The Rensselaer Prescription

Researchers on campus strive to make lives both longer and healthier

Alan Moorse

When the pharmaceutical company DuPont Merck received approval from the Food and Drug Administration to market a drug for use in treating alcoholism last year, it wasn't news to Larry Reid, professor of psychology and neuroscience at Rensselaer. ReVia, a drug that reduces cravings for alcohol and is a useful adjunct to other treatments for alcoholism, is based on a compound Reid has been studying for more than a decade.

With his studies of drug effectiveness, Reid is one of dozens of Rensselaer professors and students who conduct health-related research in a wide variety of disciplines. Here is a brief look at what is going on in Rensselaer offices and laboratories to make our lives longer, healthier, and happier.

Helping Addicts Break Free

Reid has dedicated much of his career to finding ways of helping people who are addicted to drugs or alcohol. Having provided a large portion of the basic science behind ReVia, he has turned his attention to possible treatments for cocaine addiction. With colleagues at the University of Arizona and the University of Minnesota, he recently patented the use of certain compounds of a class called delta opioid antagonists for treating cocaine addiction.

His goal is to free addicts from their addictions enough that, with psychosocial treatment, they will be able to develop life styles that don't involve illegal and addictive drugs. "We probably can't find a 'magic bullet' that will cure addictions," he says. "What we can find, however, are drugs that can help addicts do what they should do and usually want to do."

Delaying Cataracts

Gillray Kandel, professor of psychology, has built a prototype system that can determine how close the lenses of a person's eyes are to forming cataracts, one of the leading causes of blindness. Studies Kandel undertook with physicist John Schroeder led to the measurement system, a new theory of how cataracts form, and more important, a treatment that might keep them from forming.

Schroeder and Kandel have shown in tests on donor lenses that lithium, a drug commonly used to control a psychiatric disorder, can delay the formation of cataracts. If treatment with this or a similar drug were to delay cataract formation for 10 years, they believe it could reduce the number of cataract operations in the United States by up to a million a year.

Schroeder and Kandel also found evidence that the irreversible process by which cataracts form is similar to the phenomenon of devitrification in glass. The contents of lens cells, unlike most other cells in the body, persist throughout life, Schroeder explains. Early in a person's life, the lens materials membranes, water, and proteins form a uniform and ordered "solid solution." As years go by, ionizing radiation and other insults bring about submicroscopic defects in the solution. As these defects multiply, phase separation begins, forming regions of high and low protein concentration within the cells. The regions, in turn, result in macroscopic flaws which, when they become very large, constitute cataracts.

During the 1960s, Schroeder found that certain molecules he termed "structure makers" could help repair sub-microscopic defects of the type that occur in the lens. Lithium is one of those structure makers.

Kandel and Schroeder plan to bring their measurement system into play to determine how effective the drug is in delaying cataracts. Although the instrument could be used to determine whether an eye has an operable cataract, it is not primarily a diagnostic tool. It measures the concentration of cataract precursors. Kandel and Schroeder plan to compare measurements from people who have been treated with the drug and from people who have not used it to see whether the drug slows formation of the precursors.

Though very costly (more than $3.5 billion per year in the U.S.), cataract surgery is an extremely effective treatment, Kandel says. In some parts of the world, however, the need is even more acute than in the U.S., and surgical treatment is not readily available. For this reason, researchers worldwide are trying to find preventatives, and many of them could use the measurement system to gauge the effectiveness of prospective treatments.

Keeping an eye on cells

Institute Professor Ivar Giaever and Senior Research Scientist Charles Keese have progressed from studying a phenomenon to inventing a device to benefit from it. About 10 years ago, while studying how electricity affects cells, they realized that an electrical signal could be used to monitor cell growth, division, and movement. They've been working on a monitoring system ever since.

"Most cell culture studies use optical microscopes to look at cells, so the cells can't be constantly monitored," Giaever explains. "The researcher does something to the cells in culture, waits an hour or a day, and looks at them to see if there's a change."

The system they created uses minute amounts of electricity to measure changes in real time. The sensors, which some call "electronic Petri dishes," contain wells for cell cultures, each equipped with a gold electrode. A computer monitors changes in current flow through the electrode to identify and quantify changes in the cell cultures.

Giaever and Keese have formed a company, Applied Biophysics Inc., in the Rensselaer Incubator Center to manufacture the sensor wells and to assemble and program the computerized instrument. The complete system called the electric cell substrate impedance sensor allows researchers to study mammalian cells, in vitro, in real time. Eight systems are already in use, three for studies of endothelial cells, the cells that line blood vessels.

The sensor system is new enough that its eventual impact on cell-culture research cannot be predicted, Giaever says. He and Keese, with colleagues at Johns Hopkins University, plan to study whether cells in culture can replace animals for toxicology tests such as those done for new drugs and cosmetics.

They are already collaborating with researchers at Johns Hopkins on a study of prostate cancer to see whether the sensor might offer a simple, reliable test for distinguishing between a form of the cancer that spreads slowly and forms that spread extremely quickly. If doctors could tell which form patients have, they might be able to save lives, Giaever says.

A Close Look at Cancer

Another professor whose research may help save lives is Badrinath Roysam, assistant professor of electrical, computer, and systems engineering. He and James Turner at the New York State Health Department Wadsworth Research Center have designed a system that uses high-speed computing, imaging, and image analysis techniques to conduct three-dimensional screening of Pap smears, the most common test for cervical cancer.

Manual screening of Pap smears yields false negatives for 18 percent to 25 percent of samples that contain cancerous or precancerous cells, Roysam says. This level of error can be deadly because while cervical cancer caught early has a cure rate of nearly 100 percent, cancers allowed to progress are often fatal. The delay caused by a false negative can make the critical difference.

Several companies have developed automated systems for preparing and screening Pap smear slides, Roysam says. Unfortunately, these systems, like human slide screeners, have difficulty examining regions of test slides where cells lie in multiple layers. That's where the new system can help, Roysam says. The high-speed, 3-D microscope system should give automatic screening systems the ability to analyze layered cells. Boston-based Cytyc Corp., which manufactures slide preparation and screening systems, is testing the system's effectiveness at processing slides prepared using their machines.

The 3-D microscope is just one application of high-speed computing, imaging, and image processing technology to medical problems, Roysam says. He is also developing systems to control lasers for eye surgery and procedures to treat eye diseases such as age-related macular degeneration, diabetic retinopathy, and AIDS-related CMV retinitis.

Still a Few Years Off

The most common question asked about any new development in health care is "When will it be ready for use?" Unfortunately, the processes of refinement, approval, and manufacture can be dauntingly slow.

Asked when the adaptive current tomography system he and colleagues have been working on will arrive in hospitals, Jonathan Newell, professor of biomedical engineering, smiles.

"I've been guessing one-and-a-half years for the past five years," he says. After some mental addition next-generation prototype plus clinical studies plus manufacturing he estimates "at least three years, probably longer." That would bring to roughly 14 years his total time invested in the imaging system, which lets doctors see in real time what's going on inside the body.

Newell manages the tomograph project, which was conceived by David Isaacson, professor of mathematical sciences. Intrigued by electrocardiograms and how they work, Isaacson wondered whether electrical signals might make possible a real-time, 3-D imaging system. After extensive work on the theory behind such a system, he brought a series of questions to the Department of Biomedical Engineering in 1985.

Newell volunteered to help test Isaacson's theory, though he was sure such a system could not work. They quickly designed an experiment. An undergraduate student built the test apparatus out of a plastic pie saver, in which they floated a plug of salted Jell-O. It worked.

Two design generations later, their system can produce 20 sharp images every second, worlds away from the two-per-minute rate of the first version. They're raising funds to build what Newell calls the "ACT 3," the prototype that will render images in 3-D.

"This project grew out of the Rensselaer community," Newell says. Electrical and biomedical engineers, mathematicians, and computer scientists have called on one another with questions or volunteered help. Undergraduate and graduate students have invested countless hours, writing computer programs and building equipment. "There are roughly 15 groups working on impedance imaging worldwide," Newell says. "The group at Rensselaer is the only one in the U.S. that can do it all in one place.

Focusing on the Eye

A student working with Jane Koretz, professor of biology, has built a system that may revolutionize studies of focusing in the eye. Koretz and Christopher Cook, who completed his doctorate in 1994, broke new ground with their studies of structures in the lens called "zones of discontinuity." Using photos of the lens taken with a slit-lamp camera, they studied the zones and were able to determine the ages at which the zones formed. This allowed them to match up age-related visual changes with changes in structure.

During their studies, Koretz and Cook noted that their work would be far easier if the slit-lamp camera could take motion pictures and feed them as digital data directly into a computer for analysis. After finishing his doctorate, Cook stayed on at Rensselaer to build precisely such a camera system, based on new charge-coupled device (CCD) technology. Late this summer, Cook shipped the camera system to a colleague at the University of Wisconsin who has collaborated on their work. There, the system will be tested to see how well data can be extracted from the images. If it works well, the camera may then be used in the first real-time studies of focusing to see how long the eye takes to adjust, and how it does so, for people of different ages.

Koretz, who has been studying the mechanism of focusing for nearly 20 years, also hopes the new camera system will make possible studies of children's eyes. It requires far less light than existing slit-lamp cameras and so might be judged safe for use with young eyes. "There are some very big differences between children's eyes and adult eyes that have never been characterized," she says. Combining information on development of the lens in children with that on aging of the lens would enable her to establish a lifetime baseline of physical and optical characteristics, Koretz says, something that has never existed before.

More Medical Research

Jeffrey Bell, assistant professor of chemistry, is studying crystalline forms of proteins to see how their structures change as they are dehydrated. He hopes his findings will speed development of methods for dehydrating and rehydrating proteins used for medicinal purposes.

Modeling Drug Molecules

Curtis Breneman, associate professor of chemistry, is working on design and computer modeling of drugs. He first uses the electronic signatures of parts of molecules to predict the effects of a potential drug. Once candidate drugs are identified and tested, Breneman uses modeling techniques to predict a compound that would work better than the original candidates.

Dental Implants

John Brunski, professor of biomedical engineering, is studying dental implants to gather data on stress, strength, and loading and to develop models that could be used in treatment planning with implants. He is also studying the mechanisms of bone loss that can occur around implants that are overloaded during chewing.

Devices to Fight Scoliosis

A team led by Kevin Craig, associate professor of mechanical engineering, is developing an implantable system to help straighten the spines of people afflicted with scoliosis and other spinal disorders. The system uses minute devices built of shape-memory alloys to pull the spine into shape gradually and is expected to be both more effective and less risky than current surgical techniques (see Rensselaer, March '95).

Examining Dynamic Forces

Natacha DePaola, assistant professor of biomedical engineering, is studying the effect of fluid dynamic forces on mammalian cell function. One goal is to develop a description of what occurs in the arterial surface during the early stages of atherosclerosis. She is also working on the development of tissue-engineered vascular implants, in which cells and synthetic materials are combined to provide a living interface with blood.

Shedding Light on Tissue

Lee Ostrander, associate professor of biomedical engineering, has founded Lights On Technologies Inc., an incubator company that develops medical applications based on the interaction of light and soft tissue. The company has built a prototype of a light-based brain oximeter, a device that can measure the concentration of oxygen in brain tissue without the intrusion of a needle.

Controlling Light in Incubators

Mark Rea, director of the Lighting Research Center, and research associate John Bullough '91 have built a prototype incubator lighting system for premature infants. The system could be used for studies of a vision disorder called retinopathy of prematurity or for studies of environmental conditions on premature infants.

Unraveling NO Synthesis

John Salerno, associate professor of biology, is studying enzymes that synthesize nitric oxide. NO, which is poisonous and highly reactive, is a critical signal molecule in the body and is used to fight infections. Salerno hopes to determine how the enzyme works, how it is controlled, and how it can be harnessed for medicinal purposes, possibly to control hypertension.

Stocking the Chemical Tool Box

Studies in stereochemistry have shown that if two molecules are made up of the same elements in the same order, but one is the mirror image of the other, one might be an effective medicine, while the other is not. Arthur Schultz, the William Weightman Walker Professor of Chemistry, works in a number of areas, one of which is inventing new chemical reactions to select the desired mirror-image molecule. These reactions serve as basic tools for organic synthesis, allowing chemists to produce batches of molecules uniformly of one orientation.

Modeling Joints

A team of researchers at Rensselaer and Columbia University is developing a computer simulation of diarthrodial joints for instance the knee,elbow, or shoulder. The goal is to accurately simulate the interaction between soft tissues such as cartilage that carry loads through the joint and to be able to model joints to help determine where problems are occurring and plan interventions. Robert Spilker, chair of biomedical engineering, is co-director of the project.

Synthesizing Anticancer Agents

Mark Wentland, professor of chemistry, is a new member of the chemistry faculty, though he served as an adjunct professor while a medicinal chemist with Sterling Winthrop Laboratories. He's synthesizing molecules of potentially medicinal use, with particular interest in anticancer agents.

This article was originally published by Rensselaer Magazine in December 1995, and is used with permission.