Many important medical discoveries of the first half of the 20th century involved metabolism, but by the 1960s scientists had shifted their attention to understanding how genetic mutations cause disease. They thought that illnesses like cancer caused metabolic changes, but didn’t think that metabolism caused disease. Then in 1996, a group of scientists reported that mitochondria play a signaling role in conditions leading to cell death and, practically overnight, the organelle best known as the cellular power plant, regained the spotlight.
Navdeep Chandel, PhD, David W. Cugell Distinguished Professor in Medicine-Pulmonary and Cell and Molecular Biology, was a doctoral student in cell physiology at the University of Chicago when he heard the news.
“My soccer buddy Craig Thompson (now president of Memorial Sloan-Kettering Cancer Center) told me about it, and I was skeptical at first,” he says. After reading the paper, Chandel says he became excited about the likelihood that mitochondria played a signaling role not only in cell death, but also in a range of physiological conditions.
Signaling is part of the complex system of communication that governs cellular activity. To coordinate activities including growth, repair, immune response and normal maintenance, cells release substances that transmit information both inside and between cells. Errors in information processing can lead to aberrant activity and disease.
For decades, scientists have been analyzing signaling pathways in the hope of developing effective therapies. Today, Chandel says, “accumulating evidence suggests that metabolism regulates signaling pathways and gene expression, and metabolic changes underlie conditions including diabetes, neurodegeneration, cancer, drug-induced liver damage, and cardiovascular and inflammatory diseases.” He believes that diet and environmental changes are at the root, and metabolism senses these changes.
An undergraduate work-study gig in an organ transplant lab at the University of Chicago, where scientists were trying to improve organ preservation, first piqued his interest in metabolism. In 1996, Chandel was finishing his thesis on the oxygen dependence of the mitochondrial protein cytochrome c oxidase with Paul Schumacker, PhD, now Patrick M. Magoon Distinguished Professor Pediatrics at Feinberg. An outlier among his fellow graduate students, Chandel though that “there might be interesting biochemistry under limiting oxygen conditions, such as with tumors, ischemic disease, and during in-utero development.”
Research Finding Challenges Orthodoxy
Just two years after earning his doctorate, Chandel and Schumacker published a groundbreaking finding about mitochondrial signaling; however, few of their fellow scientists believed it was correct. “The initial response was ‘Huh?’ followed by ‘Nah!’” he says. Today, the finding that mitochondrial reactive oxidant species (ROS) are signaling molecules that help cells sense and adapt to low-oxygen conditions is widely accepted.
The idea that ROS facilitate healthy cell function countered leading theories about their role in aging and disease. The free radical theory of aging proposed that damaged mitochondria produce excessive amounts of ROS that cause tissue damage and aging. The idea that antioxidants could promote health, prevent disease and slow aging, first advanced in the 1950s, had given rise over subsequent decades to a flood of antioxidant research.
“Everybody became an expert on antioxidants. To this day, my mom tells me to take vitamin C when I get sick,” Chandel admits. “Yet, after decades of research, there is scant clinical evidence showing that antioxidants are effective against age-related diseases.” Conversely, there is a growing body of research, Chandel says, suggesting that “a little oxidative stress may be a good thing and that excessive use of antioxidant supplements or drugs could cause harm.”
A Lab is Born
Some of this research is conducted by Chandel and an enthusiastic cadre of Northwestern Medicine collaborators across disciplines including immunology, rheumatology, allergy, and dermatology. He joined the Division of Pulmonary Medicine in 2000 to establish a laboratory dedicated to understanding how mitochondria function as signaling organelles and how metabolism dictates biological action. Among the most significant findings are that ROS regulate metabolic activation, stem cell differentiation, and also activate infection-fighting T-cells.
Jacob “Iasha” Sznajder, MD, chief of the Division of Pulmonary Medicine, attributes the lab’s success to Chandel’s deep scientific knowledge and his passionate personality.
“Nav exudes enthusiasm. He not only is brilliant, but also is great fun. He’s kind, a great mentor to students, and a wonderful and generous collaborator,” says Sznajder, who recently received Northwestern’s Ver Steeg award for mentoring graduate students.
Of Sznajder, Chandel says, “He is the perfect chief-enthusiastic, positive, engaged-and gives me complete scientific freedom.” Chandel also praises his mentors Schumacker and Thompson, with whom he continues to collaborate.
Cancer Research Returns to its Roots
The insights that Chandel and his counterparts have gained into mitochondrial signaling have led to a sea change in cancer research over the past 10 years. The emerging field of cancer metabolism returns cancer research to its roots. In the 1920’s, Nobel scientist Otto Warburg reported that cancer cells proliferate by converting glucose to energy without oxygen, whereas normal cells generate energy (in the form of adenosine triphosphate) more efficiently through cellular respiration. He erroneously considered cancer a mitochondrial dysfunction, but by the mid-1900s most scientists had concluded that cancer’s voracious appetite for glucose was merely a consequence of the disease.
Recent research, however, suggests that mutations alter metabolic pathways and drive tumor growth, so experts seek to develop drugs that target cancer cell-specific metabolic pathways. “Most people still think metabolic changes are late events in disease,” Chandel explains, “but the new hypothesis is that metabolic changes precede genetic and phenotype changes. If metabolism is leading the way, then that’s where you should intervene.” His recent research demonstrates that mitochondrial metabolism is essential for tumor formation.
Chandel cautions that this research faces formidable challenges. Scientists must be careful to preserve metabolic pathways that immune cells, for instance, rely on to proliferate rapidly; and since cancer cells, like all cells, are adept at finding alternative metabolic pathways, targeting just one is unlikely to be effective.
Diabetes Drug Targets Cancer?
Chandel’s lab is elucidating how the drug metformin, used to reduce high blood-sugar levels caused by diabetes, could also be used to treat cancer. Epidemiology studies show that people on metformin experience lower incidences of multiple types of cancer and slower tumor growth. Clinical trials are underway to determine this drug’s potential as an anti-cancer agent. Since insulin causes cancer cells to divide, the slower rate of progression may simply be the result of metformin reducing insulin. The Northwestern Medicine researchers, with colleagues at the University of Tampere, Finland, however, have been studying if metformin directly targets cancer cells.
This year, they discovered that the drug inhibits cancer cell mitochondria from producing energy in the form of adenosine triphosphate during cellular respiration. Cancer cells, however, have a propensity for converting glucose to energy without oxygen. The researchers further determined that metformin inhibited cancer cell division when glucose was available, but killed the cells when they were deprived of glucose. They also reported that metformin reduces the activation of pathways that help cells survive low-oxygen conditions, a characteristic trait of many tumors.
Understanding Lung Disease and Injury
In the lab’s home base of Pulmonary Medicine, Chandel and his collaborators are gaining insight into the biological mechanisms that underlie lung injury and fibrosis. He and long-time collaborator Scott Budinger, MD, associate professor in Medicine-Pulmonary and Cell and Molecular Biology, found that mitochondrial-generated oxidants in the lung are responsible not only for injury and fibrosis, but also for the positive consequence of activating signaling pathways that help cells adapt to environmental stress.
“This work explains why repeated efforts to give nonselective antioxidants to patients with lung injury and fibrosis have failed in clinical trials and also offers new avenues for more targeted therapies,” Dr. Budinger says.
The researchers theorize that they may be able to design more effective therapies for patients with acute respiratory distress syndrome (ARDS) or lung fibrosis, by targeting damaging oxidants and preserving low levels of signaling oxidants. “These studies also suggest that it may be beneficial to induce oxidant generation in the cell to promote cellular adaptation before a planned environmental stress like a surgical procedure,” Budinger says.
Back to Basic Science
Chandel, a leader in the emerging field of metabolic signaling, spends more time than ever presenting at conferences around the world. After more than a decade in the hinterlands of scientific research, he is enjoying his turn in the spotlight and hopes to serve as an ambassador for basic science research. The U.S. Congress, general public and even physicians, he says, are indifferent and sometimes antagonistic towards the discipline.
As a physician-scientist, Dr. Budinger provides a unique perspective. “An unfortunate and unintended consequence of the NIH push for translational research has been the failure to recognize the contribution of basic science,” he says. “People don’t realize that drug discoveries are rooted in basic science. They think drugs spring from drug companies.” He notes that none of the drugs prescribed to patients when he was in training 20 years ago are used today. “The target or mechanism for every drug we prescribe today was discovered through basic research 20 years ago.”