The University of Chicago can fill a couple of classrooms with all of the Nobel Laureates affiliated with the school, from Milton Friedman to Saul Bellow to Barack Obama. After Monday, a third room might have to be opened up, as Pritzker School of Medicine graduate Bruce Beutler became the 86th member of the exclusive club. Beutler, who graduated from our medical school in 1981, was honored with this year’s Nobel Prize in Physiology or Medicine, along with Jules Hoffman and Ralph Steinman. The three scientists were credited with advancements in the field of immunology that have paved the way for new strategies fighting infections, cancer, and other diseases.

“I thought it was possible, but nobody can count on winning the Nobel Prize, so I’m just ecstatic,” Beutler, now at University of Texas Southwestern Medical Center, told the Chicago Tribune.

In the confusing calculus of the Nobel, Beutler and Hoffman split half of the total award for research on the innate immune system, known as the first line of the body’s defenses against infectious invaders. In the late 1990’s both scientists’ laboratories were looking for immune receptors that respond to signals on the surface of bacteria - Hoffman looking in fruit flies with genetic mutations, Beutler in mice. Within two years of each other, Hoffman discovered a fly mutant named “Toll” involved in the response to an infection, and Beutler found a similar gene in mice for a receptor (named, appropriately, the “Toll-like receptor”) that binds to lipopolysaccharide (LPS), a signal on the surface of bacterial cells.

These findings opened the floodgates to learning about new players in the innate immune system, including the discovery of a dozen more Toll-like receptors that recognize various pathogen signals - what some call “the eyes of the immune system.” Clinically, mutations in these genes can lead to either increased susceptibility to infection (if the innate immune system is too weak) or autoimmune and inflammatory disorders (if the innate immune system is too strong). Drugs that target this system might therefore be promising for the treatment of many different diseases.

“I think the most hopeful line or realm is in inflammatory and autoimmune disease,” Beutler told the Nobel website. “Inflammation is something that evolved to cope with infection, and when we speak of sterile inflammatory diseases like rheumatoid arthritis and autoimmune diseases like lupus, probably some of the same pathways are utilized. It may very well be that by blocking TLR signalling you’ll have very specific therapies for those kinds of diseases.”

Beutler said that he received the news in bed, waking up in the middle of the night and reading an e-mail on his cell phone.

“I was a little bit disbelieving, so I went downstairs to look at my laptop,” Beutler said. “I went to Google News and saw my name there, so I knew it was real.”

At the University of Chicago Medical Center campus, the news quickly spread among former colleagues and teachers of Beutler, as well as scientists that who work in his field.

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In the 2000s, a new kind of genetic experiment was born: the genome-wide association study, or GWAS. If geneticists could recruit enough people with a particular disease and compare them to an equal number of disease-free controls, they believed GWAS would point the way to common gene variants associated with disease risk and novel biological pathways. One of the strengths of GWAS was that it was hypothesis-free, an unbiased comparison that could reveal surprising risk-associated genes that had not occurred to scientists in the past. More than 1,000 GWAS studies have been conducted to date, on diseases ranging from diabetes to Parkinson’s disease to Crohn’s disease to various types of cancer.

While these studies have identified thousands of gene variants (called single nucleotide polymorphisms, or SNPs) associated with disease risk, they can still only explain a small fraction of the heritability of disease. Some scientists have thus moved on from GWAS to the next wave of genetic studies, including whole-genome sequencing to look for rare variants and gene-environment interaction studies. But some geneticists think the field may be moving too quickly onto the next big thing, and that there remains value in the volumes of GWAS data collected over the last decade. A second generation of GWAS is taking place, where the data from the first round is approached in new ways to find previously hidden gems of information.

In two recent studies, assistant professor of health studies Brandon Pierce applied this Reuse/Recycle/Reduce philosophy to GWAS data on pancreatic cancer risk, a disease where genetic and biological explanations are particularly lacking. For both experiments, Pierce bended the “hypothesis-free” rule of GWAS in order to narrow the field of gene variant candidates and allow for a more selective scan of pre-existing data. By reducing the number of candidates from the ~550,000 of a full GWAS, the statistical threshold for confirming a SNP association with risk can be set lower. If the original GWAS experiments were the equivalent of looking for a needle in a haystack, the new techniques are a much less daunting task, he said.

“You conduct fewer tests, so the haystack is smaller,” Pierce said. “In all of the tests you are conducting, you know the SNPs are biologically meaningful, whereas in a typical GWAS, a large percentage of the SNPs may have very little to do with human biology.”

In the first study, published in March in Cancer Causes & Control, Pierce adapted a connection discovered by epidemiology studies to his genetic scan. Patients with type 2 diabetes were measured to have elevated risk for pancreatic cancer - a logical relationship given that diabetes is primarily a disease of the pancreas. Pierce took 37  SNPs associated with type 2 diabetes and tested them in the GWAS data collected by a previous study of pancreatic cancer. None of the SNPs tested showed a strong association with pancreatic cancer, though two new gene variants produced suggestive evidence of an association. The results suggested that the biological link between type 2 diabetes and pancreatic cancer may not be as strong as the epidemiology data indicated.

“We didn’t find any major associations that popped out at us from the diabetes study, so the conclusion was that these established genes for type 2 diabetes don’t seem to have a big effect on pancreatic cancer risk,” Pierce said.

But a second study, published in Cancer Research, would lead Pierce almost full circle. This time around, he ran the pancreatic cancer GWAS data through what he dubbed a “pleiotropy scan,” testing only SNPs previously demonstrated to have a biological effect in humans. For many of the more than half-million SNPs typically tested in a GWAS, scientists have yet to discover a linkage to any disease or biological effect, suggesting that these markers may sit without effect in the long gaps between protein-encoding genes in human DNA. Like the first study, limiting his GWAS tests to only these SNPs (1,087 in this case) allowed Pierce to pick up more subtle associations than in a full-blown GWAS.

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Welcome to pilot episode 2 of our Medical Center research news podcast. We’re keeping the water wings on for now as we continue to refine the format and discover all the technical struggles inherent in podcasting, but please do listen and give us feedback on how we’re doing - and if you have good ideas for a name.

In this episode, we talk to J. Martin Leland about the Stay in the Game event and preventing injuries for baseball, golf, and tennis season. Dianna Douglas reports on the oldest patient to ever receive Whipple surgery at the University of Chicago Medical Center, talking with Kevin Roggin and William Dale about the procedure. And Rob Mitchum reports from a news conference held last weekend by Sen. Dick Durbin about the impact of potential cuts to the National Institutes of Health budget currently being debated in Congress. Thanks for listening!

University of Chicago Research Podcast Episode #0.2 by robmitchum

[If you missed episode 0.1, you can listen here.]

Dr. Tanguy Seiwert at the 15th Annual Phase II Symposium (photo by David Christopher)

Phase II clinical trials are the clutch moments of translational science, the place where the star medical advances are separated from the disappointing pretenders. Backed by years of promising laboratory findings and a Phase I trial to assess toxicity, a Phase II trial is the first chance for researchers to see whether a new drug or treatment will fly in the real world by showing effectiveness in the patients for which it was intended. Though the number of subjects typically remain in the dozens or low hundreds, a promising result can send the treatment onward to larger trials and (hopefully) eventual approval and acceptance, while a lackluster performance usually sends researchers back to the drawing board.

That tipping point tension was the backdrop for the 15th annual symposium for the University of  Chicago Phase II Consortium, a national group of 11 centers working together to recruit patients for cancer clinical trials. Because the specifications for eligible study subjects are often very narrow, casting a wide net for patients allows treatments to be tested faster - and if the trial is successful, to reach approval faster, said Walter Stadler, professor of medicine at the University of Chicago Medical Center and director of the network. Friday’s symposium allowed for a progress report, updating the consortium participants on clinical trials already underway or in the application stage, so that clinicians are aware of trials potentially available to their patients.

The symposium is also a chance to compare notes on how to best design a clinical trial so that a treatment’s effectiveness can best be determined. With speakers from the University of Chicago Medical Center, the University of Michigan, the University of Maryland, and the MD Anderson Cancer Center at the University of Texas, it was a lightning-round survey of what cancer trials look like in 2010 and how the field is changing as personalized medicine inches toward becoming reality. Here are some of the themes I pulled from the symposium - from an outside perspective, these topics seemed to be the big stories going forward in modern clinical trials.

Biomarkers are a Big Deal

Clinical trials, by their very nature, must homogenize a patient population, combining people with different subtypes and stages of disease into the large pools necessary to analyze with statistics. But it is becoming increasingly accepted that most cancers are actually made up of several different diseases with different causes. Furthermore, each of these cancer types will respond differently to a particular treatment. Complicated, yes, but uncovering which treatments are best for each cancer subtype will pave the road to more effective, personalized cancer care.

Those answers may already be hidden in the data of a clinical trial, if researchers can figure out why specific patients respond better to an experimental treatment than others. The best way to do this - for now - is to collect tons of “biomarkers” about each patient - blood samples, genetic information, tumor biopsies, and even clinical measurements. As such, nearly all of the trials described at the symposium included plans to preserve biomarkers from patients that can be used for further study. Michael Maitland, assistant professor of medicine at UCMC, even talked about using potentially harmful drug side effects, such as hyperglycemia and hypertension, as rapid feedback biomarkers to assist in finding the appropriate dose of drug to give each patient.

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As you’ve no doubt heard by now, actor Patrick Swayze died yesterday at age 57 after a battle with pancreatic cancer. In March, blog founder Jeremy Manier interviewed University of Chicago Medical Center physician Dr. Irving Waxman about pancreatic cancer, one of the deadliest and hardest to treat cancers. The challenge, as Waxman explains, is twofold - the symptoms of pancreatic cancer typically do not present until the disease is in advanced stages, and the organ’s location deep behind the abdomen makes makes surgical treatment more difficult. The statistics are sobering: even with treatment, only about 5% of those diagnosed with pancreatic cancer survive 5 years.

But doctors are hopeful that the momentum could be shifting in the battle against pancreatic cancer. “Smart chemotherapy” with less severe side effects, new imaging techniques to detect pancreatic cancer in its early stages, and new drug treatments - a study released just yesterday found that an already-existing diabetes medication may be effective in combination with chemotherapy for selectively killing tumor cells.

Here again is the interview with Dr. Waxman where he discusses the clinical challenges of pancreatic cancer and some of the promising frontiers of research to reduce those challenges.

Pancreatic cancer has made an unusual amount of news lately, with the very public struggles of Supreme Court Justice Ruth Bader Ginsburg, Apple Inc. CEO Steve Jobs, and actor Patrick Swayze. The diagnosis can be dire news; the mean survival time following diagnosis is often measured in months, though that can vary depending on how far the tumor has progressed.

I recently talked with Irving Waxman, M.D., about why the disease is so difficult to treat, and how he finds hope in this relatively bleak arena. Here’s a snippet:

Q: We’re attuned to thinking that pancreatic cancer is a very bleak diagnosis, and clearly it is. So how do you and patients keep up hope in a seemingly hopeless field?

Waxman: That’s a very good question. I think that chemotherapy today has entered in my opinion, in the last decade, what we call smart chemotherapy. We’ve stopped using some of the “one agent kills everything” drugs, and now we try to be a little bit smarter, doing targeted therapy that affects a specific part of the growth. Every day there are new protocols, new clinical trials, and we have some going on here. The new therapies may not cure the disease, but they can definitely slow its progression. And with better imaging modalities we can now detect growths at a smaller size.

But in general your point is well taken. It is still a devastating disease. There is a wonderful organization, Pancan [the Pancreatic Cancer Action Network], and they do an amazing job of giving support and information for the patients, and they are also involved in philanthropy and research grants. It’s really a tremendous organization that gives a lot of hope for patients, and that’s an important resource.

Below you can see more of Waxman’s explanation of why pancreatic cancer is so difficult to detect and treat. He describes the organ’s location as a highway junction within the body where numerous arteries and veins crisscross, making it difficult to operate if a tumor is locally advanced. He also discusses the encouraging prospects for better early screening of the disease.

There’s a fine pancreatic cancer piece in the Chicago Tribune today by Robert Mitchum, a friend of the blog who recently got his Ph.D. in neurobiology at the University of Chicago. Rob uses a new study on a potential method of detecting pancreatic cancer to talk about the urgent need for such early screening methods. Pancreatic cancer typically causes few symptoms until a relatively late stage, when the tumor has spread and treatment options are limited. The statistics are stark - each year, more than 37,000 people get pancreatic cancer and 34,000 die from it.

Despite the grim numbers, some people do survive, and new efforts at early detection could boost their chances further. What I find amazing is how patients - and doctors - find the hope to continue their fight in the face of such daunting odds. How do you muster the energy for a struggle you know you’re unlikely to win, though future progress may depend on lessons learned from your failure? Many diseases that are now treatable once seemed hopeless. Most of those successes are built on knowledge gained from countless tragedies.

We hope to write a lot about pancreatic cancer in this blog. I’ll return later this week to the subject of finding hope in a seemingly hopeless field.