ON THE FRONT LINES: The Burnham Institute goes to the molecular level to fight against bio-terrorism

A few years ago, hardly anyone worried about bio-terrorism. The term itself was obscure, a label attached to a set of circumstances that few believed would ever really materialize.
Things have changed.

Post Sept. 11, 2001, the threat of biological warfare and terrorism in the United States has metamorphosed from a bizarre conspiracy theory to a distinct possibility and even a tool for political spin. The wars in Iraq and Afghanistan and the war on terror have served to whip up public concern about the dark world of infectious diseases and biological warfare. Meanwhile, news about the spread of natural diseases such as SARS and West Nile Virus continues to make headlines the world over.

On the front lines of man’s battle with deadly bacteria and viruses, scientists continue to struggle to understand the micro-mechanics of diseases that threaten human life. As viruses mutate over time, becoming more and more complex and dangerous, organizations such as La Jolla’s Burnham Institute are running full-tilt to research and develop programs that might yield drugs that protect humans from these deadly diseases.

In fall 2001, The Burnham Institute’s Dr. Robert Liddington had just sent a ground-breaking article to the scientific journal “Nature” for publication. After several years of study, Liddington and his team had finally completed the first stage of their work. They had completely mapped out the three-dimensional structure of the lethal factor of Anthrax, one of the world’s most deadly and complicated toxins.

While Dr. Liddington’s paper sat in the offices of “Nature” awaiting publication, a number of letters laden with anthrax spores were sent to the offices of media personalities and United States senators. The resulting furor, coming just weeks after the terrorist attacks in New York and Washington, meant that Liddington’s work was suddenly thrust into the public eye.
In a remarkable coincidence, the team’s work had reached fruition at a time when the public and the government were just beginning to whet their appetite for information about biological weapons.

“We published about two weeks after the first people had died,” said Liddington, a look of amused bewilderment crossing his face. “And, as far as I know, it was a complete coincidence.”
Dr. John Reed, director and CEO of the Burnham Institute, was equally astounded by the turn of events.

“We’ve sort of just been in the right place at the right time,” he said. “It was totally fortuitous. It was a seven-year project at that time that led up to fortuitously having the publication coming out right about the time the anthrax became a public issue.”
The Burnham Institute has traditionally been concerned with cancer, aging and neuroscience research. Founded more than 20 years ago, the center has grown from a small group of researchers into a 500-strong faculty, including some 50 internationally renowned scientists and physicians. Ranked in the top dozen institutions of its kind in the world, the Burnham is one of only eight National Cancer Institute basic-science cancer centers in the country.

Earlier this year, the institute made the decision to formally expand infectious and inflammatory disease work into a third major branch of the organization. In conjunction with the purchase of a 35,000 square-foot property adjacent to the existing buildings, the director made the decision to codify the work of a number of existing programs into a new Center for Infectious and Inflammatory Diseases.

It was officially born July 4, 2004, a particularly apt date, considering the work the new team would be undertaking,
“We just decided that it was time to launch,” said Reed. “We decided that July 4, with the symbolism of the bio-defense mission and with the symbolism of freedom and freedom from disease in this case, would be an apropos time to officially declare the center in existence.”

The Burnham Institute has had its fair share of success in attracting both federal and private funding for its bio-defense and related work. They have just secured $35 million in federal grants for work in bio-defense and have secured a number of the world’s pre-eminent experts to work in this field.

Professor Alex Strongin is one such expert. An intense Russian man with swept-back white hair and dark sunglasses, he looks more like a KGB-era secret agent than a visionary scientist. His thickly accented but careful explanations of his work reveal a sense of deep pride in the success of the team of scientists he oversees.

“In my opinion, this center will be a focal point for other centers in the country. … This center – and, actually, the Burnham Institute itself – is the pride of the neighborhood.”

In a neighborhood that boasts a number of world-class research institutions, a leading university and several dozen successful bio-tech companies, that is quite a claim. It is also indicative of a belief that is mirrored by institute staff, that the Burnham Institute is blazing trails not just in research, but how that research is conducted.

The institute was founded on a theory of cross-fertilization of ideas. Words like communication, interaction and crossing boundaries are the seeds from which this theory has grown and matured.

“We are talking about crossing boundaries,” said Strongin. “The Burnham Institute is organized as a team work place. Its cultural collaboration is intrinsically embedded in the cultural tradition of the institute. Trust me, I’ve been in several places, this is the best place in the world, in terms of collaboration.”
This collaboration extends beyond the 220,000 square feet of facilities at the institute. On a grant application on Strongin’s desk are listed the principal scientists involved in a forthcoming project. Among a number of names from the Burnham Institute are a few members of the Scripps Institute staff.

All the scientists interviewed at the Burnham Institute maintain they work in conjunction, rather than competition, with scientists at the Salk Institute, UCSD and other La Jolla research centers. The same will be true of the new center, with Burnham striving to examine new and ground-breaking areas of research.

“We’ve purposefully elected … to work in other areas of inflammation research that we think will complement what’s going on at the other institutions,” said Reed. “By doing so, we’ll also then create opportunities for us to think about how we might then link our special expertise in inflammatory research to the special expertise that exists in other institutions – and hopefully get a cross-fertilization of ideas and a synergistic merger of talents – that will help us to understand disease better and to move towards new therapies.”

The focus on the discovery and development of drugs that can be used to combat viruses and diseases that have been weaponized will be a large component of the new center’s work. However, the new areas of research are also intended to augment work in which the institute has been involved for a number of years.

Much of what is learned from the study of diseases used in biological warfare and terrorism will hopefully provide new lines of attack in the battle against more common diseases such as cancer, diabetes and arthritis.

One good example of such multi-faceted work is the Liddington team’s study of anthrax. Put very simply, the initial research into the disease was focused on whether the anthrax toxin could be manipulated in such a way that it attacked not healthy cells, but cancer cells, so that it might be used as a tool for fighting cancer.

That study is ongoing, but its scope has broadened to encompass a more detailed study of the effects of inhalation anthrax, an agent that has already been weaponized by many countries. The idea is to use whatever information is gleaned from either approach to build a better understanding of how the toxin works.

That information can then help scientists to piece together the puzzle that is nature.

“Really what we try to figure out are the nuts and bolts of how things work,” said Tomas Mustelin, an expert in inflammation and a key member of the new center. “The trick is in the little details. … The devil is in the details.”

Mustelin is pragmatic about the process of developing medicine. He likens his work and the work of those around him to an ongoing race between disease and medical science, in which both parties strive for the advantage.

While diseases constantly evolve and adapt to find new ways of overcoming the human immune system, scientists work hand in hand with technology to stay ahead of the game. According to Mustelin, the last time humanity really had the edge was when penicillin was discovered in 1928. But many strains of deadly diseases have, particularly in the last decade, become resistant to antibiotics.

“We pretty much keep step. From time to time, bacteria are slightly ahead of us and we catch up,” said Mustelin. “We live right now in a time when we have some new challenges to solve and where we are learning that antibiotics are not going to be the solution forever. We need new things, we need new approaches to combat infection.”

Some such new approaches are already being tested in the Burnham Institute’s laboratories. Mustelin and his team have been working to find a treatment for plague, otherwise known as Black Death. This disease, caused by the bacterium Yersinia pestis, killed 30 percent of the population of Europe in the 14th Century and has by no means been eradicated worldwide.

Yersinia pestis has also already been developed as a weapon by several nations, primarily in its most deadly aerosol form, which is contracted by inhalation.

“You get multiple bacteria into your airways,” Mustelin said, “all the way down to your lungs, which will cause a very rapid and very lethal disease. You have to treat patients within six to 12 hours with strong antibiotics before it’s too late.”

Mustelin’s team started by finding out as much as they could about the bacterium’s molecular detail, striving to establish just how it works and why it is so deadly. They discovered that the bacterium uses a mechanism Mustelin described as “very clever” to attack the cells of the host or victim.

The team has recently developed what are called small molecule inhibitors, which prevent paralysis of the immune system by the bacteria. While still in the early stages of developing this treatment, the team has test tube experience to show that it works, and Mustelin displayed a muted excitement about the success of his work thus far.

“Biology is not predictable, like mathematics,” said Mustelin. “You still have to go out and see. You have to keep an open mind, ask questions and be willing to see yes or no answers. You have to be willing to revise your perceptions.”

As it continues to work towards a greater understanding of diseases and a closer examination of potential bio-terrorism threats, the Burnham Institute will bring a steady stream of dividends to La Jolla. In his refreshingly sanguine manner, Strongin outlined the variety of benefits the institute brings.

“We have raised so much federal money that we have created an additional flow of jobs to California,” he said. “Highly skilled, highly trained people who are going to buy the houses, who are going to pay taxes, who are going to spend the money in the grocery shops.”

The institute remains heavily dependent upon federal money to continue its research and continue attracting such scientists to La Jolla. Currently, some 80 percent of their operating budget is made up from federal grants. The remainder comes from private foundations and philanthropy.

Roughly half of the funding and support for the institute’s new center will be linked directly or indirectly to the federal government’s bio-defense mission, most of which has been funded by the National Institute of Health, with the blessing of the director of Homeland Security. The remaining work will be related to the more established areas of research involving inflammatory diseases.

Reed is treating this funding as an ongoing relationship, to which there is no end in sight.

“(The center will be) bringing more government research money into town,” he said, “primarily from the National Institute of Health – San Diego already receives more of the NIH grant money than any other city in the country – and we’ll continue to keep that theme going. But also through the bio-terrorism, the bio-defense angle, to other pots of money in Washington. We expect to be bringing money into our community through that.”

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