It weighs a mere three pounds and looks rather nondescript-a wrinkled, convoluted mass of tissue-but the brain drives our lives, permitting us to think, walk, talk, see, laugh, cry and love. In short, to express our humanity.
In the landscape of the brain, the fundamental unit is a cell called the neuron, what the 19th Century Spanish artist and neuroscientist Santiago Ramon y Cajal described as ”the aristocrat among the structures of the body.”
There are billions of neurons in the brain-thousands would easily fit on the head of pin-and trillions of synapses, the gaps between adjacent neurons that the nerve impulses must breach with chemicals called neurotransmitters.
It may be disconcerting to think of life, neurologically, as a series of biochemical events, but when this signal system goes awry or nerve cells die, the result is ravaging, incurable disease that can steal movement, memory and rational thought.
Millions of Americans are presently suffering from disorders of the brain. One of every 16 babies is born with some sort of neurological problem, and a mentally retarded child is born every five minutes. One-and-a-half million people have Alzheimer`s disease, and more than 40,000 cases of Parkinson`s disease are reported annually. More than 500,000 people have multiple sclerosis, with 10,000 new cases reported each year. And one out of every four hospital beds is occupied by a patient with a mental illness.
At the University of Chicago`s Brain Research Institute, scientists are struggling to decipher the workings of the brain and, in the process, taking the first steps toward cures for such afflictions as Alzheimer`s disease, Parkinson`s disease, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig`s disease), multiple sclerosis, myasthenia gravis, epilepsy, stroke, schizophrenia, narcolepsy and brain tumors.
Every day Dr. Bruce Wainer, associate chairman of the school`s department of pharmacology and physiology, works in his laboratory supervising experiments that are chipping away at one of the riddles of the brain, Alzheimer`s and the intellectually incapacitating disease of aging.
Wainer studies neurotransmitters and ”growth factors,” other chemical substances released by nerve cells that appear to be important for keeping the connections between the cells working, which he says is ”the heart of the problem in neurodegenerative diseases like Alzheimer`s and Parkinson`s.”
In Alzheimer`s disease there`s a loss of nerve cells called cholinergic cells that are located in an area of the brain called the nucleus basilis and that send connections into the cerebral cortex. The cortex is responsible for thought, memory, movement and sensation. This cell death results in a corresponding decrease in the cortex of a neurotransmitter called
acetylcholine.
For a time, scientists thought that replacing acetylcholine in Alzheimer`s patients would alleviate the symptoms of dementia. Although a number of approaches have been tried and are still being pursued, the prospects for developing an effective therapy don`t seem promising. And a number of investigators, including Wainer, have turned to other types of questions to address what is going wrong in Alzheimer`s disease.
Now Wainer is interested in finding out what growth factors allow the cholinergic cells to make connections in the cortex and how they can be kept healthy.
It is impossible to answer that question by studying a human brain in autopsy or even dissecting a rat brain, so Wainer`s lab has turned to cellular and molecular techniques-namely, growing ”microbrains” from nerve cells taken from mouse embryos.
The mouse neurons are taken at the point where they have committed to becoming nerve cells but have not yet formed any connections. Cholinergic cells from the nucleus basilis are taken and combined in a flask with their normal ”target cells” (cells needed for their development) from the hippocampus, a part of the brain involved in memory that Wainer and his investigators suspect makes important growth factors. A tissue-culture medium is added to the two types of cells, and the little flasks are agitated, causing the cells to collide and form tiny balls called re-aggregates, or microbrains.
”It`s remarkable in that many of the processes that occur in the whole brain occur in these little re-aggregates, so it`s useful to refer to them as microbrains,” Wainer says. ”We take these microbrains and can either study what kinds of chemicals are being produced or how nerve cells are
developing.”
In addition to the microbrains, Wainer`s lab also makes ”immortal cells” by combining the re-aggregates with cells from a neuroblastoma, a tumor of the neuron, and the chemical polyethylene glycol, which he gleefully notes is the main ingredient of anti-freeze. (It causes cell membranes to become more fluid.) These immortal cells, which continue to divide, unlike normal neurons, provide unlimited microbrains for study, eliminating time-consuming dissections of mouse embryos to harvest nerve cells.
”I`m very excited about (our experiments),” Wainer says. ”I can`t guarantee it will cure Alzheimer`s disease. But I think that in addition to coming up with some therapeutic strategies, we`re going to learn an awful lot about what makes the brain tick.”
Wanting to know what makes the brain tick is what attracted Wainer and 64 other scientists, all faculty members of the University of Chicago, to the Brain Research Institute, considered one of the leading neuroscience centers in the United States.
The Brain Research Institute opened in 1978, but its roots go back to the early 1950s. It was the dream of three physicians, Frederic Gibbs, Ladislas Meduna and Carl Pfeiffer. Gibbs and Meduna, a neurologist and psychiatrist, respectively, were on the staff of the University of Illinois Research Hospital, while Pfeiffer was a professor of pharmacology at Atlanta`s Emory University. They started a foundation in 1953 to promote research and professional education, but their fund-raising efforts were quite modest.
Then in 1957, Lisa Fay, the young daughter of William E. Fay Jr., a prominent Chicago investment banker, was diagnosed with hypsarhythmia, a rare and very severe form of epilepsy. Her doctor was Gibbs, who identified the disorder in the medical literature and is considered the father of
electroencephalography (EEG)-a test of the electrical activity in the brain. Experimental drug intravenous treatment eventually controlled Lisa`s constant seizures, but her delicate developing brain had already been damaged, and she was mentally retarded.
When Fay and his wife, Margaret, learned of Gibbs` dream of a brain-research facility, they decided that it would be a worthy philanthropic cause. They discussed it with Fay`s close friend Clinton E. Frank, who founded the advertising agency that bears his name and whose daughter Marcia was born brain-damaged. Both families wanted answers, so they joined forces.
Each year they sent out the Fay-Frank Letter to potential donors, asking for money for the Brain Research Foundation. And whenever they could, they promoted their cause, reciting a litany of brain-related diseases whose secrets might be unlocked by scientists in a brain-research center.
The first $250,000 they raised went to Children`s Memorial Hospital in 1962 to establish a department of pediatric neurology. Another $150,000 was spent to purchase the old Chicago Wesley Hospital on Chicago`s South Side, which they planned to renovate and turn into a research facility. When they learned it would cost too much to remodel it, however, they ended up selling it.
In 1964 the foundation signed an affiliation agreement with the University of Chicago, and fund-raising by both parties shifted into high gear. They envisioned a large building dedicated to brain research.
Still, even with a substantial grant from the Kresge Foundation, the $3.5 million that the foundation raised and some $6 million the university contributed were not enough after an already-approved grant from the National Institutes of Health fell through.
What resulted was not a building completely dedicated to brain research but a sort of compromise. Dr. Clarence Reed, a successful California plastic surgeon who had trained at the U. of C., contributed money for a surgery building, and the Brain Research Institute ended up occupying three floors of a six-story white limestone-clad building at 5812 S. Ellis Ave., in what is called the Surgery-Brain Research Pavilion.
”The institute is not simply the building,” says Dr. Barry G.W. Arnason, chairman of neurology and director of the institute. ”Its strength is in its membership, in the coming together of people with various interests involving the nervous system.
”The laboratories of the psychiatrists, the neurologists, the neurosurgeons and the basic neurobiologists are, for the most part, concentrated in a single locale, which is almost unique, and, believe me, I know enough universities to tell you this. It fosters very close interaction between the basic and clinical scientists.”
The Brain Research Foundation`s continued support and involvement in the Brain Research Institute is another unique aspect. The foundation provided money to build a positron emission tomography (PET) scanner, the only one in the Chicago area, and each year it awards $200,000 in crucial ”seed grants” to younger scientists. The money allows scientists to conduct experiments that might yield the promising preliminary data needed to obtain larger federal research grants.
”The foundation was started by unique people, Fay and Frank,” says Dr. Alfred Heller, professor of pharmacology and physiology. ”They`re cut from a different cloth than most philanthropists that you meet. They responded in an extremely intelligent way. Rather than (saying), `We`re going to cure the disease my kid has,` they said, `We`re going to find out more about the brain; that`s going to be important.`
”The building hardly houses all of neuroscience, but it formed sort of a place where we can recruit new faculty to the university, and the fact is that much of the neurobiology that I was responsible for was possible only because we had that space.”
Only about one-fourth of the 65 Brain Research Institute members and their support personnel-postdoctoral students, graduate students,
undergraduates, technicians-fit into the building, and other scientists have research space in departments elsewhere in the medical-center complex. Even so, offices, laboratories and radiology equipment spill into the research facility`s two adjoining buildings, Abbott Hall and the Franklin McLean Memorial Research Institute.
”We are seriously crowded,” one doctor says. ”We`re bumping into each other in the labs. It`s one of our major limitations.”
In a way, that overcrowding could be construed as a metaphor for the neuroscience field, which is the hottest area in medical research and is still growing, to wit: A national Society for Neuroscience was formed in 1969 with 200 charter members. Today its membership numbers about 13,500, and at its five-day annual meeting, the book of abstracts of presentations fills two thick volumes.
Not surprisingly, the Brain Research Foundation recently announced a new fundraising campaign, Brain/1990, with a goal of $4.64 million to hire new faculty, expand and equip laboratory space, acquire technical equipment for radiochemical laboratories and provide more startup grants for new research.
Recruitment efforts will concentrate on luring bright young scientists.
”We`ve talked about going after big-name scientists from Johns Hopkins, Yale, Harvard and University of California-San Francisco, but it`s not a wise expenditure of our funds,” says Rita Jennings, longtime executive director of the foundation and now liaison between it and the institute.
”We once went after a man at Hopkins, and when the bottom line was drawn, it would have taken $5 million to get him because his wife is a doctor and he wouldn`t move without taking three full professors with him. That would be putting all your money in one basket.”
That`s not to say that the Brain Research Institute lacks respected scientists. ”There are a large number of very distinguished scientists with national reputations in the group,” says Dr. Robert Y. Moore, chairman of neurology at State University of New York (Stony Brook) and a member of the Brain Research Institute`s Board of Scientific Counselors.
This little community of scientists interested in the brain includes basic scientists, clinicians and some who have both Ph.D. and M.D. degrees.
Last year, at the urging of its advisory board, the institute reorganized and, for the first time, established criteria for membership. It is offered to faculty members who have achieved the rank of at least assistant professor, are engaged in neurobiologic research ”for not less than one-third of their time” and have authored or coauthored and published in scientific journals at least 10 papers relevant to the mission of the institute.
Arnason, who became director of the institute in 1985, is advised by an executive committee made up of the chairman of the various departments involved in the institute, which meets at least quarterly to assess the institute`s affairs.
Multiple sclerosis (MS), a debilitating disease involving deterioration and destruction of myelin, the insulating material that protects nerve cells, is Arnason`s main area of interest.
Among many studies that Arnason is involved with is one that focuses on the interaction between the nervous system and the immune system. Many MS patients experience periods of active disease and symptom-free periods, or remissions, and, Arnason says, ”they will frequently tell you that they believe their attack of MS was caused by some particular stress they were under at the time that preceded the attack. But stress is very difficult to measure, and so the concept of the relationship of stress and MS has been very difficult to come to grips with.”
Arnason and Dr. Ewa Chelmicka-Schorr, professor of neurology and pediatrics, decided to explore the possibility of direct nerve contact with lymphocytes, white blood cells that manufacture antibodies that defend against disease. They did so by breeding an animal in the laboratory without sympathetic nerves, the kind that spur the ”fight or flight” reaction and ramify in the lymph nodes and spleen, organs involved in generating the immune response.
Experiments on these animals showed ”substantial consequences” in the immune system of this interruption of communication between the two systems.
Other complicated studies on the cellular and molecular level have yielded important information that soon will be tested clinically using drugs that attempt to regulate the immune system in the hopes of helping patients whose MS is rapidly progressive.
