The Harris lab: A cooperative spirit (feature story InTouch Fall 2008)
Ann Harris, PhD, is on a mission. As the director of one of the youngest programs at Children’s Memorial Research Center, she understands good science, dedication and the value of a lively exchange of ideas. Harris is committed to infusing her laboratory, the Human Molecular Genetics Program, and the research center with these qualities.
The past is prologue
Harris began her scientific career by studying insects and their color preferences in her family’s garden in the U.K. By age 14, she knew that she wanted to pursue biology. After studying zoology at Oxford University, she continued in her PhD studies at the University of London. It was then that she met up with the genetic disease that would dominate her work, cystic fibrosis (CF). Paul Polani, an eminent cytogeneticist at Guy’s Hospital Medical School in London, offered her a position to study its genetics, about which little was known.
Unfortunately, the funding that was supposed to support her didn’t materialize. Harris managed to secure a training fellowship from Action Research for the Crippled Child. Her postdoctoral fellowship completed, she received a New Blood Lectureship position, one of only 100 to be offered that year in the U.K. university system.
It was at this point that Harris took on her next sharp learning curve: becoming a principal investigator (PI) at Guy’s Hospital Medical School at the age of 28. She says that “all the important things it takes to run a group effectively” had to be learned on the job.
“In 1991, I gave up tenure in London and moved to Oxford. The Institute was a fantastic place to work — there was a huge interest in human genetic disease,” Harris says. She continued there for over 12 years.
In 2003, Harris decided that something different was in order. The Program Director position description at Children’s Memorial Research Center was written as if it were tailor-made for her. “When I talked to the faculty, there was a sense of a wish to work together to grow and do new things. It was clearly a scientific environment that both Bento [Soares] and I are trying to foster.”
Harris knows what her lab’s ideal makeup should be: international in scope, outward looking and open to new ways of thinking. She brought lab members who chose to relocate from Oxford to the research center, and also recruits worldwide. She has strong opinions about connections and interactions, placing a high value on collaborations with other labs at the research center, clinical colleagues at Children’s Memorial Hospital, Northwestern University investigators and many others.
The Projects and the People Driving Them
But it’s clearly the research that motivates Ann Harris. Her projects involve:
- A gene called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), which shows enormously complex patterns of expression. There are more than 1500 errors in the gene that have been associated with disease, and its expression is controlled by many genetic elements, and by the three-dimensional structure of the chromatin (DNA and proteins bound together).
- The mucus layer of the body’s epithelial surfaces (such as in the airways), which keeps these surfaces healthy. Mucins, proteins that are major components of the mucus, play a role in health and disease, cell signaling and cancer progression.
- Collagen XV, which may act as a tumor suppressor.
Christopher Ott, graduate student, studies how CFTR is transcriptionally regulated in the different tissues where it’s expressed. Looking at the whole locus in high resolution, he is finding that chromatin structure patterns vary by cell type. He has also been able to find regions of the gene that bind specific transcription factors and turn on the gene. “You only need about 5 percent of functional gene to alleviate the phenotype and cure the disease. So finding out what transcriptional programs are acting on genes to attempt to increase the transcription could potentially help,” says Ott.
Marzena Lewandowska, PhD, postdoctoral fellow, seeks to elucidate the contribution of the alternative 5’ exons of the CFTR gene, which are temporally and developmentally regulated, in CFTR transcription and translation. Results show that the presence of the upstream exons blocks CFTR translation but does not impact transcription. Lewandowska collaborates with the Bento Soares lab, Cancer Biology and Epigenomics Program, on the role of epigenetics in CFTR expression, and with the lab of Margarida Amaral at the University of Lisbon in Portugal to study alternative CFTR translation initiation.
Neil Blackledge, PhD, former postdoctoral fellow, recently completed his PhD studies in the Harris lab, focusing on the boundary elements of the CFTR locus. During this time, he became interested in epigenetics, or heritable changes in gene expression caused by mechanisms other than changes in the underlying DNA sequence. Blackledge is now at Oxford University as a postdoctoral fellow, investigating histone demethylases in the lab of Rob Klose.
Kirsten Morris, PhD, postdoctoral fellow, focuses on type XV collagen as a tumor suppressor in pancreatic cancer cells. Previously, Harris and a colleague, Michael (Tony) Hollingsworth at the University of Nebraska, found that cancer cells that over-expressed collagen XV could not generate tumors and spread in vivo. Morris is following up with other cell types, and is also interested in the proteins involved in this mechanism. “The lab is great. Everybody has been really nice, we try to help one another, and we work well together,” she says.
Michael Mutolo, MS, laboratory manager and research associate, works with Morris on type XV collagen and its role in tumor suppression. Using tissue culture and molecular biology techniques, he is conducting studies to characterize the gene. Mutolo says that a team approach allows members to complete projects and share updates frequently. He thinks Harris is a great mentor who maintains a high degree of involvement in all the projects.
Shih-Hsing Leir, PhD, postdoctoral fellow, is studying the MUC6 glycoprotein and its role in tumors. Normally MUC6 is highly expressed in the stomach but not in other tissues. He works with cell lines that express the mucin protein to determine whether expression affects their migration or invasion. Leir and Morris use similar techniques, and they discuss them frequently to resolve technical problems. He has been working with Harris for about seven years, first in her Oxford lab and now at the research center.
Kimberly Watts, MD, attending physician in the Division of Pulmonary Medicine, sees patients as part of the Children’s Memorial Cystic Fibrosis Center care team. In the Harris lab, she researches modifier genes in Hispanic patients with CF; these patients have increased morbidity and mortality from their disease. The basic science question is how modifier genes contribute to this outcome disparity. Watts says, “True translational research is seeing something in the clinic and asking why it happens. Susanna McColley, MD, head of Pulmonary Medicine and director of the CF Clinic at Children’s Memorial, has always wondered why the outcomes of her Hispanic patients are not better, despite their receiving the same treatment as all other CF patients.”
Collaborations Above and Beyond
What is the future of CF research? Harris thinks it involves forming a community of sorts, to pool resources and brain power. “Northwestern has outstanding science in many areas. We now have very accurate records of everybody on the campuses who is interested in genetics and how they identify themselves in the bigger genetics community, and the dialog has started between the campuses.” As always, her enthusiasm for forming partnerships to help solve the riddle of CF genetics remains high.
Ann Harris, PhD, director of the Human Molecular Genetics Program, is professor of Pediatrics at the Feinberg School and the Valerie and George D. Kennedy Research Professor in Human and Molecular Genetics at Children’s Memorial Research Center. Her research is supported by the National Cancer Institute, Cystic Fibrosis Foundation and start-up funds from the research center and the Medical Research Institute Council.
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