Pharmacologist makes Unexpected Connections with COX-2 Inhibitors
By Dan Hurley
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Dr. Ferreri discusses the schedule for the day with Huda Abdullah, a Ph.D. candidate in his laboratory. The amiable full professor has had two turns in the Department of Pharmacology - as a graduate student and, seven years later, a faculty member. |
There's been more than a little success for Dr. Ferreri of late, including a recent Fogarty Grant from the National Institutes of Health permitting him to delve deeper into an unlikely connection he and colleagues first glimpsed years ago between hypertension and the COX-2 molecule typically associated with painful inflammation.
"One of the important things about our research is showing that COX-2, while important in inflammation, also has a function in normal body mechanisms, including the kidney's regulation of blood pressure," he explains. "So we say, wait a minute guys, when you inhibit COX-2 for pain relief, you will alter kidney function in a way that could cause problems for certain people."
Although his studies could eventually lead to the development of new medications for managing hypertension, the long road to this insight began when Dr. Ferreri arrived for his first stint at the College in 1978 - that time as a graduate student. His mentor was the newly appointed chair of the Department of Pharmacology, John C. McGiff, M.D.
Key colleagues
"Even then he was totally supportive," says Dr. Ferreri. "He's always cleared the way for me to do things. Dr. McGiff is someone I just truly admire. He's a powerhouse." Dr. McGiff is equally effusive about his one-time student, now colleague and friend. "From day one," Dr. McGiff says, "it was evident that Nick Ferreri would be one of the commanding presences in his field. He took the long view and never used shortcuts. Without Nick Ferreri, many of the studies in this department would never have been initiated. And beyond his scientific capability, he's a splendid human being who handles all sorts of graduate students with ease and concern."
Dr. Ferreri credits Dr. McGiff with making connections for him with three key colleagues. The first, Michal L. Schwartzman, Ph.D., now a professor of pharmacology, was then a visiting fellow from Israel seeking to understand how arachidonic acid metabolites regulate kidney function.
Dr. Ferreri began writing on a chalkboard to patiently explain it all to a visitor who doesn't know his arachidonic acid from his elbow. "Dr. McGiff did kidney research on molecules called prostaglandins," he says. "We wanted to look at how prostaglandins, metabolites of arachidonic acid, a 20-carbon fatty acid, affected ion transport in the kidney. COX is the enzyme that takes arachidonic acid and makes prostaglandins. Miki Schwartzman had done research in Israel on prostaglandins."
What they discovered was a huge surprise. "Instead of finding prostaglandins," he says, "we found a new pathway for arachidonic acid metabolism via an enzyme called cytochrome p450. That was pretty much my thesis." The discovery, as reported in major journals in the early 1980s by Drs. Ferreri, Schwartzman, McGiff and others, brought national attention to the College.
Moves on
Dr. Ferreri moved on to post-doctoral study - first at the Scripps Clinic in California, then at Yale - in the seemingly unrelated field of immunology. "I wanted a whole other field under my belt," he says. "I just felt that science is so multidisciplinary. We tend to think of it simplistically, as such a linear thing. I thought, this is the last chance I'll have to add a big field to my repertoire. And I have to say it was Dr. McGiff who helped it pay off."
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Introducing the laboratory team of Nicholas Ferreri, Ph.D., Department of Pharmacology, from left: Paulina Pedraza, technician; Dr. Ferreri, professor; Wilson Young, M.D., Ph.D. candidate; Irene Lee, technician; and Huda Abdullah, Ph.D. candidate. |
"I came back to study cytokines and how they regulate COX-2 in the kidney," he says. That's when Dr. McGiff introduced him to the man he calls the second key person in his career: Bruno Escalante, M.D., Ph.D., then a faculty member who has since returned to his native Mexico. He had been participating in the department's research on cytochrome p450 when Dr. Ferreri suggested they investigate whether COX-2 is made by certain cells in the kidney with a rather peculiar name: thick ascending limb (TAL) cells.
"This was back in the early 1990s, when the COX-2 story was developing, mostly as it affects inflammation," recalls Dr. Ferreri "I started asking if there could be some of these molecules in the kidney. No one had looked yet. We looked and found that under certain conditions, the gene for COX-2 can be turned on in the TAL cells."
TNF and COX-2
The cytokine that stimulated the production of COX-2, Dr. Ferreri found, was tumor necrosis factor-alpha (TNF). "COX-2 in the kidney is normally expressed at very low levels, and only under certain conditions do you get more of it. One of the ways is with TNF. This is when Dr. McGiff put me in touch with the third key person in my career, with whom I currently work on this project: Carlos Vio, M.D., of the Catholic University in Santiago, Chile. We were working on the same thing but have different kinds of expertise. Carlos is an expert in immunohistochemistry and I look at individual cells." The individual cell is indeed Dr. Ferreri's passion. "Even when I was an undergraduate at Case Western Reserve, I always had a fascination for working with individual cells," he says. "I had a natural inclination for that. It's like why you prefer jazz or classical music. I could always think better in terms of cellular mechanisms - which is what made for such a beautiful relationship between Dr. McGiff and me. He was more of a wholeorgan researcher. I thought you had a better chance if you picked a cell you knew was a potential target for a drug or a function, and then tease out what was happening in that cell."
Gazing into the distance, seemingly straight through the chalkboard, Dr. Ferreri waxes philosophical about the cell. "It is the center of the universe, in terms of what makes the whole organism work," he muses. "These little guys have to communicate with each other to make this whole human being that does all the crazy things we do.
Complicated TAL cells
The more Dr. Ferreri talks about those "little guys," the more he sounds as if he's talking about tiny little people. The idea doesn't faze him. "Well, I thinkÉthey're not as diverse as people with personalities, but they're not all the same either. The more you get to know them, the more complicated they are. We found that out about the TAL cells. I think that's also true about smooth muscle cells," he says.
Dr. Ferreri's latest grant concerns how COX-2 and TNF regulate the growth of smooth muscle cells in blood vessels, which often become abnormal in people with hypertension. "Same molecule, different cell types, different organs, different functions. That's what makes this whole field of cytokine biology so confusing" - and, one suspects, so fascinating to him. "It's almost a shame to call this work," he admits. "It's just waking up and doing what I do. That's the environment Dr. McGiff creates, by being so supportive and bringing in people who can help each other." Few have helped Dr. Ferreri more than a medical photographer named Nancy who was working for Dr. McGiff back in the early 1980s. He and Nancy got married and now live in Connecticut with their two children ("my treasures"), Nicholas, 13, and Nina, 6.
Better make that four key people Dr. McGiff has introduced him to.