Health Sciences Report Spring 2005

The Greatest Challenge:
The New Brain Institute Commits to Understanding the Brain from Molecules to Circuitry to Behavior

By Phil Sahm

Photos by Sean Graff

Behind every human thought, feeling, and action lies a process complex and mysterious as any in the universe: millions of neurons fire and send chemical signals from one part of the brain to another.

From this microsecond of electrical impulse arises our purest pleasure and deepest sadness, the ability to recognize an old friend, and every cognitive sensation that lets us perform a thousand daily tasks, from contemplating the cosmos to tying our shoes. Yet, at a time when humans can peer trillions of miles into space and manipulate genes, the 3-pound tangle of neurons, circuits, and gray and white matter inside the human skull remains stubbornly enigmatic.

The causes of neurological diseases and disorders, from autism and multiple sclerosis to depression and schizophrenia, remain largely unknown. Elemental, yet amazingly complex, brain functions that give rise to the traits that define human beings are still barely understood.

"Consciousness, recall, personality... to understand these as emergent qualities of molecules and cells is mind-boggling," said Erik M. Jorgensen, Ph.D., professor of biology and scientific director of the new Brain Institute at the University of Utah. "But these qualities of the brain do rise out of molecules and cells-and we're going to find out how."

Finding the answers to what many call the greatest challenge in biological science will require an effort of sweeping scope for decades, according to Jorgensen, recently named a Howard Hughes Medical Institute investigator, whose research focuses on the synaptic connections between nerve cells that may underlie memory. Experts in neurology, biology, genetics, computer science, physics, radiology, math, pharmacology, and psychology are among those who'll join the quest.

Former University President Bernie Machen cited the U's history of interdisciplinary collaboration when he announced the formation of the Brain Institute with $5 million in seed money in the summer of 2003. More than a dozen U.S. universities, including Harvard, MIT, and the University of California, have established brain institutes in recent years. But drawing on its world-class expertise in human genetics, engineering, imaging, and computer science, the U is set to tackle brain research in a way unlike other institutes: to understand the brain from molecules to circuitry to behavior through the use of mouse models and other organisms.

A major part of this effort will involve brain imaging and will draw on the University's computer and medical imaging programs to develop new ways of taking pictures of the brain. "We want to look inside the brain to determine which parts of it are active at certain times," Jorgensen said.

Researchers will begin by examining basic functions-how brain cells and molecules work. Then they'll start to unravel how networks of cells operate and interact to form the circuits that allow different regions of the brain to communicate with one another.

Molecular geneticists, such as Jorgensen, usually study the role of proteins in specific cells with mutations. By observing defects in cells that lack specific proteins, they can infer a protein's role in the cell. Brain Institute researchers will use similar techniques to study the role of circuits-larger groups of cells in a particular region of the brain-in behavior. By observing mice with non-functional cells in specific areas of the brain, they can deduce the circuit's role in the brain based on the animal's behavior, according to Jorgensen.

Thomas N. Parks, Ph.D., professor and chair of neurobiology and anatomy at the U School of Medicine, and executive director of the Brain Institute, expects the institute to make important contributions to neuroscience.

"The Brain Institute will focus on discovery, such as understanding the basic functions of the brain," Parks said. "Ultimately, we hope that basic science research will lead to clinical applications in treating, or even curing, brain disorders and diseases."

Brain diseases are among the most costly and intractable to treat, Parks said. But U of U researchers already have discovered genes involved in neurological diseases from epilepsy and macular degeneration to Williams Syndrome (a genetic condition that causes medical and developmental problems), and sleep disorders.

The institute will comprise seven research modules to study the brain from the sub-cellular level to behavior:

  • Genetic Disorders of the Brain and Nervous System

  • Studies of human genetics will identify genes involved in normal and abnormal brain functions and diseases.

  • Mouse Models of Human Disease and Brain Function
    Because humans and mice have similar genomes, human diseases can be studied in mice through gene targeting, which was invented by U geneticist Mario R. Capecchi, Ph.D., distinguished professor of human genetics and biology, co-chair of the Department of Human Genetics in the School of Medicine, and an investigator with the Howard Hughes Medical Institute. Gene targeting disables genes in mice to see what happens when specific genes do not perform their normal function. This technique helps identify the normal function of proteins in genes.

  • Molecular Pathways
    Genes hold the instructions to produce proteins for specific purposes that carry out the functions of all living organisms. Using zebrafish, Drosophila (fruit flies), and planarians (flatworms), U scientists will learn how these proteins work together to produce functional nerve cells in the brain.

  • Cell Biology
    To understand the role of proteins in the brain, researchers will tag them with fluorescent molecules to determine exactly where they work in the brain. They'll use electron microscopes for an even closer look at where proteins work within cells.

  • Physiology and Circuits
    When groups of nerve cells interact, they form circuits in the brain. By recording the electrical activity in cells of both normal and diseased brains, researchers study how circuits work. They'll also learn about circuits by creating and studying them in the laboratory.

  • Brain Imaging
    Every time a person performs a "higher order" function, such as using sight or employing memory, neural circuits go to work in different regions of the brain. Some of the most sophisticated imaging techniques in the world will be developed to study the changes in these neural regions in humans and mice.

  • Mouse Behavior
    By activating and inactivating circuits in mice brains, researchers will study the role of particular circuits in mice behavior. For example, if a group of neurons in a particular part of the brain is deactivated and it interferes with memory, researchers can infer that that circuit plays a key role in memory.

Establishing a Brain Institute not only is a logical step, but also a necessary one for the University, said Parks, who co-founded NPS Pharmaceuticals and whose research focuses on the effects of deafness on central nervous system development. "A university that wants to be among the major research centers can't avoid having a brain institute," he said.

The Brain Institute, now in temporary quarters in the University's Research Park, is taking shape.

A development and operations director, Rick Mandahl, M.B.A., and strategic communications manager, Jennifer Logan, Ph.D., have been hired. Three researchers, who'll have primary academic appointments in other departments on campus, have been hired, as well. These include: Edward W. Hsu, Ph.D., currently an assistant professor of biomedical engineering at Duke University, whose primary appointment will be in the Department of Bioengineering and whose research includes diffusion tensor imaging; Norman L. Foster, M.D., professor of neurology at the University of Michigan School of Medicine, who'll join the U medical school's neurology department and specializes in research on Alzheimer's disease and imaging the brain; and John M. Hoffman, M.D., currently chief of molecular imaging at the National Cancer Institute, whose interests include molecular imaging in cancer and PET scan imaging of brain tumors.

In mid-March, the Brain Institute introduced its Web site, designed by Logan, who also led the development of the U of U's Genetic Science Learning Center's award-winning Web site ( prior to joining the Brain Institute. With the Brain Institute moving from concept to reality, 2005 will be a "pivotal year" to start raising money and awareness both locally and nationally, according to Mandahl. "I'm approaching the Brain Institute as a high-tech start-up in terms of its concept and goals," he said. Operating costs, including a new building, are estimated at upward of $200 million in the next five to 10 years. Fund-raising will kick into gear this year with potential funders to include private citizens, foundations, corporations, the state of Utah, and federal agencies, such as the National Institutes of Health.

The Brain Institute will work closely with other research centers at the University, according to Logan. The Utah Addiction Center will be a natural partner, because the study of addiction involves every aspect of brain science. For example, it remains unknown whether changes in the brain associated with cocaine addiction are the result of drug abuse, or are caused by inherent structural differences in the brains of addicts.

Along with the Utah Addiction Center and the U's Osher Lifelong Learning Institute, the Brain Institute held "Brain Day" April 25, when experts spoke on various aspects of brain science.

As the institute recruits members, imaging is a logical area to begin, according to Parks. The University has top-notch technology, including CT (computed tomography) and PET (positron emission tomography) scanners and a 3T MRI (magnetic resonance imager)-one of the most advanced MRIs available-as well as first-rate researchers. Dennis L. Parker, Ph.D., a medical physicist, professor of radiology and medical informatics, and director of the Utah Center for Advanced Imaging Research, is known internationally for his pioneering MRI work. Computer scientist Chris Johnson, Ph.D, distinguished professor of computer science, and director of the School of Computing and the Scientific Computing and Imaging Institute, is among the best in the world in computer imaging. Johnson's research accomplishments include groundbreaking 3-D images of brain tumors and the heart.

When Parks looks five years into his crystal ball, he says it's realistic the Brain Institute will have its own building, or one well under construction, with 15 nationally recognized research groups studying the brain. The institute eventually could have up to 80 investigators, according to Parks.

More than 70 U faculty already conduct neuroscience research, offering the Brain Institute an impressive depth of expertise. Along with the six researchers profiled in this article, other U faculty contributing to the institute are: Richard A. Normann, Ph.D., professor of bioengineering and ophthalmology and visual sciences, who is a pioneer researcher in artificial vision; Maureen L. Condic, Ph.D., associate professor of neurobiology and anatomy, who studies the brain's networks of dendrites and axons; and Alejandro Sanchez Alvarado, Ph.D, associate professor of neurobiology and anatomy recently named an investigator with the Howard Hughes Medical Institute, who studies regeneration in planarians.

An entity this large-fully operational, the institute may house 500-600 scientists, lab and administrative workers, and students-can produce a huge economic impact, according to Raymond F. Gesteland, Ph.D., distinguished professor of human genetics and University vice president for research. Studies have shown that, for every dollar invested in scientific research infrastructure, $6 is generated in the local economy. That means the Brain Institute has the potential to bring $1 billion to Utah's economy over the next five to 10 years

"This isn't just research. It really is an economic development engine," Gesteland said. "What we do here is important to the business community and the entire state."

The Salt Lake Chamber recognized that and, in a study released in January, urged the Utah Legislature to budget $100 million for the Brain Institute as part of $400 million in technology and research infrastructure funding for the University and Utah State University. The money is essential for the kind of high-paying jobs Utah needs to attract and keep, the Chamber concluded.

The Legislature evidently took that idea to heart. On the final day of this year's session, the Legislature passed S.B. 192, the High Technology Economic Development Appropriation Act, which gives the U $3 million in one-time funding to buy "equipment and supplies for high-technology research and development." In addition, the Legislature allotted $2.4 million in ongoing annual funding, beginning in fiscal year 2006, to recruit senior research teams, and the Brain Institute may receive some of this money. Sen. Al Mansell, R-Sandy, sponsored the legislation.

Like many large endeavors, the Brain Institute had its genesis in humble beginnings. Gesteland accepted the post of vice president for research with the understanding that he'd steer the University's next big research venture. In 2001, he hosted a series of informal dinners of Mexican food and pizza with faculty campuswide. The simple fare must have been "brain food," because after tossing around a number of ideas, the group identified a brain institute as the most challenging and promising endeavor. In retrospect, the decision was easy, according to Gesteland.

"The most significant problem facing the scientific community is how the brain develops and works," Gesteland said, "and it's an area where we can make an impact."

U of U President Michael K. Young has wholeheartedly endorsed the Brain Institute since taking the reins of the University last August. In speeches and appearances throughout Utah, Young has touted the institute as an endeavor in which the University can make an impact at the basic science and clinical levels to improve people's lives in numerous aspects. "The human brain is, perhaps, the last great frontier in science," Young said. "The knowledge we gain from understanding the brain can not only revolutionize treatment for medical and behavioral problems, but also help all of us realize our full potential."

Applying knowledge of brain circuits to computer circuits. Finding cures for neurological diseases. Deciphering the mystery of consciousness and other defining human traits. Brain science, in many ways, is still in its infancy. But that means the potential for discovery is great-which makes it all the more opportune to establish the Brain Institute. And that puts the University squarely where it should be, according to Parks.

"Research universities are supposed to tackle the big problems," he said.

Richard I. Dorsky, Ph.D.
Assistant Professor of Neurobiology and Anatomy

As a human embryo develops, cells receive instructions for what they'll become- part of the eyes, hands, nose, etc. Using zebrafish as a model, Richard I. Dorsky is studying the signals of a specific protein, Wnt, that influence dividing cells to develop into particular types of neurons in the brain. When developing brain cells receive Wnt signals, they control the activation of downstream genes. Dorsky's lab specifically is trying to identify the targets of Wnt signaling in developing brain cells. Studying the mechanisms that underlie Wnt signals is important for understanding not only normal brain function, but also the establishment of regenerative therapies for brain diseases, according to Dorsky. He is addressing three major questions regarding Wnt signals: (1) What are the Wnt-responsive cells in the brain? (2) What is the function of Wnt signaling in these cells? (3) Which genes does this signaling pathway turn on during brain cell differentiation?
- Phil Sahm

Mario R. Capecchi, Ph.D.
Distinguished Professor of Human Genetics and Biology
Holder of the Helen Lowe Bamberger Colby and John E. Bamberger Presidential Endowed Chair in the Health Sciences
Co-chair of Human Genetics

Mario R. Capecchi, Ph.D., co-chair of human genetics at the University of Utah, developed "gene targeting," a method of disabling or "knocking out" any desired mouse gene. Scientists worldwide use the method to learn what genes do normally by seeing what goes wrong when they are disabled. Knockout mice are bred to develop human diseases, allowing researchers to study molecular details of how diseases occur and how to better treat them.

In recent years, Capecchi has used gene targeting to study hox genes, which control other genes during mouse embryo development. He showed how hox genes help "wire" the brain to various parts of the body: a hox gene must work at both ends of a nerve before the nerve can link the brain to each body part it controls.

Capecchi also identified genes that ensure nerves develop in the correct part of the brain, so mice can wiggle their whiskers, pull their ears back, and blink their eyelids. All mammals share these genes, so Capecchi believes they also control human facial expressions.
- Lee Siegel

Erik M. Jorgensen, Ph.D.
Professor of Biology

Nerve impulses are transmitted from one nerve cell to another across a gap known as a synapse, with the impulse carried by chemicals called neurotransmitters. Changes in the strength of these connections are thought to underlie the formation of memories in the brain. Biology Professor Erik Jorgensen and colleagues are working to identify genes necessary for synapses to work.

Using tiny nematode worms, they have identified scores of such genes, including one that is essential to get nerve cells ready to fire. They also have identified six genes required for the workings of GABA, an �inhibitory neurotransmitter� that acts like a traffic light to regulate the flow of nerve impulses. GABA plays a role in "higher" brain functions, such as forming memories, controlling movements, and interpreting what we see and hear.

Ultimately, Jorgensen wants to identify all the molecules that work at synapses and how those molecules act to weaken or strengthen a synapse, and thus to store memories and help us sense, think, and act.
- Lee Siegel

Chris Johnson, Ph.D.
Distinguished Professor of Computer Science
Director, University of Utah School of Computing and the Scientific Computing and Imaging Institute

As director of the University of Utah's School of Computing and the Scientific Computing and Imaging Institute, Chris Johnson develops computerized visual analysis tools that increase understanding of complex data. Johnson and colleagues are seeking new ways not only to visualize the inside of the human body to diagnose disease, but also to help surgeons plan operations.

Johnson oversaw development of ground-breaking computer software that helped brain surgeons get a better look inside the skull before operating on patients. The software converts two-dimensional pictures from CT scans and magnetic resonance imaging (MRI) into extremely detailed 3-D pictures. Surgeons can wear 3-D stereo glasses and interact with images on a large screen, rotating the pictures, zooming in on details, and even looking at the brain from a viewpoint inside of it.

The software and resulting pictures were used by surgeons to plan operations to remove a brain tumor in a 2-year-old girl and repair a peanut-size aneurysm (ballooned-out blood vessel) that was in danger of bursting inside a man's brain. One neurosurgeon told Johnson it was the first time in his career he knew exactly where he was going before operating on someone's brain.
- Lee Siegel

Kevin M. Flanigan, M.D.
Associate Professor of Neurology

Upward of 10 million Americans suffer from Essential Tremor, a neurological disease that causes a person's hands to shake, although it also can induce shaking in the head, neck or other parts of the body. Kevin M. Flanigan's research with the Brain Institute will look at Essential Tremor and other degenerative diseases of the spinal cord and central nervous system. Using linkage analysis- the study of large families to identify specific regions of chromosomes that harbor genes associated with disease- Flanigan is searching for genes that cause Essential Tremor. When genes with mutations responsible for a disease are passed from parent to offspring, genetic markers near the disease gene are passed along as well. By pinpointing genetic markers shared by Essential Tremor patients within families, Flanigan hopes to locate the regions containing genes responsible for the disease. Identifying the genes and characterizing their function likely will lead to improved pharmacologic therapies for this debilitating disease.
- Phil Sahm

Dennis L. Parker, Ph.D.
Professor of Radiology and Medical Informatics
Holder of the Mark H. Huntsman Endowed Chair in Advanced Medical Technologies
Director, Utah Center for Advanced Imaging Research (UCAIR)

As a medical physicist, Dennis L. Parker has dedicated his career to improving imaging technology, with a major focus on blood vessels in the brain. He is internationally recognized for contributions to the field of magnetic resonance imaging (MRI) and in imaging the brain's blood vessel anatomy through magnetic resonance angiography. The principal applications of this work are in detecting and monitoring brain aneurysms, and identifying atherosclerosis in the neck. Parker also has collaborated on research to develop techniques for imaging the white matter in the brain. This is important for understanding the wiring of the brain and also for detecting multiple sclerosis and other diseases of the brain's white matter. Parker and other UCAIR researchers work with many groups across campus, and the Brain Institute is yet another opportunity for collaboration, he said.
- Phil Sahm

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