A More Perfect Union
Basic science meets public health
If public health is science painted with broad brush strokes, basic science is pointillism, the art of connecting infinitesimal dots. Public health engages with populations of people; basic science pores over populations of mosquitoes, cells and enzymes. But in a public health setting, the endgame for these bedfellows is the same—large-scale prevention of disease. So how does the study of mechanisms in cells and tissues at their most fundamental levels complement the public health mission to protect millions? The answers are myriad, all hinging on translation. As you’ll find in the case studies that follow, disciplines such as toxicology, biochemistry, molecular and microbiology, epidemiology, and biostatistics can endlessly inform each other, and lead to cross-fertilization, clues, predictions—and ultimately—solutions to the world’s most vexing health problems.
Food Can Fix You
The vitamin D story may have its origins on a Kansas farm, where a young boy helped his father raise pigs. Elmer Verner McCollum and his brother were given the runts of the litter and told that they could feed them as they chose, and keep whatever money the pigs would bring. The boys fed the runts milk, the runts became healthy, and the brothers made a profit.
Years later, as a biochemist, E.V. McCollum used an elegant methodology to answer questions about the basic science of nutrition. With methodical precision, he perfected what is now referred to as molecular nutrition, using lab rats on restricted diets to isolate properties found in foods.
As head of the Department of Chemical Hygiene at the Johns Hopkins School of Hygiene and Public Health, he collaborated with pediatricians and pathologists who wanted to study rickets in a laboratory setting. McCollum fed his rats cod liver oil, used for centuries in Europe to treat the bone disease. Their investigations led to the discovery of vitamin D, the fourth vitamin to be discovered.
But McCollum’s work extended beyond the laboratory. Dedicated to the dissemination of knowledge about nutrition and “protective foods,” he advocated tirelessly for putting milk and leafy vegetables on dinner tables. Over time, McCollum’s discovery was translated into a population-wide prevention program in the U.S.—the fortification of milk and bread with vitamin D. As a result, rickets was eradicated in this country.
McCollum’s department became part of what is now Biochemistry and Molecular Biology (BMB). Pierre Coulombe, PhD, the newly appointed E.V. McCollum Professor and BMB Chair, believes that McCollum’s work represents the mission of all basic scientists working in public health: “If you identify the chemical principle, if you can find the purified substance, that becomes the basis for a potential mass intervention.”
Virus Plus Toxin Equals Cancer
In China’s Jiangsu province, the rates of liver cancer far outpace the global averages, and its victims are far younger than elsewhere. At a population level, Jiangsu is an obvious outlier. “Any time you see a lack of uniformity in disease, it smacks you in the face, and you realize that there must be dramatic exposures to something in the environment,” says chemist and toxicologist John Groopman, PhD, chair of Environmental Health Sciences (EHS).
Thirty years ago, Thomas Kensler, PhD, a toxicologist and professor in EHS, considered the questions posed by the epidemiological research in Jiangsu, and he began to look for answers on a molecular level. Hepatitis B (HBV), which is four times more prevalent in Asia than in developed nations, was part of the explanation.
Could there be a chemical agent, a “DNA damage product,” operating in conjunction with HBV? Kensler and Groopman identified just such an agent, which works with HBV to create mutations in a tumor-suppressor gene known as TP53—the most commonly mutated gene in all human cancers. The agent, aflatoxin, is a product of moldy crops such as peanuts and corn, is ubiquitous in Jiangsu, and can’t be cooked out of food. By itself, it can mutate cells in small measure. But a person who has biomarkers for both risk factors—aflatoxin exposure and HBV—has 60 times more risk of developing liver cancer than someone who has neither biomarker.
The translation of these basic science discoveries is a two-pronged population-wide prevention plan that incorporates vaccinating against HBV at birth, and communications programs that help Jiangsu residents to consume less aflatoxin. Both efforts are now under way.
The toxicologists are also exploring ways to diminish the impact of unavoidable exposure to aflatoxin. With a clear molecular target—the antioxidant signaling pathway Nrf2, which eliminates toxins and protects against mutations to TP53—they’ve conducted clinical trials involving drugs and compounds that include oltipraz, chlorophyllin, sulforaphane and tea made from broccoli sprouts. All compounds were found to significantly reduce DNA damage. “And even a modest reduction in DNA damage,” says Groopman, “can confer quite a large reduction in cancer.”
Hunch to Bench to Vaccine
One of the questions that epidemiology answers is, “Who is at risk?” After epidemiologists identify risk factors and biomarkers for a disease, basic scientists try to understand the mechanisms behind the markers. They “go molecular” to answer the questions, “What is going on in the cells and tissues?” and “How does that mechanism work?”
“Cervical carcinoma is a beautiful example of this,” says Diane Griffin, MD, PhD, the Alfred and Jill Sommer Professor and Chair of the W. Harry Feinstone Department of Molecular Microbiology and Immunology (MMI). “Epidemiology identified that having a particular infection was a risk factor for cervical cancer, and basic science is helping us to understand it.”
Cervical cancer is the most prevalent form of cancer among women in developing countries. According to Keerti Shah, MD, DrPH ’63, MPH ’57, an MMI professor, clinicians have suspected for more than 100 years that there might be a connection between cervical cancer and a sexually transmitted infection; the cancer seemed most prevalent in women who had many sexual partners.
In the late 1980s, Shah was approached by two epidemiologists who were looking for a virologist who could help them link a human papillomavirus (HPV) to cervical cancer.
The meeting led to a long and productive collaboration. Building on work by German scientist Harald zur Hausen, who won the 2008 Nobel Prize in Medicine for his work in cervical cancer, and using new recombinant DNA technology, Shah and his collaborators conducted comprehensive epidemiologic studies that established the relationship between HPV and the cancer. They published a paper that proposed the causal relationship, and seven years later, Shah and colleagues had proven that nearly all cervical cancers—in all parts of the world—are caused by HPV. Furthermore, they showed that cervical cancer is caused solely by a virus.
The current translation of these discoveries is a mass intervention, an HPV vaccine that will prevent the cancer-inducing infection.
In the battle against malaria, which kills more than one million people every year, resistance is an important consideration, and it wants molecular solutions, says Griffin, founding director of the Johns Hopkins Malaria Research Institute (JHMRI).
One of the strategies for protecting human populations against malaria is to kill the mosquitoes that transmit the malaria parasite to humans. For this work there is insecticide. But what happens when the mosquitoes become resistant to that insecticide? More malaria. Using molecular population genetics, microbiologists at JHMRI are studying ways to overcome insecticide resistance.
Also vexing in malaria work is the incidence of resistance to drug therapies. Ideally, antimalarial drugs restore health to a malaria-infected person by killing the Plasmodium parasites in his body. For decades chloroquine was a very effective treatment against malaria. However, the parasite has developed a widespread resistance to that drug, and there are reports of resistance to newer artemisinin-based antimalarials. To build a better drug, basic scientists at JHMRI are at work now to better understand what happens inside the cells when antimalarial drugs are resisted.
And then there are transgenic mosquitoes, insects that have been exquisitely engineered by scientists to resist infection by the parasite. MMI professor Marcelo Jacobs-Lorena, associate professor George Dimopoulos and assistant professor Jason Rasgon are involved in Plasmodium-resistant mosquito research. Ideally, the modified mosquitoes would not only survive in the wild but replace the wild-type mosquitoes because of a selective advantage.
Defense of the Lung
The lung disease known as chronic obstructive pulmonary disease (COPD) is the fourth-leading cause of death in the U.S. An irreversible condition, it results from environmental insult—mainly cigarette smoke but also air pollution—and as pollution and smoking rates increase, so do the death rates from COPD.
In our bodies, there are hundreds of antioxidant genes that can be switched on to prevent cell damage in the event of environmental insult or stress from oxidants such as cigarette smoke or pollution. According to Shyam Biswal, PhD, EHS associate professor, all of our lungs’ defenses—the entire pulmonary antioxidant network—are regulated by signaling pathway Nrf2, the same one targeted by Groopman and Kensler. The pathway not only protects our lungs but regulates many carcinogen-fighting enzymes throughout our bodies.
“With such a complex environmental stress response network as Nrf2,” Biswal asks, “how come people are still getting lung disease?” Further vexing is the question of why 20 percent of ex-smokers develop COPD, sometimes years after quitting.
In their attempts to answer such questions, Biswal and colleagues conducted experiments and found that COPD was linked with significantly reduced levels of Nrf2 activity. The research has yielded insight into lung conditions that extend beyond COPD. With Patrick Breysse, PhD ’85, MHS ’80, director of the Center for Childhood Asthma in the Urban Environment, Biswal is working to explore the role of Nrf2 in asthma.
In fact, drug development is in progress, as Biswal’s lab explores how “small molecule activators” can spur the Nrf2 pathway to “turn on” and tackle more toxicants. Biswal, Breysse and colleagues are hopeful that asthmatics will soon have access to a therapy that will kill the symptoms and halt the disease.
Biswal’s lab may soon make another big leap with its explorations into the lung health/Nrf2 partnership. The lab has found that the pathway is important in the body’s defense against lung infection, which can lead to pneumonia, one of the world’s most ruthless killers. An intervention that stimulates the gene and protects against pneumonia would be a great advance in public health.
The Mysteries of Age
Last summer, BMB professor Barry Zirkin, conducted an experiment using people, not rats. “We put a bunch of scientists in a room to see what would happen,” he says. “As usual, things happened.”
What resulted was a collaboration among BMB reproductive biologists, a cell biologist and a genome biochemist, all of whom want to answer questions about how, when and why cells are damaged as they age. “We know that when a cell ages, there is an altered balance between pro- and antioxidants, and that the imbalance may do irreversible damage,” says Zirkin, PhD. What’s unclear, however, is whether “aging” is merely an accumulation of damage that results from insult after insult over time, or whether, in addition, age-related events make cells particularly susceptible to an acute insult. These scientists—Haolin Chen, Mike Matunis, Paul Miller, Bill Wright and Zirkin—are writing a project program grant that would fund studies into both questions.
The team studies the mechanisms that affect the cell’s ability to protect and repair itself as it ages. They research the aging cell’s increased susceptibility to stress, its decreased ability to fend off insult and its diminished skill at repairing itself. Among its participants, biochemist Paul Miller, the grant’s principal investigator, is an expert in genome integrity and DNA repair; Zirkin, a reproductive biologist, knows stem cells and Leydig cells, which provide a tractable system for genome chemistry. “Studying genome integrity with these elegant methods [used by Miller] is not something a reproductive biologist would have thought about doing on his own,” says Zirkin. “It’s the coolest chemistry I’ve ever seen applied to a reproductive cell.”
Aging is a field rife with questions that beg to be explored. There is no real consensus, even, on what it means for a cell to be “aged.” How do we measure aging? “It differs from type of cell to type of cell,” says Zirkin. Do stem cells age? “We think they do.” Can we prevent cells from aging? “We can in a rat.”
The goal of BMB’s forays into the basic science of aging is intervention that would prevent or postpone conditions afflicting the elderly—osteoporosis, Alzheimer’s, decreased cognition and vitality, to name a few. Zirkin credits the public health mindset with guiding his own and the team’s research toward this kind of translation.
“You get seduced here,” says Zirkin, “and you ask yourself, ‘Is this basic science applicable to a population?’”