Vaccinologist follows inner compass to right place at right time

November 30, 2004

By Flinn Foundation

Bellies full, and with minds still buzzing from the morning’s seminars, the 35 researchers and graduate students lazed in the afternoon summer sun of Long Island, picking over the remains of their picnic lunches. It was a meeting much like those held every year at Cold Spring Harbor, with one exception: Whether they sensed it or not, these scientists, the pioneers of molecular biology, were standing on the threshold of a new world.

A young man from upstate New York sat among them as the discussion turned to the years ahead—the implications of the year’s discoveries, what remained to be done, and who was going to do it. He had always had a knack for turning up at the right place at the right time, for finding teachers when he needed them, and for asking the right questions.

This year was no different, for, as the sun sank low over the old New York whaling town, a new day was about to dawn for all of them. The year was 1958, and six of the scientists gathered here—five within the next decade—would be recipients of Nobel Prizes for work in a field that had not even existed 20 years earlier.

The Cold Spring Harbor symposia of the 1940s, ’50s, and ’60s were the kind of discipline-defining encounters that are only possible at the changing of a paradigmatic tide—biology’s answer to the gatherings of physics luminaries that had produced quantum mechanics.

The traditional, descriptive biology of the 19th century was going out; quantitative biology, with its nascent disciplines of molecular biology and genetics, was on its way in. And Roy Curtiss, an underpaid, 24-year-old technician at Brookhaven National Laboratories, was coming ashore with it.

Forty-five years later, Arizona State University would put up $3.8 million to lure Dr. Roy Curtiss III from Washington University in St. Louis and convince him to co-direct the Center of Infectious Diseases and Vaccinology within the university’s burgeoning Biodesign Institute. Once again, Curtiss seemed just the right man in the right place at the right time. Having made good use of his time since his days as an intellectual castaway, and was now on the cutting edge of bacterial genetics and vaccinology.


Meeting a dire and growing need

Vaccines have figured heavily in the news of late. The Centers for Disease Control and Prevention have said that an average of 5-20 percent of Americans contract flu annually, with more than 200,000 hospitalized and approximately 36,000 dying from the virus. According to Oct. 15, 2004, article in Science, most virologists say a flu pandemic is a virtual certainty within the next few decades. In this election year, the flu vaccine shortage even attained the status of political football.

Curtiss has built his career on exploring how bacteria cause disease. Now he has a new approach to vaccinology. His strategy provides a layer of defense that other vaccines do not, and—unlike vaccines based on weakened or killed viruses—does not require the viral infection of the patient. What’s more, he says, he can potentially solve the current flu vaccine shortage via a manufacturing process that takes less than a month.

It might seem an idle boast, were it not for the fact that Curtiss, 60-year-old biology superstar, is also an abidingly humble man—a kind of intellectual-hippie Santa Claus. His eyes, framed by square wire-rimmed glasses, are alive with joy and just a touch of mischief as they float above the sea of white beard that reaches to his mid-chest. Those eyes seem to reach out as he talks, drawing the listener in; for Curtiss is also a natural teacher—from the top of his snow-covered head to tip of his red-socks-and-Birkenstocks-adorned feet.

In this emerging biosciences economy, with its so-called “rock star scientists,” real humility can be hard to come by. Perhaps Curtiss’ own successes afford him the luxury of appreciating those of others; or maybe the fact that he has established himself in his field inspires him to make room for ideas and people who might otherwise be overlooked. But when he is asked about what experiences from his youth made a real impression on him, the source of his modesty comes sharply into focus: Once again, he had a remarkable teacher.

Many remember Max Delbruck as the joint winner of the 1969 Nobel Prize in Physiology or Medicine with Alfred D. Hershey and Salvador Luria, but in the years prior he was better known as the charismatic and brilliant leader of the Phage group. The German physicist-turned-biologist had helped found the cross-university collaborative, which used bacteriophages to unravel the replication mechanism and the genetic structure of viruses, at Cold Spring Harbor in 1941.

“I remember sitting in a dorm hallway with Max and a few others at the University of Colorado in 1965,” Curtiss recalls. “It was the 100th anniversary of Gregor Mendel’s discovery of genetics. We were all deep in discussion when a custodian came along and asked us for a dime so he could make a phone call. Max—who, by the way, was suffering from arthritis at the time—immediately said, ‘I’ll go upstairs and get you one.'”


Doing it better

For Curtiss, who spent his formative professional years among people too obsessed with their work to be bothered with pretense, there is no room in the world of intellectual discourse for snobbery or territoriality. Everyone, whatever their background, has something useful to contribute.

Alone in his makeshift office, hunched over two laptops and a precarious pile of grant proposals, Curtiss explains what he means.

“I always tell my students, ‘You’ve got to be able to look at anything and think how you can do it better,'” he says. “See that plastic bottle? When those first came out they didn’t have any ridges [grooved along the sides]. Then some engineer somewhere figured out that by adding ridges you could use 30 percent less plastic and increase the strength of the bottle.”

It is an observation typical of Curtiss, who asks questions of everyone and everything. In the tradition of basic scientific inquiry, he follows his interests where they lead him, even if they take him out of his field. To him, it comes down to making sense of things, and to having things make sense.

“You don’t have to know anything about something to have an idea that might help out someone else,” he says. “Look at the coffee holder in your car. You don’t have to be an automotive engineer to know that placing the coffee holder at the rear of the armrest is a hazard.”

Curtiss inherited his intellectual curiosity from field-hopping mentors like Delbruck and from his father, who never held a college degree but took college courses of one kind or another throughout his entire life. His affinity for the sensible, which has expressed itself throughout his career, derived from the same sources.

“My father detested any procedure or form that could not be described to a sixth grader,” he recalls. “He was a nut about making the world simpler.”


Fixing what’s broken

Most of us do not associate simplicity with genetic engineering or molecular biology. Beyond the complexity of the work itself lies a Kafkaesque network of paperwork—approvals to be sought, grants to be written and maintained, and legalities to be met and overcome. Curtiss sees plenty to be done to improve the process at ASU.

“I get crazy when I see these forms,” he says, gesturing to the pile on his desk. “I would like to try to work out simpler, more reasonable protocols. The problem is, if things get bogged down, the people reviewing them don’t have time to review it all, so they don’t.”

As his track record shows, Curtiss is not afraid to make a few much-needed changes. In his first position as a professional biologist at Oak Ridge National Laboratory, he helped get the interdisciplinary biomedical graduate training program off the ground. Interdisciplinary work was unusual in the field at the time—students generally chose a vocation and were on educational rails from that point forward.

To Curtiss, an intellectual wanderer, such a balkanization was ludicrous and, in 1972, he got a chance to show how he thought it should be done.

As a professor and senior scientist at the University of Alabama at Birmingham, one of Curtiss’ responsibilities was overseeing the microbiology graduate program. Instead, he decided to create a new one. Without approval from the dean or the state board, Curtiss hand picked faculty from departments across the curriculum and built his own vision of the program. It is still going today.

“It was all interdisciplinary, that was the key,” says Curtiss. “Students who came out could do anything they wanted.” Curtiss shakes his head when he thinks about how little progress has been made since then.

“In the 1970s, the National Institutes of Health said that, in regard to graduate training, you have to be multidisciplinary. But until about a year ago [when the university reorganized its life sciences], ASU was, to be blunt, still in the Dark Ages.”

But Curtiss also says that the last few years have seen some encouraging changes, and that he would not be at ASU if he were not excited about them. He sees ASU as becoming more entrepreneurial and encouraging students to do things they have not done before.


Following an inner compass

It is the kind of freedom to explore that brought Curtiss, and modern biology, to where it is today.

Before Max Delbruck began playing around with phages, he was a physicist in Germany, counting Wolfgang Pauli and Albert Einstein among his colleagues. Had he remained in Germany after 1937, the Unites States—and possibly the world—would have lost a great scientist. If he had remained a physicist after his interest in the subject had waned, biology would have been deprived of one of its most important minds.

If Roy Curtiss had not spent his life following his interests, he might never have gone to Cold Spring Harbor or pursued a career in microbiology. If he had listened to his uncle, he might have given up on the whole thing and missed out working in a field with the likes of Albert Hershey, Barbara McClintock, and an associate professor from Harvard named James Watson.

“My uncle didn’t care for it,” says Curtiss. “You know, a lot of these people didn’t have jobs. He didn’t like the fact that all of them were on soft money.”

If he had gone for a more sensible job, Roy Curtiss certainly would not have gained the background in genetics and molecular biology that allowed him to develop his novel vaccines.


Building the better vaccine

Harmful pathogenic bacteria cause problems when they invade the body and reproduce, often because they produce a by-product that makes the host sick. Cholera bacteria, for example, grow in the intestines, and secrete a toxin that causes their host to lose fluids at a dangerous rate via diarrhea and vomiting.

If the host’s immune system already recognizes the bacteria, and if the host is healthy, then the bacteria will likely be kept out of the body entirely. But the immune system often does not know about such a pathogen unless it has encountered it before and “remembered” it.

The typical way to teach the immune system about a pathogen, and the principle underlying many vaccines in use today, involves introducing a weakened or killed version of the pathogen into the body. The immune system recognizes the pathogen as foreign and mounts an immune response.

A weakened, or “attenuated,” version still causes an infection, but its replication is slowed down enough that the immune system can crush it before it does much harm. Ideally, it would be possible to trick the immune system into recognizing and remembering a pathogen before it could do any harm at all.

That is one idea behind Roy Curtiss’ vaccines, which consist of genetically engineered organisms that are very much like the bacteria that cause disease, except that they turn off their own harmful proteins shortly after the individual receives the immunization. To get them to do this, Curtiss uses principles of bacterial genetics to his advantage. In order for bacteria to successfully invade, they must be able to multiply, or “replicate,” in their human host. This requires that the bacteria manufacture certain proteins, necessary for both their life cycle and for making toxins to disable the host.

For protein production to occur, the bacteria’s DNA is first copied via a process called transcription, in which one strand of a DNA molecule “unzips” from its opposite and becomes a template for synthesizing complementary RNA. This messenger RNA molecule will then be decoded into the required protein.

Once transcription has begun, RNA polymerase usually sees it through to the end. But in most bacteria, like E. coli, there is a spot in the DNA sequence where the RNA polymerase “copy machine” can make a choice—often based on environmental factors—to either keep copying or stop. If it stops, then the genes that lie beyond that point in the DNA are not expressed.

Attenuation makes pathogenic bacteria unable to adapt to their environment in the immunized individual. It also makes them prime candidates to serve as vaccines, since they can be tricked into attenuating the expression of their harmful proteins. That way, the body recognizes the presence of the bacteria and raises an immune response, but the harmful proteins that attack the body are not allowed to be made.

It is a tricky business. The vaccine has to be invasive enough for the body to not only mount an initial (or “primary”) response, but also to “remember” the pathogen so that it can launch faster, more effective counterattacks in the future. But it also has to be attenuated in such a way that the body does not suffer any ill effects.

And this attenuation cannot rely on host defenses, health, or diet if—as Curtiss intends—it is to be used to help people around the world, including those who are already sick. The bacteria have to be programmed to attenuate themselves, no matter what.


More “soldiers,” fewer needles

Given the advantages of the approach, the effort could well be worthwhile.

In addition to being able to help people who are already sick, the vaccines have the advantage of being administered orally or nasally. Oral and intranasal vaccines eliminate the use of needles and, with them, the fear and pain that many associate with “getting a shot.” More importantly, they are also safer, as needle reuse in developing countries can lead to the spread of blood-borne infections such as HIV. And oral and intranasal vaccines are cheaper, meaning they can reach larger parts of the developing world.

Such vaccines have another key advantage: They promote mucosal immunity, a type of disease resistance that is, Curtiss says, generally overlooked.

“There are three kinds of immunity—mucosal, systemic, and cellular,” he explains. “The vast majority of vaccines only cause systemic or cellular immunity—sometimes both. I say use every soldier you have at your disposal.”

Tears and saliva are among the body’s chief defenses against bacteria, and are packed with antibodies. Curtiss’ vaccines build on that principle, stimulating cells on the surfaces of such areas as the lungs and the stomach to create a kind of protective film of antibodies. Before disease agents can enter the body, they must first penetrate this reinforced mucosal layer.

Curtiss believes that he can use the methods of molecular genetics to design, construct, and manufacture large quantities of such vaccines quickly. Once in effect, he says, the program could meet the present flu vaccine shortfall within two weeks to a month. He has submitted proposals to NIH and to the Foundation of the National Institutes of Health, funded by the Bill and Melinda Gates Foundation, and is awaiting replies.

A major grant from either would be a crowning achievement for a man who built his career on understanding the primary mechanisms of bacterial infection—a worthy note to retire on. But here, as the waning sunlight of an Arizona autumn afternoon falls across the piles of grant proposals lining the otherwise empty shelves of his Spartan temporary office, the atmosphere is one of beginnings.

“This year is kind of like having two full-time jobs,” says Curtiss, who is holding down positions at two universities during the transition. “But I’m not complaining. It’s a gas.”

He pauses as a smile splits his massive beard.

“I don’t work—I play all day.”