Dr. Richard Pagano - Lipid Cell Biology Pioneer
Richard Pagano, Ph.D., died on September 22, 2010. We honor his achievements and his memory.
No matter how early lab members arrived at work in the morning, the lights were invariably already burning in Dr. Pagano's office. An intensely serious man, he thrived on routine and ritual. His approach to life was methodical and organized, yet he possessed a wry sense of humor. He exuded a warmth that made every individual in his lab feel special by inspiring compassion, loyalty, integrity and diligence in those with whom he worked. He was a man of intense faith, and he loved his family deeply. While Dr. Pagano's untimely death leaves a void for his collaborators, there is little doubt that his research provides a sound basis for future important discoveries. The field of lipid metabolism and lipid trafficking defined Dr. Pagano's scientific career, and his work defined the field.
Life depends on lipids. All of the cells in your body are contained by a surrounding lipid membrane that prevents structures within the cell — such as the nucleus, where the DNA is kept and the mitochondria, where energy is generated — from leaking out and harmful substances from getting in. Endosomes, which are little lipid bubbles that get pinched off from the cell membrane, bring bits and pieces into the cell from outside. The bubbles then move around the inside of the cell and merge with other bubbles, depending on the needs of the cell. Dr. Pagano was interested in how the lipid composition of the membranes of different subcellular structures can influence their behavior.
Dr. Pagano came to Mayo Clinic from the Carnegie Institution Department of Embryology in Baltimore. There, for more than two decades, his lab undertook pioneering work in how cells process lipids (Nature, 1974). He was celebrated for developing new methods with which to study lipid biology. He then used these tools to make discoveries about the important roles that lipids play in a wide variety of cellular functions.
Illuminating lipid biology
Richard Pagano, Ph.D.
Dr. Pagano's lab created synthetic compounds that behave the same way as natural lipids. The lab team also found ways to add fluorescence to these "probes," which made it much easier to track the lipid bubbles. These "fluorescent lipid probes" are the tools of the trade for lipid biologists.
Dr. Pagano was interested in a particular group of lipids called sphingolipids. By synthesizing fluorescent sphingolipid probes, his lab was the first to tag a cellular structure, called the Golgi apparatus, in a living cell. The Golgi apparatus behaves like a post office, sorting and packaging lipids and proteins into the correct bubbles for secretion or use by the cell. Being able to tag this important cellular structure allowed them to find out much more about sphingolipid metabolism.
Lipid metabolism is complex, and there are many opportunities for things to go wrong. There exist a group of rare inherited disorders, called sphingolipid storage diseases, in which abnormal amounts of fat build up in organs of the body such as the liver, spleen, and brain. Dr. Pagano's lab discovered a missing enzyme that caused one of these defects and created a probe that can be used as a diagnostic tool. Furthermore, they showed that excess cholesterol in the cell actually interferes with sphingolipid transport, causing even more fat accumulation (Nat Cell Biol, Oct 1999; Mol Biol Cell, Oct 2004). Interestingly, they were also able to demonstrate that if you get rid of the cholesterol, no matter what method you use to do that, you can restore normal cell function.
In collaboration with Robert Bittman, Ph.D., from The City University of New York, the Pagano lab discovered a potentially exciting method for blocking some viral infections. The lab had laboriously tested dozens of compounds and had previously shown that sphingolipids internalize via one particular pathway. Subsequently, the research team was the first to identify that a lipid has the ability to act like a traffic cop, selectively stopping some materials from entering the cell. (J Cell Biol, Mar 2007). The discovery may well provide the foundation upon which others can develop new treatments to block infections.
Seeking clinical application
The upper image shows a normal skin fibroblast with lipid accumulating in the Golgi apparatus. The lower image shows how fluorescent lipid concentrates in lysosomes, a feature that identifies a lysosomal storage defect such as Niemann-Pick disease.
This image illustrates a technique developed by Dr. Pagano to study the Golgi apparatus in living cells. Lipid fluoresces in green when diffusely present in the cell and red when concentrated in the Golgi apparatus.
Dr. Pagano came to Mayo Clinic in 1994 as an internationally recognized, distinguished scientist for his discoveries on how sphingolipids are processed by the cell. His laboratory discoveries affect many biological responses and, therefore, have the potential for broad application to clinical problems. Dr. Pagano was drawn to Mayo because he wanted his work to make a difference in people's lives. While his research was driven by his intense curiosity, he also sought interaction with scientists and clinicians who could find practical application for his work.
Lung specialist and researcher Andrew Limper, M.D., had a fruitful decade-long collaboration with Dr. Pagano, which is leading to the development of potential new treatments for pneumocystis pneumonia, an infection that affects immune-compromised patients such as those with AIDS or those undergoing treatment for cancer or organ transplantation. Dr. Limper’s lab subsequently discovered a new class of drug that can both kill the fungi that infect the lung as well as stop the abnormal inflammation that is often fatal in immunosuppressed patients.
"Dick's probing questions about my work, his insights and unique tools allowed me to take a new approach to understanding lung inflammation in response to pneumonias," says Dr. Limper. "Dick was the consummate scientist and this work will continue as Dick would have wanted it."
Rolf Hubmayr, M.D., also greatly valued his collaboration with Dr. Pagano. Dr. Hubmayr is a critical care specialist whose research interest is lung cell injury. Lung cells can be injured by microbes, chemicals, acid aspiration or stress from mechanical ventilation used to support patients who cannot breathe effectively by themselves.
Using Dr. Pagano's fluorescent lipid probes, Dr. Hubmayr's lab has shown that lung cell injury results in lipid transport to the cell membrane. By changing the composition of the cell membrane, researchers prompt different receptors to be expressed, which, in turn, change the traffic lane by which lipids and proteins are brought into the cell. Their studies suggest that lipid trafficking is involved in wound repair. Dr. Hubmayr's lab is now studying ways to manipulate cell repair with the goal of applying novel treatments to protect the lung from injury.
"As a result of Dick's work, we now appreciate that certain inflammatory reactions are regulated by lipids," says Dr. Hubmayr. "Dick helped us understand what path a given protein takes to get internalized, how it's regulated, and whether it's expressed at the cell surface or down regulated — all vital knowledge that contributes greatly to our studies in lung cell wounding and repair."
Another Mayo collaborator, Hirohito Kita, M.D., is an immunologist and allergist who researches airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The key feature of such diseases is inflammation of the respiratory mucosa.
"Dick's studies on sphingolipids have the potential to regulate inflammation and treat patients with airway disease," says Dr. Kita.
In addition to his scientific recognition, Dr. Pagano trained over 50 fellows and students, many of whom are current leaders in the field of lipid metabolism and lipid trafficking that he pioneered. He leaves behind a research family of former trainees and collaborators who carry his passion for lipid biology research.