SEARCH NEWS & VIEWS


Hugh Rosen Makes Strides Toward New Treatments for MS, Flu and PTSD
TSRI and Takeda Pharmaceuticals Expand Collaboration
Institute Appoints Innovative Biotech Scientist to Cancer Biology Department

NEWS & VIEWS HOME
PAST ISSUES
KUDOS
SCIENTIFIC CALENDAR
CA AUDITORIUM EVENTS
CONTACT




FOLLOW US

Hugh Rosen Makes Strides Toward New Treatments for MS, Flu and PTSD

By Mark Schrope and Mika Ono

In 1940, racing to produce enough material for experiments that would transform modern medicine, a man named Norman Heatley, working in a lab at the Sir William Dunn School of Pathology at Oxford University, used bedpans to grow a fungus. Healey and his colleagues then extracted from the water on which the fungus grew a chemical named penicillin.

The leaders of that penicillin project, Howard Florey and Ernst Chain, were a critical intellectual influence on Hugh Rosen, a chemical biologist at The Scripps Research Institute (TSRI) who trained at the Dunn School. Rosen even conducted his own research in the very lab where Healey produced those initial penicillin samples.

So, it’s fitting that Rosen has chosen to dedicate his career to finding unique biological pathways that govern disease and to discover drugs that can influence those pathways. “To be honest,” says Rosen, “It’s bred in the bone.”

Rosen, who grew up in South Africa, earned an MD from Cape Town and a doctoral degree from Oxford. After a research fellowship at Jesus College, Oxford, he joined the pharmaceutical giant Merck in New Jersey, where he remained for 11 years.

Rosen found the work compelling, and he led the discovery and development of two intravenous antibiotics now used to treat infections in intensive care unit patients. However, pharmaceutical research and development was starting to move away from basic research in favor of emphasizing development. So, in 2002 he accepted an offer to join TSRI to continue and expand his work on inflammation and infectious diseases with the type of long-term research he felt was needed.

“I felt that the tools for chemical discovery had changed so that identification and study of important therapeutic problems were, for me at least, better achieved in an academic setting,” says Rosen. Judging by his successes at TSRI, it was a prescient move.

Toward a New Treatment for MS

As Rosen likes to point out, therapeutic advances require serendipity and the prepared mind. At TSRI, Rosen felt he had found an environment where clarity of vision was enabled by the cross-disciplinary contributions and excellent colleagues. “The multi-disciplinary scientific environment at TSRI is a force multiplier,” he says. “And nothing happens except for the hard work and efforts of my colleagues in the lab.”

Rosen and his TSRI colleagues began a string of notable successes, many focusing on vital cellular structures called S1P1 receptors. These are proteins found in the membranes of various cell types that regulate immune responses.

In one major effort, the scientists showed that one crucial role of S1P1 is controlling the flow of lymphocytes, a type of white blood cell, out of and then back into the lymph nodes. In multiple sclerosis (MS), the lymphocytes attack the protective sheaths around nerve cells in the central nervous system, sparking nerve misfires and scarring, and leading to pain and debilitation in MS sufferers. Further experiments suggested that modulation of S1P1 could be clinically useful in treating the disease.

Starting with a primary screen, devised and developed on the TSRI campus in La Jolla, California, and then carried out in the Molecular Screening Center at Scripps Florida, the team identified potential drug compounds that were novel activators of the S1P1 receptor. These molecules were then optimized by TSRI Professor Edward Roberts and colleagues, who produced a series of candidate molecules including one called RPC-1063. “Working with Ed is delightful,” says Rosen. “He is a gifted and intuitive medicinal chemist with an ability to integrate in multiple dimensions—I cannot stress enough how much I enjoy the scientific collaboration and meeting of minds.”

This work, funded by the National Institute for Allergy and Infectious Disease (NIAID) and the National Institutes of Health’s (NIH) Common Fund Molecular Libraries Initiative, has resulted in the first potential drug from this strategic NIH program to make it to clinical trials. RPC-1063 was licensed to Receptos, a company whose scientific founders included Rosen, Roberts and TSRI structural biologist Ray Stevens. RPC-1063 has now entered Phase II/III clinical trials for MS and ulcerative colitis, an inflammatory bowel disease.

Recently, Rosen, Stevens, and colleagues in their labs and at Receptos determined a detailed three-dimensional structure of the S1P1 receptor. Receptors activate when certain molecules in the body or drugs bind to them. In the case of S1P1, activation leads to a cascade of biochemical changes that produce clinically useful alterations to the immune system. The structure showed the pocket in the protein where this binding occurs is very difficult to access, so that activating molecules can only bind with the receptors by moving through a cell’s membrane—a previously unrecognized mechanism.

High Points

RCP-1063’s success to date is a new high point for Rosen, who has experienced several, any one of which would be enough to label a career a success. But Rosen says the title he values most is husband and dad. He’s the father of two now-grown boys, ages 21 and 18.

Rosen is also fond of the outdoors, and he’s an especially passionate fly fisherman who enjoys the fine art of tying his own flies. Research demands keep him from pursuing that passion as much as he might like, but he does take occasional trips with TSRI colleagues. And if they happen to end up at a conference in Montana, for example, they might just tack on a few extra days to wade some streams.

TSRI Professor Michael Oldstone is one of Rosen’s fishing and research collaborators. “He’s terrific,” says Oldstone of Rosen, “I call him a philosopher-scientist. He’s intellectually very smart and he’s philosophically very interesting. He’s also a rather good fly fisherman.”

The two like to discuss everything from politics to literature to gypsies and fishing flies. They also share a love of Sherlock Holmes and try to follow some of the famous sleuth’s dictums in their research, such as, “It’s a capital mistake to theorize before one has data.”

Another favorite quote is, “The game is afoot.” That’s not a bad description of some of their work together on a different aspect of S1P1 receptor activity, a long-term collaboration well on its way to generating more new drug candidates.

Influenza and Cytokine Storms

Oldstone and Rosen are exploring a different aspect of S1P1 activity that may well prove as fruitful as the MS work. S1P1 receptors found in the cells on the inside of blood vessels control the flow of small signaling proteins known as cytokines. Viruses such as influenza trigger the release of cytokines, which, in turn, trigger immune system responses, including inflammation.

In some cases, this effect is magnified with a release of an overabundance of the molecules, known as a cytokine storm. These storms can cause the lungs to fill with fluid and white blood cells, potentially even leading to death. This type of reaction is thought to be a cause of the 1918 to 1919 influenza pandemic and to play a major role in swine and bird flus.

In exploring the cytokine storm, Rosen, Oldstone and their colleagues were able to show that this phenomenon is a separate effect, rather than a part of the normal impact of viral cell infection, as previously thought. And they’ve shown that by manipulating S1P1 receptors in blood vessels, they can alter the cytokine release enough to allow the mouse immune system to fight off influenza, dramatically improving survival rates.

With this new understanding, team members expect they’ll be able to find a compound that will change cytokine release to a level that protects vulnerable patients from cytokine storms but doesn’t eliminate S1P1’s positive immune effects. Such drugs might be used in conjunction with other treatments, such as Tamiflu, that target the influenza infection itself.

“Immune responses are regulated on a knife edge,” says Rosen, “The biological consequences of even small changes to S1P1 activity are profound—that’s one of the reasons we’ve studied it.”

More Promising Compounds

Rosen says there’s also great potential in work with other receptors in the S1P group. He is working with Roberts to study a receptor that binds with naturally occurring compounds similar to drugs such as opium. This receptor’s activity plays critical roles in controlling anxiety and depression.

Rosen and Roberts have already identified promising compounds that may regulate this activity as a potential treatment for post-traumatic stress disorder and other anxiety-related conditions. They are now working to establish a development plan for the compounds.

“What we’ve done with RPC-1063 is not an isolated event,” says Rosen, “Because of the human talent at TSRI we have the ability and the scientific infrastructure to do this more than once. The unique advantages we have in terms of scientific environment, colleagues and facilities means our impact on human health can be disproportionately large.”



Send comments to: press[at]scripps.edu



rosen
“Immune responses are regulated on a knife edge,” says Professor Hugh Rosen. “The biological consequences of even small changes to S1P1 activity are profound—that’s one of the reasons we’ve studied it.” (Photo by BioMedical Graphics.)