

In this case, as in many others, the decision was made largely for accounting reasons, without knowledge of the project. The manner in which civil servants, appointed officials and politicians in Washington made a fiscal decision, and how that decision affected one particular team of scientists, illustrates the type of unseen results that flow from broad policy choices.

Other Cuts More Visible

The cuts that affect such large and visible groups as farmers, college students, transit riders and veterans have garnered the greatest attention, being most apparent and direct and involving billions of dollars.

Moreover, with a $200-billion budget deficit, a chorus of voices remind that choices must be made in all fields, and that everyone has lobbyists loudly proclaiming their special needs.

But many in the scientific community believe the biomedical cutbacks may in the long run have an impact of an unexpectedly large dimension, affecting not just current work but also the quality of scientists entering basic research and the type of studies they attempt.

Biomedical research in the last two decades has produced the sweeping breakthroughs now applied to studies of cancer, heart disease, immunology, molecular genetics, neurological disorders, birth defects and strokes.

Manic-depressives are kept from hospital wards by the development of lithium. Iron lungs were rendered obsolete by polio vaccines. Agriculture has reaped the biggest financial gains of all through the genetic engineering of crops.

But the major successes have fed on earlier failures or minor accomplishments. So scientists fear what is lost by the cutbacks may never fully be measurable or understood.

“The interesting thing is that you can’t tell where the great discoveries will come from,” said Dr. Michael Shelanski, professor and chairman of the NYU pharmacology department, who was to be project director for the brain development study.

‘Is the Only Way’

“Basic research must go off along various different avenues, not knowing which is the best or right. Biology is like a secret diary. You learn where the lock is, you find the key, you open it. Then you find it’s written in code. You’ve got to fool biology into giving up its secrets. Sometimes it doesn’t work. But if you ever want answers, this is the only way.”

The NYU team first happened upon its particular avenue in 1982. Scientists for some time have known that besides the neuron cells in the brain, which provide the main electrical activity, there are also other cells, called astroglias, which essentially form the fabric of the nervous system.

But it was not until 15 years ago that a broader understanding of those cells, often referred to as glias, first suggested that when the brain of a fetus and newborn is developing, granules form into neurons and migrate into position by traveling along a certain type of elongated glia cell. In an adult, the glia cell then takes a more star-like shape and serves as a complex switching system or filing cabinet for the neurons, which cling to the glia’s several arms.

This meant that all manner of neurological defects might be caused by problems in the glia cells, not the neurons. But most scientific inquiry into the brain has always focused on the neurons.

So the NYU team decided to study the often-disregarded glia cells.

Choice Understandable

It was not by chance that these scientists chose this task. They are young enough still to have been students when much of modern molecular biology was evolving. They had literally gone to school on the glia cell.

Shelanski, 43, earned a medical degree and a doctorate in biophysics at the University of Chicago, then taught for four years at the Harvard Medical School before he left to take over the NYU pharmacology department in 1978.

He came with a plan: He would assemble a diverse team combining several complementary specialties, a team uniquely equipped to study diseases of the central nervous system.

Shelanski brought with him Ron Liem, 39, then a postdoctoral fellow at Harvard with a Ph.D. in biophysical chemistry from Cornell, who specializes in structural chemistry of cells. He would be the purifier, separatilg and identifying the cells for the others to play with.

Rest of Team

Shelanski hired Mary Elizabeth Hatten, 35, then a postdoctoral fellow in neuropathology at Harvard with a Ph.D. in biochemical sciences from Princeton, who specializes in how various cells recognize each other and interact. She would be the manipulator of cells, observing how they then behave.

Shelanski recruited Carol Ann Mason, 38, who holds a Ph.D. in zoology from the University of California, Berkeley, and specializes in the development of the anatomy of the nervous system. She was the precise and reflective surgeon who would conduct delicate operations on developing animal brains.

Finally, also from Harvard, Shelanski lured Ekkhart Trenkner, 46, a molecular biologist who had earned his doctorate in Germany after first studying philosophy, stopping just short of a Ph.D. in that field before turning to science. He would consider the overall molecular systems, focusing more on cell similarities than differences.

“Because we each looked at things from different viewpoints,” Hatten said, “we could ask each other stupid questions. It was a motivation to keep our eyes on the big picture. The tendency otherwise is to focus too much on small issues.”

From the start, the NYU team reasoned that if they could grow brain cells in a dish, they would be able to see them develop and start to understand the rules of the game. Why do neurons migrate on glia cells? They must recognize them in some way. Certain molecules must be present that make the connection.

Identifying Cell Types

Trying to identify those molecules, Hatten at Harvard in 1977, had developed a method for growing tiny portions of the cerebellum. But she was having trouble identifying cell types. She needed some way to distinguish between neurons and glia cells in her cultures.

It was here that the various team members began to complement each other’s efforts. Shelanski in his lab developed an antibody “marker” that would identify neurons by staining them a distinctive color. Then Liem did the same for the all-important glia cells.

The NYU team now could look at glia cells in culture and study what they did.

Hatten, using a high-powered microscope hooked to a videocassette camera, filmed evolving neurons as they lined up along the arms of glia cells. The scientists marveled at what they saw: little balls wiggling along a glia toward their mysteriously predetermined destinations. When blocked by another neuron already at its final spot, the wiggling ball would ooze over the obstacle and continue on its way.

Hatten found that if she put glia cells in a dish by themselves, they would divide and proliferate in odd, indeterminate forms, out of control. If she added neurons to the dish, the glia cells would stop dividing wildly and take their normal star-like shape.

Neurons Affect Glias

The potentially great meaning of this did not escape the scientists. The neurons must somehow tell the glia cells to stop dividing and take form. So brain tumors and neurological scarring might very well be caused by glia cells that had lost their neurons.

As the pieces of the puzzle began to fit together, the scientists’ excitement grew.

When they injured a developing cat or mouse brain, the scientists knew it would repair itself, but a more mature brain would not. What if they could biochemically see why the repair process worked at one age, and not another? What if they could see the elements that change or get lost?

“The goal,” said Hatten, “would be to present the surgeon with the string of molecules needed for the mature brain to repair itself.”

Individually, the five scientists already were at work on isolated parts of the problem, funded by NYU and small personal grants. But they lacked the time and support personnel to operate as a cohesive team and tackle the larger questions.

Needed Large Grant

The NYU team would need a large multi-year grant to hire seven technicians and postdoctoral assistants, in addition to other support personnel, including an animal technician, photographer and secretary. In December, 1983, they started writing their proposal.

Putting together a grant proposal is an art by itself. The proposal must promise breakthroughs, but not be so riskily disconnected from existing knowledge that results seem doubtful. Problems in the planned experiments must be foreseen, and alternative paths indicated. Scientists accustomed to looking for the unexpected must put in words what they expect.

After two rewrites, the team submitted its final proposal May 29 to the National Institute for Neurological and Communicative Disorders and Stroke.

NIH grant proposals are evaluated by special study committees and given priority ratings, with the lower scores being the best. A perfect rating is 100. The year before, proposals at the NINCDS with scores of 150 and below had been funded.

‘Impressed’ With Project

In mid October, an NIH committee, saying it was “impressed with the long-range direction of this research group which is committed to an important problem which is not being pursued in many other laboratories,” awarded the NYU team a 148 priority rating. The institute had more money than last year, Shelanski knew, so his group would be funded if everything stayed the same.

Formal notice of the grant would have to wait official approval by an NIH council in early 1985, but the NYU team celebrated with considerable emotion. Preliminary planning sessions began for an April start up.

But even as the NYU team exulted, events and forces unknown to them, and greatly distanced from their world of science, were unfolding inside two buildings in Washington.

The Old Executive Office Building, a historic structure adjacent to the White House, houses among others the offices of David A. Stockman, director of the federal Office of Management and Budget. The New Executive Office Building, a more conventional tower across the street from the White House, houses the offices of the various civil servants who work for Stockman and the OMB.

Room 7002 of that newer building is occupied by John Glaudemans, the OMB budget examiner whose particular assignment is the NIH account. To perform his tasks, he is equipped with an IBM XT computer, a package of software programs, and the capacity to plug into the OMB’s mainframe computer.

Student of 1980s

As it happens, Glaudemans has strolled across the same campuses as some of the NYU scientists, earning a bachelor’s degree in political science from MIT and a master’s degree in public policy administration from Princeton. But at age 28, he is a college student of the 1980s, not the 1960s.

Glaudemans agreed to describe how the biomedical cutbacks were made, provided he not be quoted directly.

He joined the OMB in 1983 because he thought that was where the action was. Glaudemans knew he would not function as a policy-maker, that he would be a fool if he did not keep in mind what his bosses’ policies were. His job would not be to decide where they were going, but rather, to point out how to get there.

In late 1984, the basic policy that Glaudemans and all others at OMB were left to wrestle with was the Reagan Administration’s determination to freeze the fiscal 1986 budget at 1985 levels while not raising taxes. This goal presented a particularly unusual problem for the budget examiner in charge of the NIH.

President Reagan’s 1985 budget had included money for 5,000 new NIH grants, as does his recently submitted 1986 budget. But Congress for fiscal 1985 had sweetened the pot, enabling NIH to fund some 6,500 new grants. Those 1,500 extra grants in 1985 would create a built-in escalator in the 1986 budget, because all are for multi-year projects and funding automatically would have to be continued in succeeding years.

Several Options Considered

So the OMB would be hard pressed to freeze the ’86 budget at ’85 levels. Glaudemans and others at OMB began to consider several options.

One was to reduce sharply the number of new grants made in 1986, to compensate for the extra 1,500 being carried over from 1985. Another was to reduce the number of grants handed out in 1985 by 1,500, so that both years would be stabilized at 5,000.

The Administration could not directly refuse to spend the money Congress had appropriated for 1985 without a bloody fight. But OMB officials saw an easier and entirely legal path.

The Administration could simply set aside millions of dollars of the 1985 allocation to fund grants in 1986 and 1987. Because the money would formally be “obligated,” it would appear in the NIH’s budgetary bottom line for 1985 and the President could not be accused of illegally impounding money appropriated by Congress.

The various options were kicked around among Glaudemans and his superiors. As usual in such processes, there were internal disagreements, with some preferring different approaches.

Glaudemans’ reasoning included several elements.

From 1972 to 1985, the number of NIH grants had grown 67%, and the average size of the grant 158%, placing both categories at historically high levels. So these cuts were not devastating to the scientists, he thought. He saw no compelling argument in their favor.

It also seemed to him that more and more scientists must be getting funded by the private sector. Besides, the government is supposed to be buying science, not scientists, and is not an employment agency. And basic research is all fine and good, but we also have babies dying in Mississippi and smokestack industries that need larger environmental monitoring teams. What do you choose?

The easy way would be to just give 3,500 grants in 1986, Glaudemans felt, but that would be more disruptive than keeping both years even at 5,000. Withholding funding this year instead, Glaudemans reasoned with some satisfaction, was an imaginative solution to the problem.

Glaudemans would not allow himself to think in particulars about those losing out this year. He was dealing with millions of dollars, while those individual scientists thought of dollars and cents. Personally, the whole matter had its disturbing moments for Glaudemans; his father, after all, is an NIH scientist, although because he is salaried there he is not dependant on grants. But Glaudemans was just one person dealing with a larger problem.

In early December of 1984, he along with several other of the OMB’s 150 budget examiners met with Stockman to present and answer questions about the written reports they had previously sent the budget director, reports which outlined possible options for their particular accounts.

By all reports, Stockman himself at that meeting made the formal decision to cut 1,500 grants from NIH’s 1985 program.

The NIH had already awarded one third of the planned 6,500 grants for fiscal 1985, and was about to dispense another third, when NIH chief budget director Richard Miller received a surprising phone call one day in mid-December from Harold Little.

Budget Branch Chief

Little is chief of the budget branch at the Public Health Service, the section of the Department of Health and Human Services to which NIH belongs. He scheduled a meeting for 2 p.m. that same day with the NIH people, and gave them the news.

There would be an immediate halt to all grant decisions, while NIH figured out what it all meant and how many grants each institute still had to distribute. Complicating the problem was the fact that since some 1,750 grants had already been distributed, all 1,500 cuts would have to come from the remaining 4,750. The effect on each institute would differ, depending on the number of pending applications and how competitive the proposal scores were.

It soon became clear that The National Institute of Neurological and Communicative Disorders and Stroke would be particularly hard hit, because it is a hot field full of highly qualified scientists. The institute was holding 111 proposals with priority ratings between 100 and 140, and 97 with ratings between 140 and 150. The cutoff line would have to drop from 150 to 140.

The NIH issued no formal announcements in December. The news did not start to emerge until January of this year. Shelanski, typically, had his ear to the leaky pipes.

On Jan. 16, he heard the bad news and told the others on his team.

Hatten Felt Stunned

That afternoon, driving home from work, Hatten felt stunned, as if she had spent her childhood on a horse that had suddenly bolted and thrown her. She listened on the car radio as it was reported that in Reagan’s 1986 budget, overall federal financing for basic scientific research would actually climb by 12%, but only because military research was getting a hefty boost. Military projects, in fact, would make up almost three quarters of the entire federal research budget.

Hatten then heard Defense Secretary Caspar W. Weinberger defend his request for more research money as being a mere drop in the bucket.

She knew he was in a sense right, that in other circles her funding needs were negligible amounts. Her own husband is an investment banker who flies to distant cities first class, while her department scrambles for every $100. And yet, even though her professional efforts had never enjoyed luxurious support, all quality work in the past had won funding. Now this was not so.

She felt betrayed, anxious, depressed. She also feared she would never again attempt the risky projects, because grant proposals with uncertain results do not get the highest priority ratings. She would work scared and be careful, because she could not afford turns up blind alleys. What a waste, she thought.

“It felt like a guerrilla assault, because it came out of nowhere,” Hatten said. “There was no debate on whether this was wanted or good. It was just a long arm reaching out. Was it policy, or was it some damn accountants crunching numbers? Where did it come from? Either way, a choice had been made.”

Researchers Felt Grief

Response among the NYU team, and among colleagues in the corridors of the school’s medical center, resembled grief.

Shocked clusters of scientists gathered in hallways, talking of friends at various universities whose work had been eliminated by the budget cutbacks. Since the government decided after World War II to base most biomedical research at university medical centers, those schools and their professors have become increasingly dependent on outside grants.

It was not that long ago when proposals with 180 ratings were sure to get funding, the professors said. Although the number of grants had doubled to record levels since 1972, the maturing baby boom generation’s yield of new young scientists and the burgeoning nature of the biomedical field meant that the number of grant applications during that same time had more than tripled. So the percentage of applications funded had actually fallen from 51% to 31%.

“This is the first time I am seeing people who I usually cite and rely upon in my own work, who are my major sources and touchstones, being threatened with losing their grants,” Shelanski said.

The scientists repeatedly echoed the same warnings and arguments about ramifications far beyond the moment.

Might Slow Response

They might not be able to respond quickly to the unexpected, such as AIDS and legionnaire’s disease, because that requires a foundation of basic research to work off of.

Corporations, most interested when there was something to test and develop that promised profits, would not pick up the funding slack. A team at NYU on the verge of manufacturing a malaria vaccine through gene-cloning lacked financial support because the places in the world where malaria flourishes do not have money, and the World Health Organization does not allow protective patents.

But above all, the scientists gloomily predicted that the country may lose an entire generation of first-rate researchers.

“The brightest, those with the most options, will go elsewhere, particularly into practicing medicine, which is safe and lucrative,” Shelanski said. “You won’t see it, because we will still have plenty of people going into the research field, but they won’t be the best of their generation.”

Ron Liem allowed that if he had known in 1967 how his field would be funded two decades later, he probably would have studied for a medical degree. So did Hatten.

“If I were coming out of undergraduate school now,” she said, “I wouldn’t do this. I would have gone for an M.D. instead of a Ph.D. It’s hard to get up each morning and deal with students and lie about the future potential. That says something awful.”

Officials Annoyed

In Washington, Administration officials were more annoyed than concerned about the scientists’ reactions.

The NIH research community has plenty of powerful and articulate lobbyists on Capitol Hill, and they have noisily been taking their case there ever since the cutbacks were announced. Shelanski himself had lunched with the congressman from NYU’s district. But all manner of other interest groups also had come knocking on the door in much the same fashion. The farmers were even planning to march.

Inside Room 253 of the Old Executive Office Building, just down the hallway from Stockman’s office, OMB spokesman Ed Dale was keeping a tally sheet of letters sent to his office. The scientists had written more than 850, far more than the farmers’ 250.

“It’s a close race between students, farmers and scientists as to who are the biggest moaners and groaners,” he said. “They all let us know how they feel. You ought to hear the farmers bleat. At least the scientists aren’t marching. Maybe the scientists wrote more letters because they have less to do.”

Dale felt no need to justify or apologize. He was plainly exasperated with the questions posed to him.

‘Can’t Do Everything’

“The underlying reason for all this, which the various interest groups tend to forget, is that we have a $200 billion deficit and we can’t do everything. Every group that has its subsidy reduced thinks it’s doing the Lord’s work. But the President makes choices . . . Somebody else always has other priorities, but the whole issue of government is to make choices.”

As it happened, Shelanski did not entirely disagree. He felt it important to remember that the giant deficit exists because Reagan cut taxes and then refused to raise them. But he knew funds always are limited.

“Our work is not sacrosanct,” he said. “Priorities are a hard issue, and must be balanced. Clearly, it is not a one-sided question. There are lots of needs. For the most direct, best health of everyone, money arguably should be poured into feeding and housing the homeless and on prenatal care and nutrition, since preventive care is cheapest and most effective. But we wouldn’t cure cancer or AIDS then. It is a difficult choice.”

Philosophical, Resigned

In recent days, as formal notice from NIH made it even more clear his team would not get its grant, Shelanski remained philosophical and resigned. After all, unlike other scientists he knew, no one on his team would lose a job or a lab, for they each had individual grants and support from NYU.

“I can’t say that what we would have learned next year would have cured spinal cord injuries,” he said. “In all honesty, I can’t tell you this work would have found any answer. In the aggregate, though, with other work, we may have found an answer if there is an answer to learn. We might have been able at least to see why we can’t do anything with our present tools, and to start then thinking of other tools.

“The short-term effect of the cutback? Very little. The long-term effect? God knows.”