The Colgate Scene
January 2004

Genetic code warrior
Jeffrey Rothstein '77 leads fight against ALS

In his laboratory at Johns Hopkins University Hospital, Jeffrey Rothstein '77 and several co-researchers used a new technique to extend the life expectancy of mice afflicted with amyotrophic lateral sclerosis (ALS), widely known as Lou Gehrig's disease. The technique uses a genetically engineered virus that "tricks" muscle nerve cells into generating a growth protein aimed at repairing the damage caused by the deadly ailment. [Photos by Jim Burger]

Gabriel Schechter '73 explains how Lou Gehrig was much more than the name of a disease.
Drop by Jeffrey Rothstein's busy laboratory at Johns Hopkins University in Baltimore on a typical weekday morning, and the odds are high that you'll find this internationally renowned expert on amyotrophic lateral sclerosis (ALS) talking excitedly about the "powerful new weapon" he and his fellow researchers recently invented to combat the deadly ailment, more commonly known as Lou Gehrig's disease.

The weapon: a genetically engineered virus that knows how to "trick" muscle nerve cells into manufacturing a growth protein aimed at repairing the devastating damage caused by the disorder, which currently affects more than 30,000 Americans. Last August, Rothstein (A.B., neuroscience, 1977) and several co-researchers triggered headlines around the world when they announced in the journal Science that they were able to use the new technique to extend the life expectancy of ALS-affected mice by nearly 50 percent.

Is this a promising breakthrough in treatment? You bet. But Rothstein is quick to point out that the battle against this fatal scourge of the nervous system is far from won.

"We're not miracle-workers, and we aren't going to find a cure for this terrible disease overnight," said the Johns Hopkins Medical School professor and neurologist. "Still, our recent study does show clearly that this new gene therapy technique -- using the virus to help diseased cells manufacture their own growth hormone -- could be an enormously helpful tool.

"Put simply, what happens with this approach is that the virus sneaks into the affected nerve cells and sends them a DNA-coded message to begin manufacturing the growth-stimulating substance on their own," Rothstein continued. "What we've done, with the creation of this gene therapy technique, is to set the stage for clinical trials in a year or so. And for the first time ever, those trials will allow us to get an important growth protein past the body's formidable `blood-brain barrier' -- and deep into the nervous system, where it can work to restore health and vitality to cells that have been damaged by the disease."

For the bespectacled and relentlessly energetic Rothstein, the 2001 winner of the $100,000 LIFE International Research Award, the successful development of this latest tool in the ongoing struggle against ALS represents "one more small victory on the long, hard road to an eventual cure."

Breakthroughs rarely predictable
Ask Rothstein to predict how long it will take the 20 researchers and technicians in his humming Johns Hopkins lab to "eliminate" ALS from the ranks of the world's most dread-ed diseases, and he'll surprise you by laughing out loud at the question.

"I'm sorry to disillusion you," said the widely published physic-ian-researcher (he holds a medical degree and a doctorate in neurochemistry from the University of Illinois), "but the reality is that disease researchers spend most of their time building on little bits and pieces of information they share with one another.

"I'm excited about some of the strides we've been making here at Johns Hopkins. But this is an extremely complex and challenging disorder, and we have to work on it painstakingly, step by step. I don't think you're going to pick up the paper tomorrow and read a headline: `WE CAN CURE ALS!' The process doesn't work that way; what it actually requires is a slow, methodical building on past discoveries."

But a moment later, as if reassuring a discouraged patient, Rothstein is grinning and waving his hands through the air: "Look, I'm not saying we won't get to a cure, sooner or later. Right now, it does seem quite likely that new forms of stem cell research will eventually permit us to replace neurons [nerve cells] killed by the disease. And when that happens, it will completely alter our approach to the disease. Unfortunately, the human body doesn't make new neurons; once you lose them, they're gone forever. Stem cell therapy could rapidly increase our ability to replace diseased nerve cells, and that would change the equation.

"But that scenario is probably still a decade or two in the future. Meanwhile, progress with ALS will require the same kind of grinding, patient work that led to our [recent] development of the genetically altered virus as a delivery vehicle for the growth protein."

For the thousands who suffer from this progressive, incurable disease, breakthroughs such as the one at Johns Hopkins provide bright beacons on a grim landscape. Although ALS can attack at any age, it usually affects adults between age 40 and 70, and it usually kills them within five to seven years -- although a few notable exceptions (such as the well-known physicist Stephen Hawking) have managed to survive much longer with the illness.

Being diagnosed with Lou Gehrig's disease usually means a bleak future for the patient, since the disorder breaks down motor neurons, the nerve cells that regulate voluntary muscle movement. As the neurons die off, muscles atrophy, resulting in increased fatigue, weakness and slurred speech, followed by labored swallowing and breathing, and finally, death.

Although the cause of the disease remains unknown, most researchers today believe that it results from biochemical imbalances resulting from a combination of genetic factors and environmental triggers that may include environmental toxins of one kind or another.

Fascinated by brain feedback
How did the enthusiastic, science-loving student who arrived at Colgate in the fall of 1973 wind up 30 years later as one of the world's leading generals in the war against a disease that slowly asphyxiates its victims by paralyzing their muscles?

"I got lucky," said Rothstein, while leaning back in his office swivel chair and fiddling with the computer mouse on the table before him. "Soon after I started at Colgate, I heard about a brand-new program they were starting in neuroscience. It was unique in the United States -- and I wound up as an undergrad major studying under the professor who created it, Bill Edmonston. And he was terrific! He got us all fired up about the brain and how it works, and he did it by showing us what happens when it doesn't work."

To illustrate, Rothstein holds up one hand, then waggles it for a moment. "You know, most people don't realize that when you grab something, your hand is sending constant feedback to your brain about where it's located in space. It's amazingly complex and interesting -- each joint is telling the brain where it is, what position it's in, and so on.

"Okay, as we all know, there are several neurological diseases -- including ALS and Parkinson's -- where a lot of that feedback information never gets back to the brain. And what happens as a result?" (Now the doctor's large right hand curls up helplessly, drops to the table.)

"Without that feedback from the neurons, your hand becomes essentially useless. Once the communication is broken, movement stops. Isn't that fascinating?"

Like Rothstein, Edmonston, now professor of psychology, emeritus, vividly recalls "some very exciting moments" in his first-of-its-kind neuroscience classes during the early 1970s.

"I remember Jeff as one of the most enthusiastic students I ever taught," Edmonston said. "The program we created attracted a lot of pre-med students, and they were pretty bright. And Jeff kept pushing all of us as hard as he could -- it was sort of like he found himself, in that course."

Dr. Raymond T. Bartus, vice president for research and development at the biotechnology firm Ceregene, Inc. and a world-class neuroscientist in his own right, also views Rothstein as a scientific wunderkind with a knack for breaking new ground.

"There's no doubt he's a pioneer in the field of ALS," said Bartus. "He and the people in his lab have been able to build both animal and human models of nerve cell physiology, and those models have made it possible to synthesize various recombinant proteins. We're convinced that Rothstein's breakthrough will play a key role in stimulating the health of motor neurons among patients struggling with ALS."

More than 5,000 annually
Cheerful and upbeat on his daily hospital rounds, Jeffrey Rothstein long ago became accustomed to putting in a regular 12-hour day in the labs and classrooms that make up the sprawling Johns Hopkins medical complex on Baltimore's east side. He doesn't mince words when discussing why he feels so passionate about making life better for the several dozen ALS patients he treats each week.

"ALS is one of the most brutal diseases in the world today and it attacks more than 5,000 people in this country each year," he said. "For many of these patients, life expectancy after a diagnosis of ALS is only three to five years. And in many cases, they eventually experience difficulty talking, swallowing, and breathing -- things that most of us take for granted each day. This is a tough disease to manage, it robs people of their ability to move, sometimes it's excruciatingly painful, and forces a horrible suffocating death upon my patients. For all of these reasons, we need to continue looking for new drugs and new therapies that will slow down the progress of the disorder."

Deeply moved by the suffering of ALS patients he observed while completing his neurology residency at Hopkins in 1986, the hard-charging Rothstein has been exploring the disease's biochemistry ever since. Ultimately, he said, defeating such neuro-degenerative disorders as ALS, Parkinson's disease, and Alzheimer's disease will depend on controversial new stem cell techniques that are just beginning to come online in American medicine.

Describing that often-debated technology, he points out that "most researchers today fervently believe that various types of stem cells -- most likely embryonic or fetal -- may provide important therapeutic tools for these degenerative diseases. But we have much work to do in order to understand how to use these cells most effectively."

Meanwhile, his key suggestion for dealing with the complex ethical issues involved in using human embryos for stem cell therapy seems surprisingly practical and down-to-earth.

"What we need is an ethical oversight board, perhaps at the national level, that would be charged with monitoring how we go about the research," Rothstein said. "At the same time, we as a society need to educate ourselves -- and fast -- about the potential benefits of stem cell research. Instead of treating the issue as a political football, we need to give our researchers the freedom to use embryonic human stem cells, wherever appropriate, because this is clearly the best hope we now have for eliminating this dreaded disease in the future."

As he waits for the bright promises of stem cell research to be fulfilled, Rothstein said he would continue taking the "slow, plodding steps" required to slow down the disease as much as possible. He'll also continue to slog through his 12-hour days at the lab and the hospital -- while sometimes regretting the fact that they so often prevent him from the Chesapeake Bay biking and boating that he so greatly enjoys.

But the fishing will have to wait a while. Right now, he's got dozens of patients to watch over, and a thriving laboratory to supervise, and the distant dream of someday helping to end the relentless suffering endured by hundreds of thousands of ALS victims all around the world.

"If everything goes as planned," Rothstein said, "we'll be getting our new gene therapy trials underway within the next calendar year.

"Hey, I really think this new tool is going to help some of our ALS patients -- and I can't wait to get started!"

A former feature writer for the Baltimore Sun, Tom Nugent is the author of Death At Buffalo Creek: The 1972 West Virginia Flood Disaster.
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