Learned at the Bench

A Quarter Century of Stories from Hopkins Medicine, 1976-2001:
25 Years at the Bench

[Related Articles: "25 Years on Campus," "25 Years of Medicine," " 25 Years of Building"]

March 1977
Cancer

1986: Three young scientists, Don Coffey, Drew Pardoll and Bert Vogelstein, who would go on to become world-renowned cancer researchers, show that cells make DNA quite differently from what previously had been thought.

Microbiology researchers here have found that they can arrest a growing or established cancer tumor most likely on a permanent basis through the use of antibodies. Though their research has been done only on mice, the findings have important implications for clinical use in humans.

Those conducting this study include Hyun S. Shin, Gary R. Pasternack, James S. Economou, Robert J. Johnson and Michael L. Hayden.

May 1978
Traveler’s Diarrhea
Montezuma’s revenge—traveler’s diarrhea—is often thought to be one of the unavoidable risks of traveling in a developing country. Now a group of scientists, headed by David A. Sack and R. Bradley Sack, found that an antibiotic called doxycycline can prevent most episodes of traveler’s diarrhea when taken in daily doses. The protective effect seems to last about a week after the drug is stopped.

May 1980
The Making of DNA

Investigators at Johns Hopkins Cancer Center have found evidence that the cell’s system of making DNA may be different from what has been visualized previously. A series of experiments shows that new DNA in mammalian cells is made along the winding, giant molecules of old DNA at a large number of fixed sites attached to the web-like structure within the cell’s nucleus.

These experiments, conducted by Drew M. Pardoll, a 1982 M.D.-Ph.D. candidate at Hopkins; Bert Vogelstein, assistant professor, oncology; and Donald S. Coffey, professor, oncology, urology, and pharmacology, appear in an article published in Cell.

The previous concept of DNA replication was that each DNA copying device moved along the DNA double helix and copied both strands simultaneously. The new experiments suggest that replication occurs at multiple sites which are fixed in place and that both strands of DNA are reeled through these fixed "recording heads."

November 1980
Glaucoma

1980: Ophthalmologist Harry Quigley (left) deciphers the mechanisms that cause the blinding disease glaucoma.

Harry A. Quigley, assistant professor of ophthalmology, has developed a primate model of chronic glaucoma, a disease which threatens the sight of more than two million Americans, but whose fundamental mechanisms are largely unknown. Employing innovative laboratory techniques including the making of casts of optic blood vessels by the injection of plastics, the researcher is tracing the events leading to optic nerve damage and severe visual loss. His work is expected to have a profound influence upon the diagnosis, medical therapy and surgical management of glaucoma.

January 1981
How Nerves Repair
The ability of nerves to repair damage, grow and regenerate becomes increasingly impaired with age, according to rat studies of peripheral nerves. Synaptic connections in the central and peripheral systems are thought to undergo continual remodeling and repair. Researchers Alan Pestronk, Daniel B. Drachman and John W. Griffin, all of Hopkins’ Department of Neurology, tested this ability in young, mature adult, and aged rats. Their studies compared terminal sprouting—branching and growth of a nerve where it meets a muscle, and regeneration of a region of the nerve called the axon.

To study the ability of the axon to repair itself after injury, researchers first crushed the test nerve with fine jewelers forceps and recorded the rate and amount of regrowth in groups of nerve fibers. Results indicated that, overall, regeneration slows with age in both motor and sensory nerves.

March 1981
CO₂ Measured Through the Skin
Continuous and bloodless monitoring of carbon dioxide levels in the blood is now possible with a new carbon dioxide sensor developed through the Department of Biomedical Engineering. Measurements are taken with a pair of electrodes placed on the skin. "The device is especially useful for patients with chronic obstructive pulmonary disease, such as emphysema," says Richard J. Johns, director of the department. The monitor can also be useful in intensive care units to determine if patients on a respirator are being ventilated properly.

July 1981
A-Choo
Circulating through the blood of allergy sufferers are molecules of IgE antibodies, substances that build bridges between themselves and an antigen, such as grass, cat hair or pollen, inducing the release of excessive histamines. Today, 15 years after Teruko Ishizaka and Kimishige Ishizaka, both M.D.’s and Ph.D.’s at Hopkins, discovered these basic ingredients of allergic reactions, they have isolated—in rats—a substance which suppresses the antibodies.

"If the IgE suppressive factor can be isolated in humans and developed in tissue culture," Kimishige Ishizaka says, "we’ll have a potent new therapy that can stop allergy at its source."

Winter 1984
First View of Neuroreceptors
Johns Hopkins investigators have accomplished the first successful imaging of a neurotransmitter receptor in the living human brain. They used a positron emission tomography (PET) scanner and a new chemical technique to show the distribution of dopamine receptors in parts of the brain concerned with motion and emotion. The 13-member team was headed by Henry N. Wagner Jr., director of nuclear medicine and radiation health sciences.

Summer 1985
Heart Disease Warning
High levels of a blood protein, apoprotein B (apo B), may signal which brothers and sisters of heart disease sufferers unknowingly have the disease themselves, a Hopkins investigator reports. The 68 individuals in the study had no symptoms of heart disease, but each had a sibling who had experienced symptoms before the age of 60, explains Peter Kwiterovich.

Of 68 brothers and sisters of heart patients, 19 had hidden coronary artery disease themselves. Levels of cholesterol in the blood, one traditional factor used to predict risk of heart disease, were high in only two of the 19, whereas 10 of the 19 had high levels of apoprotein B.

Spring 1986
New Use for Thalidomide

1988: Oncologist Georgia Vogelsang discovers that thalidomide, a drug that had been pulled from the market in horror in the 1960s, can be channeled to help patients through bone marrow transplants.

Oncologist Georgia Vogelsang was intrigued several years ago when she learned that Israeli scientists were having great success using the drug thalidomide to control leprosy. Thalidomide was a sedative pulled from the market in horror in the 1960s when it caused severe birth defects. Perhaps, Vogelsang thought, she could channel the drug’s newfound immunosuppressive properties for her own work in fighting graft versus host disease, a disease in which transplanted bone marrow rejects its host.

To test the theory, Vogelsang, Gary Gordon and Allan Hess transplanted bone marrow from one strain of rats into another and discovered that all but one of 23 other rats recovered from graft versus host disease after receiving oral doses of the drug. The results were even better when thalidomide was given before transplantation. Of 42 rats, 34 never showed any sign of graft versus host disease while eight developed mild cases which cleared up as therapy continued.

Spring 1988

Genetic Fingerprints Point Out Daddy
Finding out if daddy is really daddy will be simpler and more accurate with the new gene-based paternity testing techniques now being used at Hopkins. "Examining genetic material even enables testing of people no longer alive," says Wilma B. Bias,  director of Hopkins’ immunogenetics lab.

The technique of human "DNA fingerprinting" is based on the fact that human chromosomes include short, distinctive stretches of DNA. Called intervening sequences, these stretches may be single or, like so many beads in a string, may repeat themselves throughout a person’s chromosomes. Most important, they vary in number from person to person, providing distinct markers of human individuality. The chance of two individuals, other than identical twins, having the same band pattern is extremely remote, and a child’s bands unmistakably resemble those of both parents.

Fall 1989
Fitting Pieces into Insulin’s Puzzle
Ever since John Jacob Abel first crystalized insulin at Hopkins in 1927, scientists have been working to clarify the role of insulin in the body—exactly what happens when the molecule reaches its target cell. Now researchers here have isolated and identified two key molecules in a chain of cellular reactions initiated by insulin. The discovery may ultimately help doctors target, treat and "cure" specific defects within a diabetic’s cells.

A team of researchers led by M. Daniel Lane, director of Hopkins’ Department of Biological Chemistry, isolated the first molecule, a small double protein called pp15, from adipocytes (fat cells) exposed to insulin.

Fall 1990
Aluminum and Alzheimer’s

1990: Neurologist Don Price demonstrated that a natural exposure to aluminum can't bring on Alzheimer's disease.

"People always ask, should we give up our pots and pans, or stop using Maalox, or not use deodorants?" says Donald Price. In the blizzard of information on Alzheimer’s theories and research, aluminum has stood out as a graspable concept—as a cause easy to prevent.

"In some Alzheimer’s patients, there’s a high aluminum content in the brain," Price says. With colleagues in pathology he has produced an animal model by injecting aluminum into the brains of rabbits. Superficially, the neurofibrillary pathology is similar—aluminum injures the filaments of nerve cells exposed to it at concentrated levels. "But the more closely you look, the more you realize the pathology is not quite the same," Price says. "Aluminum produces an interesting model for damaging nerve cells. But there’s no direct evidence suggesting that everyday exposure to aluminum—it’s the third most common element on the earth—causes Alzheimer’s disease."

A separate concern is whether aluminum, combined with abnormal genes, old age and other environmental factors, hastens the progression of Alzheimer’s, Price says. "That’s an open issue."

Fall 1991
The Marfan Connection

1991: Those who suffer from it are tall of stature with elongated fingers and toes and a fragile aorta, the heart's main blood vessel. The disease is Marfan syndrome, and it has caused the death of a least two star athletes recently. Now, this team of researchers has identified the gene responsible for the connective-tissue defect. From left: Hal Dietz, Clair Francomano, Victor McKusick, Reed Pyeritz and Garry Cutting.

Scientists at Hopkins and the Portland Oregon Shriner’s Hospital have confirmed that a gene responsible for making a connective tissue protein is, in fact, responsible for Marfan syndrome.

The gene is located on chromosome 15 and normally makes the protein fibrillin, a component of connective tissue which holds skin, muscles and organs together. In Marfan patients, the gene is altered so that it either makes too little of this scaffolding, or what it does make is weak or broken.

"Evidence suggests that the earlier a patient is diagnosed and started on medications, the better his chances of survival," says Harry C. Dietz, lead author of the paper. Dietz, a research fellow, conducted this work with the scientific guidance of Clair Francomano and Garry R. Cutting, both assistant professors of medicine and pediatrics at Hopkins.

Winter 1992
A Colon Cancer Gene

Across the country, headlines trumpeted the news: "Doctors Link Gene to Colon Cancer." The excitement focused on Hopkins oncologists Bert Vogelstein and Kenneth Kinzler who have identified a gene they believe initiates the colon cancer process—a gene which also may play a key role in other cancers.

The gene causing all the stir is called adenomatous polyposis coli (APC). The APC gene is mutated in people with familial adenomatous polyposis, a condition in which someone develops hundreds of polyps along the colon lining—some of which progress to cancer, often by age 30.

Spring 1992
Nitric Oxide: Ephemeral Culprit
Nitric oxide is a gas, a minuscule molecule, distant cousin of laughing gas and—worse—a cellkilling free radical that only lasts in the body about as long as it takes to say its name. It’s an unlikely candidate for anything major.

So most researchers reacted to the news that nitric oxide mediates a host of key functions in the body, from blood pressure regulation to maintaining peristalsis to snuffing out bacteria, with incredulity. Unlikely or not, the molecule is a focus of intense research at Hopkins, mostly in the labs of neurobiologist Solomon Snyder  and his cadre of M.D./Ph.D. candidates and postdocs. With some incredibly fast and fortunate work over the past two years, the Hopkins researchers have become the first to define the probable behavior of nitric oxide in the brain. Their current studies on the basics—how nitric oxide works, where it’s found and regulated, and how its workings can go awry—may lead to drugs that minimize stroke or damage from autoimmune disease, eliminate septic shock and quell hypertension.

Fall 1993
The Cancer Genes
David Sidransky’s weapons are those of state-of-the-art molecular biology, and his battle plan targets two genes that are vital links in the cellular chain of events that leads to cancer. One of them is called the Ras gene. Ras is involved in the regulation of normal cell growth, and activated by a highly regulated substance called GTP. GTP acts as a switch that "turns on" Ras which, in normal cells, starts the process of cell signaling and division. But when Ras is mutated—by whatever it is that causes cancer—it becomes an oncogene, a gene that, when expressed in a cell, confers malignant potential.

Another key player in cancer development is p53, a tumor-suppressor gene. It is a checkpoint gene, the calm voice of reason in a cell cycle that easily can get out of hand. Its purpose seems to be to put on "brakes," to control cell division.

Using p53 as a target gene, Sidransky had been able to identify cancer cells in the urine of people with bladder cancer—and thereby develop a means of screening for this disease. He had then extended the results to colon cancer: Using the Ras gene as a target, he and colleagues identified genetic mutations in stool samples of people with colon cancer.

"Patients often get multiple tumors, and sometimes the tumors are of different histologic types; different kinds of cells can be involved," Sidransky says. Some cancer cells are mature, controlled and slower-growing; others are poorly differentiated and more aggressive. "It’s an interesting model for cancer study, a real challenge."

Spring 1994
Whirling for Medical Science
Once or twice a month, David Zee spends an hour or so spinning in a chair, diligently trying to get dizzy for the sake of medical understanding. By analyzing how his own body accommodates to this disruption, the neurologist hopes to collect information that will help him treat patients with balance disorders.

As Zee persistently rotates, a cylindrical drum facing him whirls in the opposite direction, simulating the vertigo caused by inner-ear disturbances and other kinds of balance problems. Meanwhile, tiny electrodes taped near his eye sockets measure his heightened eye movement.

Fall 1997
Schwarzenegger Mice
Hopkins researchers introduced the world to a new breed of mice last spring whose bulging biceps are double and triple the size of normal mice. The secret to their majestic muscles? Not mouse-sized weight sets or even a spinach-based mouse chow, but a change in their genetic code created in the laboratory.

What’s most exciting about the discovery is the applications it could have in humans, whom the scientists say appear to carry a matching gene. Blocking the gene’s effects eventually could prove the key to new treatments for muscle-wasting diseases like muscular dystrophy or cachexia, the fatal muscle loss that accompanies AIDS and some cancers.

Aquaporin’s Secrets
Given that organisms started out as bits of protoplasm sloshing about in tepid primordial seas, it’s no surprise that our cells are largely water—most of them about 70 percent. What’s surprising, however, is how long it’s taken to figure out how cells handle water. That is, how they move all that fluid in and out of cell-enclosing membrane.

A few years ago, Hopkins biological chemist Peter Agre changed the course of physiologists’ quest for the water-managing mechanism. In a classic case of chance favoring the prepared mind, Agre and his research team, probing around in red blood cells for the molecule that triggers the maternal Rh attack on fetal blood, stumbled across a mysterious protein. It was smaller than other proteins and had a sequence of amino acids they’d never seen before. Cloning the complementary DNA for the protein, which they then tested in frogs’ eggs, they were able to show without a doubt that the genetic information actually instructed the cells how to form water channels.

Winter 2001
Phase One
Cynthia Dunafon, a University of Chicago graduate student, is one of six volunteers in a new gene therapy clinical trial for cystic fibrosis. Scientists are hoping this will become the first step in a pace-setting approach to helping patients born with the treacherous lung disease. Physiologist William B. Guggino, who fashioned this CF gene therapy trial after years of work in the laboratory, is pretty sure that, if he and his colleagues can deliver normal copies of a gene that is a transmembrane regulator into the cells of patients with this brutal lung disease, they will effectively repair their faulty chloride channel function.