Donata Vercelli: Genes and the environment

This is a story about Charlotte, who is three days old at this writing, and a medical puzzle that might affect her susceptibility to many serious diseases. Or it might not.

For infants, their first year is crucial. The kind of environment a child of that age needs to switch on certain molecules to lift their disease immunity is fairly well known. For example, living on a farm and being around a dog and lots of microbes are helpful factors, but only for some.

Is Charlotte among them? That's where one of the Arizona Respiratory Center and BIO5 Institute's most fascinating research projects comes in. Donata Vercelli, MD, is the lead researcher in an effort to dissect the genetic patterns of thousands of children to find out. The Arizona Respiratory Center is part of the College of Medicine at The University of Arizona (UA).

Her goal is to extract lessons from the environment about how it has protected us in the distant past, and to learn how genetic variants interact with a child's environment to provide immunity to complex diseases like asthma. One payoff may be customized treatments for patients of these diseases.

Charlotte, daughter of friends and a genuine phenotype, a complex package of molecules that adds up to one organism, expresses the genetic blueprint, or genotype, that she inherited. Like the billions of other humans, she faces uncertainty about whether her genes will in fact provide immunity. The Vercelli lab seeks to understand the mechanisms that form a basis for associations between environment and genetics, shaping vulnerability to disease and many other traits.

'This is not a trivial problem,' Vercelli said. 'Asthma affects 15 percent of the U.S. population. Complex diseases are a very significant problem."

What brought Vercelli's lab to Tucson were those very unanswered questions.

Vercelli was born in Florence, Italy, and she recalls, 'Florentines are all interested in the humanities. Culturally, I am very European. My favorite reading when I was 15 or 16 was Thomas Mann, and a lot of Shakespeare.' She was no typical Italian, reading French, Latin and Greek and listening to Bach, Beethoven, Mahler and Wagner. 'Just a little Verdi,' she adds.

With her doctor of medicine degree at 25, she took on hematology, then immunology, and knew she wanted a career in research. She took a post doc at Harvard and became a fellow in immunology, focusing on problems of allergy. She studied molecular mechanisms that regulate synthesis of antibodies for allergies in the lab of Raif Geha at Children's Hospital in Boston.

'Then, something happened,' she recalls. 'I realized there was something odd in the experiments we were doing, some individuals responded with variability that I couldn't figure out. That is why I started worrying about genetics.'
In short, she came to Tucson and the UA when she was offered a chance to pursue those puzzles. A research group was developing a genetics approach to the diseases that interested her. They included Fernando D. Martinez, MD, head of the Arizona Respiratory Center and a BIO5 member, and Marilyn Halonen, PhD, a center member, BIO5 member and a well-known immunologist.

Here, she is exploring the ways that modern urban life may have deprived children of some of their genetic possibilities. Humans evolved not in microbe-free towns and cities but in lands rich with microbes. How to replicate some of that with drugs is one of the unanswered questions for her lab.

'It's not that hard to come up with a principle, when you know the effect,' she said. 'That's the black box. We don't know what is doing this. At a molecular level, what are the biological agents?'

Vercelli's lab at BIO5 is well under way toward a goal that may take a full five years of steady effort. When you see the five turtles that are the mascots inside her office door, you wonder if she's sending a message. A poster on the wall, from the University of Maryland, says simply, 'Fear the Turtle.' For her, the turtle is admirably tough on the outside, kind on the inside and persistent.

If her lab makes the breakthroughs she seeks, the theoretical insights into asthma will feed into applications in biochemistry and pharmacology for drug design that may have global impacts. The full range of interventions that science may devise for children is unknown. If the Vercelli lab unlocks the genetic chain of events for infants in various environments, other scientists may point the way to securing those benefits for infant children without sending them to live in rural areas or prescribing life with a puppy.

What seems certain is that one day parents will learn new and profound lessons on care options for infants, before it's too late. Public health agencies and schools will promote innovative ways to enhance immunity to complex diseases. And there may even be new advice on whether to buy a dog for a future generation of Charlottes.

Accomplishments
Donata Vercelli is an associate editor of The Journal of Immunology and The Journal of Allergy and Clinical Immunology, the flagship journals of immunology and allergy. She has won many of the top awards in her field including those of the Pharmacia Allergy Research Foundation, Asthma and Allergy Foundation of America, Burroughs Wellcome Fund, Women Physicians in Allergy, and the American Academy of Allergy and Immunology.
Reflecting her growing interest in complex disease biology, she was the organizer and chair of the highly successful 2006 Keystone Symposium on Allergy, Allergic Inflammation and Asthma that for the first time brought together scientists exploring epidemiology, environmental exposure, genetics, immunology and phenotypes of these pathologic processes.
Dr. Vercelli is a member of the International Scientific Advisory Board for the European Union's GABRIEL Project on Gene-Environments Interactions and the director of the Arizona Initiative for the Biology of Complex Diseases (ABCD).
She is a BIO5 member and professor in the Department of Cell Biology and Anatomy and the Arizona Respiratory Center, both part of the College of Medicine at The University of Arizona.