Top Stories - Infectious & Inflammatory Diseases

Sumit Chanda, Ph.D.
How key immune sensors arrive...

Sanford-Burnham researchers identified 190 genes crucial to the function of TLR7 and TLR9, cellular...

Dr. Jaime Green
Basic research bolsters...

While treating bone marrow transplant patients in the clinic, Dr. Jaime Green became concerned about...

Drug-like chemical compound LTV-1 (foreground) blocks the action of mutant LYP protein in human immune cells, providing a potential new therapeutic for autoimmune diseases.
New insight into mechanisms...

Dr. Lutz Tautz and colleagues show how the breakup of two proteins interferes with the immune system...

Dr. Jorge Moscat and Dr. Maria Diaz-Meco
Fueling cancer cell growth

May is National Cancer Research Month, created by Congress in 2007 to recognize the American...

Breast cancer research: from bench to bedside—and back

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Sanford-Burnham was recently honored with a visit by Irene Andrulis, Ph.D., a molecular biologist, senior investigator, and co-head of the Fred. A. Litwin Centre for Cancer Genetics at the Lunenfeld Research Institute in Toronto. Andrulis is also a world-renowned breast cancer researcher and her goal is to discover clinically relevant molecular alterations in breast cancer that can be used as prognostic and predictive factors.

So far, Andrulis and her team have been very successful. They developed a genetic test that can identify women with a particular type of breast cancer who are at increased risk of recurrence of the disease. The study was the first prospective study on the importance of a protein called HER2 (short for human epidermal growth factor receptor 2) in breast cancer recurrence. In about one of every five breast cancers, an increase in the number of copies of the gene causes cells to produce excess HER2, which in turn promotes cancer cell growth. In 1998, pharmaceutical company Genentech won FDA approval for a drug called Herceptin, which treats HER2-positive breast cancers by interfering with the receptor.

Andrulis is now interested in exploring the molecular cross-talk between cancer cells and the immune system. That’s partly what brought Andrulis to Sanford-Burnham—to discuss this research avenue with an old friend from graduate school, Carl Ware, Ph.D., director of Sanford-Burnham’s Infectious and Inflammatory Disease Center.

New insight into mechanisms behind autoimmune diseases suggests a potential therapy

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Autoimmune diseases, such as Type I diabetes and rheumatoid arthritis, are caused by an immune system gone haywire, where the body’s defense system assaults and destroys healthy tissues. A mutant form of a protein called LYP has been implicated in multiple autoimmune diseases, but the precise molecular pathway involved has been unknown. Now, in a paper published March 18 in Nature Chemical Biology, Sanford-Burnham researchers show how the errant form of LYP can disrupt the immune system. In doing so, they also found a potential new therapy for autoimmune diseases—a chemical compound that appears to inhibit this mutant protein.

How key immune sensors arrive at the front lines of infection

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In a healthy immune system, invading pathogens trigger a cascade of alerts and responses to fight off the infection. Sensors called toll-like receptors, or TLRs, act as one of the first lines of defense. Two of these sensors, known as TLR7 and TLR9, specifically recognize and respond to microbial RNA and DNA, respectively. But what determines how these TLRs get where they need to be and sound the alarm for pathogen infection? To answer this question, a team led by Sanford-Burnham’s Sumit Chanda, Ph.D. and colleagues used a technique known as RNA interference (RNAi) to silence each gene in the human genome one by one. In doing so, they were able to determine which genes are crucial for TLR7 and TLR9 functions and which are dispensable. In their study, published March 14 in Cell Host & Microbe, the team identified 190 proteins that contribute to our ability to detect and respond to microbial infection. These findings could help scientists develop new strategies to manipulate immune responses for treatment of autoimmune disorders and microbial infections.

Assembling to attack infection

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Each day, we are confronted by millions of bacteria, all attempting to invade our bodies and cause infection. It’s the job of the body’s immune system to defend against these little invaders. In order to fight off bacteria (as well as viruses and cancerous cells), the immune system has an arsenal of weapons at its disposal. One of these weapons is the complement system. Complement is so important for fighting infections that people who have mutations in certain complement proteins or their regulators often suffer from frequent bacterial infections.

How the body fends off bacteria

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To invade organisms such as humans, bacteria make use of a protein called flagellin, part of a tail-like appendage that helps the bacteria move about. Now, for the first time, a team led by scientists at The Scripps Research Institute and Sanford-Burnham Medical Research Institute has determined the 3D structure of the interaction between this critical bacterial protein and an immune molecule called TLR5, shedding light on how the body protects itself from such foreign invaders.

The study, published February 17 in Science, not only helps decipher the molecular mechanism underlying TLR5 recognition and function, but it also advances knowledge that’s key to the design of new therapeutics.

10 years of science & counterterrorism

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As the United States pauses to observe the 10th anniversary of the September 11th terrorist attacks, we reflect on the research advances that contribute to new counterterrorism measures—understanding anthrax, for example—and the health of our soldiers in Iraq and Afghanistan, including under-studied conditions such as traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). Here are a few examples, and these only cover discoveries made at Sanford-Burnham since September 11, 2001. Can you think of more? Please share your thoughts in the comments below.

Witnessing the birth of a new scientific field

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Each year, Sanford-Burnham’s annual symposium features a different topic. Past years have focused on infectious diseases, RNA biology and other disciplines. This year, however, the 33rd annual meeting introduced an entirely new scientific field: Structural Systems Biology.The June 7 symposium was opened with a welcome from Dr. Adam Godzik, director of Sanford-Burnham’s Bioinformatics and Systems Biology Program and one of the meeting’s co-organizers. “When I tell people I am a biologist, they think of organisms,” he said, showing a picture of zoo animals and wildflowers. “But I actually work on the parts.” With that, he flipped to cartoons of genes and proteins.

Structural Biology generates data related to the physical shape of these individual proteins– how they’re folded, how they form complexes with other proteins, what they look like in 3D. That information helps answer questions about how proteins perform their duties –facilitate chemical reactions, carry molecular signals in and out of cells, control cellular movements, etc. Understanding a protein’s structure and function helps identify its role in human health and disease, as well as its potential as a therapeutic target.

But, as Dr. Godzik went on to explain, these individual components all exist as part of a system. They are each a “node” in a network that controls an aspect of cellular behavior – turning genes on and off, communicating with other cells, metabolizing nutrients or performing any number of other processes. Systems Biology focuses on all these components and the interactions among them. Scientists in this field aim to create meaningful models capable of quantifying and predicting these complex cellular processes.

Fueling cancer cell growth

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May is National Cancer Research Month, created by Congress in 2007 to recognize the American Association of Cancer Research (AACR) for its contributions to the field. To honor AACR and highlight some of the important cancer research being done at Sanford-Burnham, we will be posting a series of articles on the ongoing work in our National Cancer Institute-designated Cancer Center. The vast majority of this research is made possible by funding from the National Institutes of Health (NIH), which includes the National Cancer Institute (NCI).

Fifty years ago, cancer biologists were convinced that understanding cancer metabolism would lead to a cure, until discoveries about cancer genetics shifted the research focus in other directions. But now the pendulum is swinging back , renewing interest in metabolism’s role in cancer.

Dr. Jorge Moscat and Dr. Maria Diaz-Meco, who both recently arrived at Sanford-Burnham from the University of Cincinnati, have been working together for more than twenty years to understand the mechanisms that allow cancer cells to grow at such a breakneck pace. Their investigations have led them to a network of proteins characterized by having PB1 domains. This  network of proteins controls inflammation, how cells communicate with each other, and how they sense nutrients—all key drivers of cancer growth.

For example, the PB1-containing scaffold protein p62 regulates an enzyme called protein kinase C zeta (PKCZ), which is often missing in human cancers. PKCZ is a tumor suppressor that prevents inflammation and ensures that cells remain sensitive to nutrient levels. Cells without PKCZ get reprogrammed to endure food scarcity.

“If they lack this gene, they don’t care if glucose is unavailable,” says Dr. Moscat, “they just use other nutrients.”

Systems Biology: anatomy of a network

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People often say that a city is like a living organism. Sanford-Burnham researchers are taking this analogy literally and developing new approaches to understanding problems in biology and medicine – systems biology. A single street isn’t that complicated – cars simply drive up and down. But the system gets much more complex when you add hundreds or thousands of vehicles, intersections, lights and intricate traffic rules. That’s when you get a lot of “non-local” effects. Repairs on one section of highway motivate drivers to choose alternate routes, which creates a traffic jam in a different part of town.Traditionally, researchers sought to understand isolated aspects of a cell’s biology.What does this protein look like? What does it do? This was a bit like trying to understand a city’s unique traffic patterns by separately studying individual streets. Systems biology takes a more holistic approach, attempting to understand the larger picture of how all (or most) of the components in a cell or organism function together. Dr. Adam Godzik, who directs Sanford-Burnham’s Bioinformatics and Systems Biology Program, is one of several researchers leading the way towards this “big picture” understanding.

“We have 20,000 genes in any given cell and at any given moment 7,000 of them will be transcribed and translated into proteins,” says Dr. Godzik. “And there is something like several million proteins in a cell. So how do we describe systems like this?”

Leaders among peers

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Sanford-Burnham scientists are leading several exciting symposia over the next few months. Please follow the links below for more event and registration information.

2011 Signaling, Metabolism and Hypoxia Symposium
Chaired by Dr. Ze’ev Ronai

May 6, 2011, 2:00 – 5:30 p.m. (PDT)
Sanford-Burnham Medical Research Institute
10901 North Torrey Pines Road
La Jolla, California

2011 Glycobiology Gordon Research Conference
Chaired by Dr. Hudson Freeze

May 8 – 13, 2011
Il Ciocco Hotel
Lucca (Barga), Italy

Sanford-Burnham’s 33rd Annual Symposium: Structural Systems Biology
Chaired by members of the Bioinformatics and Systems Biology Program
Drs. Adam Godzik, Dorit Hanein, Andrei Osterman, Niels Volkmann

June 7, 2011, 9:00 a.m. – 5:15 p.m. (PDT)
Hilton La Jolla Torrey Pines
La Jolla, California

Cardiomyocyte Regeneration and Protection
Chaired by Dr. Mark Mercola

Sponsored by Abcam
June 20 – 21, 2011
Hilton La Jolla Torrey Pines
La Jolla, California

2011 Molecular Therapeutics of Cancer Research Conference
Chaired by Dr. Sara Courtneidge

Sponsored by the Cancer Molecular Therapeutics Research Association
July 10 – 14, 2011
Asilomar Conference Center
Pacific Grove, California

Seventh General Meeting of the International Proteolysis Society
Chaired by Dr. Guy Salvesen and Dr. Matthew Bogyo

October 16 – 20, 2011
Hilton San Diego Resort and Spa
San Diego, California

World Health Day 2011: No Action Today, No Cure Tomorrow

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Editor’s update, April 8, 2011: It’s not too late – you can still find audio and slides from this event here.

Today, World Health Day 2011, the World Health Organization (WHO) calls on governments and stakeholders to implement the policies and practices needed to prevent and counter the emergence of microorganisms resistant to current therapies.

Antibiotics are among the most important advances in human health, but their use and misuse over the past 70 years have increased the number and types of microorganisms resistant to antibiotics – resulting in deaths, greater suffering and disability and higher healthcare costs. The challenge posed to the pharmaceutical and biotechnology industries is loud and clear – only seven new antibiotics have been introduced since 2003.

A press conference will be held this afternoon at Sanford-Burnham’s La Jolla, Calif. campus to feature innovators in antibiotic research and development.

WHAT: Innovation in Antibiotics: Medicine for the Next Wave of Bacterial Infections

WHEN: Thursday, April 7, 2011 at 2:00 p.m. – 3:00 p.m. U.S. Pacific Time

WHERE: Sanford Children’s Health Research Center, Sanford-Burnham Medical Research Institute, 10905 Road to the Cure, San Diego, CA 92121 or via webcast.

Seeing is believing

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Life is complicated. Even one tiny cell has a lot going on at any given time, even when things are running smoothly. Normal cellular functions and their emergency responses (like to injury or infection) are mostly carried out by proteins. Proteins tell other proteins what to do by carrying signals, tagging one another with chemical groups, chewing up other proteins or helping assemble new ones, and so on. They also help orchestrate which genes are turned on or off and when.

The cell itself is constantly sensing and reacting to constant environmental fluctuations, as are the individual proteins and other molecules. So how do you connect these two things?

“You can see a cell by eye, using a standard microscope. But you can’t see individual molecules that way,” explains Sanford-Burnham’s Dr. Dorit Hanein. “A cell is on the micrometer scale (one-thousandth of a millimeter), while an individual molecule is on the nanometer scale (one-millionth of a millimeter). That’s like the difference between walking the 500 miles from here [San Diego] to San Francisco, versus walking from here to the moon.”

What Dr. Hanein and other scientists need are techniques that allow them to look not just at the moon, but at the earth, the moon and everything in between.

Writing the book on protein structure

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Whether online or in print, a scientific paper typically winds up sandwiched between two equally important – but completely unrelated – articles. But a scientific journal called Acta Crystallographica Section F recently did something completely different. They ran an issue entirely devoted to research from a single group – the Joint Center for Structural Genomics (JCSG), one of the NIH’s Protein Structure Initiative centers. JCSG is led by Dr. Ian Wilson at The Scripps Research Institute, with Dr. John Wooley at UC San Diego and Sanford-Burnham’s Dr. Adam Godzik leading the bioinformatics and data management part of the project.It’s unusual for a journal to dedicate an entire issue (35 papers total) to one research group, but that’s not the only thing that made this unique.

Quick peek at Sanford-Burnham

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A video by high school student Daniel Osterman, son of Sanford-Burnham investigator Dr. Andrei Osterman, takes a quick look at the basic biomedical research being conducted at the Institute. In particular, the piece focuses on Dr. Hudson Freeze’s research. Dr. Freeze recently organized Sanford-Burnham’s 2nd Annual Rare Disease Symposium, and studies a group of rare conditions called Congenital Disorders of Glycosolation (CDG), in which sugars fail to attach properly to proteins.

Basic research bolsters clinical care

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Bone marrow (stem cell) transplants have been a life-saving tool for patients with leukemia and lymphoma. However, like most cancer treatments, they come with significant risk. Patients can be immune-compromised for as long as a year, making them vulnerable to pathogens that most people would fight off easily.

One such pathogen is cytomegalovirus (CMV), a member of the herpes virus family. People usually get CMV early in life (from childhood to early adulthood), experience mild symptoms and move on. However, for immune-compromised patients, CMV can be a serious and deadly complication.