In 1993, Sandra Lee Hofmann, MD, Ph.D., sent a fax to noted Finnish geneticist Leena Peltonen. In her Texas lab, Hofmann had mapped a protein sequence that she thought matched the location of a chromosome region that Peltonen had implicated in a rare disease. Hofmann suspected that mutations in this sequence might be the missing link in the cause of the infantile disease that Peltonen studied. The mysterious brain disorder struck babies at about 18 months, when they began to lose their just-learned skills of talking and walking. All died by age 10.
For two months, she heard nothing. Then, one day, a lengthy missive appeared in her email inbox at The University of Texas Southwestern Medical Center in Dallas. Every single one of Peltonen's patients exhibited a mutation in the gene corresponding to the protein sequence. The implication was clear: Together, they had just discovered the disease gene for one in a rare group of hereditary brain disorders, neuronal ceroid lipofuscinoses (NCL, or Batten Disease).
That discovery has fueled Hofmann's research for much of the past 20 years — even though she cheerfully admits her initial interest in the field came about by accident.
"I'm a hematologist. I don't see these patients; I'm not their doctor," says Hofmann, an AAAS Fellow.
However, her early discovery has led her to embrace a dual path, as a hematologist and as a researcher dedicated to finding the cause and cure for Batten Disease. She explains that while earning her dual MD/PhD at Washington University in St. Louis in the '80s, she developed a strong interest in enzymes of lipid metabolism, which play a complex role in cellular function; enzymes that do not function correctly are implicated in many diseases. When she established her own lab at UT Southwestern in the early '90s, she decided she wanted to study the modification of proteins by lipids, because by altering that process, there is great potential for developing drugs and treatments for a variety of diseases.
Her early work showed that lipids bound to proteins were metabolized by an enzyme, called palmitoyl-protein thioesterase, and this enzyme was defective in the Finnish infants with the particular type of NCL disease that Peltonen had studied. This was an important discovery. At the time, there was no easy way to diagnose any NCL disease; patients often bounced between doctors for years.
Now, thanks to the work of Hofmann and others, the diagnosis can usually be made in an afternoon, via a simple blood test.
"She's a go-to person in the field as to whether certain ideas are worth pursuing," says Beverly H. Davidson, Ph.D., whose research also targets neurological diseases, and who nominated Hofmann to be a Fellow. "I think she is an advocate and a voice for the families dealing with these diseases, but she's also a voice for young scientists who are entering the field."
Indeed, Hofmann keeps a busy schedule: She teaches at UT Southwestern, serves on several admissions committees, advises post-doc students, and chairs the scientific advisory board for the Batten Disease Support and Research Association — all while continuing to see patients as a hematologist three days a week. It all means "some full days, and a lot of juggling," Hofmann says.
Meanwhile, her laboratory continues to look for answers to the continuing mysteries of NCL. There is still no treatment for this group of diseases, and a poor prognosis for patients. Most die in childhood, and virtually none live to see middle age.
However, Hofmann feels that could change. Another important discovery her lab made was that the problem enzyme was a lysosomal enzyme, meaning NCL could be classified as a lysosomal storage disease. (Tay-Sachs and Gaucher diseases are among the most well-known of these disorders.)
This was important because not only did it provide clues as to what approaches might work, but it helps broaden the applicability of the research.
In an era of shrinking research funding, it has become ever more difficult to obtain sufficient funding for "orphan" diseases like Batten disease, Hofmann says. In fact, currently she is working with lung cancer cells. By working to inhibit the processes that may cause cancer cells to grow, she hopes to find paths toward treatment for cancer that could be modified to create treatments for other diseases, including Batten disease.
It is difficult to treat brain disorders like Batten with enzyme or gene therapy because of the blood-brain barrier. When enzymes or gene therapies are injected into the body, they are taken up by other tissues, but do not penetrate the brain. Still, Hofmann thinks there's a strong possibility some sort of gene therapy will be developed to treat NCL within the next decade.
It's the kind of development that keeps her passionate about science, and has fueled her rise from a high school student active in the biology club to a nationally recognized scientist.
"You work to solve one problem, and sometimes you solve another," Hofmann says. "That's just the way science works."