University of Alberta Edmonton, Canada May 30, 1997

Good walls make good neighbours

The University of Alberta's Membrane Group funded by the Alberta Heritage Foundation for Medical Research

By Kathleen Thurber

In earlier times, plague, smallpox and other diseases ravaged populations with a deadly efficiency that could only be explained as the devil's handiwork. Marginalized individuals and groups were punished as scapegoats. Disease, unappeased, raged on.

Today, we understand the mechanisms of contagion as physical, not metaphysical, yet the fundamental actions of disease beg questions. How do viruses or bacteria or diseased cells affect the normal cells in our bodies? How do they do their damage? The only way these questions will ever be fully understood, allowing new therapies and treatments to be devised, is through sustained basic medical research such as that of The University of Alberta's Membrane Group.

The membrane's connected to the. . .everything

Our cell's outer membranes hold a complex community of structures and compartments, packaged by semi-permeable membranes separating them from each other and from the outside of the cell. This allows cells to carry on several functions at the same time. Cells are studded with proteins acting like sensors that pick up signals from the outside, talk to other cell structures, and trigger responses to help the cell maintain its unique equilibrium. Some responses triggered by these proteins could have implications in diseases such as Alzheimer's, cystic fibrosis, cancer, muscular dystrophy, and arteriosclerosis.

Dr. Marek Michalak: Basic Communication

Heritage researcher Dr. Marek Michalak is interested in how cell membrane proteins function, particularly those in the membrane of the cellular structure known as the endoplasmic reticulum.

He has focused intensively on one protein, calreticulin, which is present in every organism. In fact, calreticulin is 60 per cent identical in plant and human cells. The sheer prevalence of this protein led Michalak to surmise that it had many functions. His research confirmed this. He says, "When I give talks about calreticulin, I have a slide which describes everything this protein does. Its functions are so varied that it takes half an hour to read the slide to get an idea of what is going on."

One function of calreticulin could have profound implications in treating a condition called restenosis, a form of blood vessel injury that occurs when people undergo balloon angioplasty. Although inflating a balloon in clogged vessels opens them, the resulting damage to the vessel walls can cause future clotting problems. Michalak recalls a chance meeting with a cardiologist. From their conversation, a research project was devised that involved administering calreticulin during balloon angioplasty. The result was astounding: restenosis did not occur at the angioplasty site. Somehow calreticulin stops blood cells from stimulating vessel wall growth, the first step in restenosis. Michalak and his colleague have applied for a patent to use calreticulin to prevent restenosis.

Michalak's work with other membrane-associated proteins include dystrophin, the protein that when missing, causes muscular dystrophy. This research may contribute to new therapies for the devastating muscle disorder.

Dr. Larry Fliegel:Balancing the Beat

Our hearts can only keep beating when cell pH (the balance between acid and alkaline) is kept within a narrow range. Acid produced as waste from cell metabolism is gathered and exchanged outside the cell for sodium by a cell membrane protein- the sodium-hydrogen exchanger. Heritage researcher Dr. Larry Fliegel studies the sodium-hydrogen exchanger protein, particularly its actions in heart cells.

Fliegel has found that heart cells kept alive in Petri dishes adapt to extra acid by producing more of the sodium-hydrogen exchanger protein. In the body, though, this kind of adaptation can harm the heart. Ischemia, for example, is a heart disease where arteries narrow, hampering blood flow and causing blood seepage back into the heart. Ishemia causes excess acid production, triggering a vicious cycle in which the increased sodium brought in by the sodium-hydrogen exchanger brings in an excess of calcium to the heart cells. This can result in arrhythmias and heart cell death. Fliegel's work centres on how to control the activity of the sodium-hydrogen exchanger protein to prevent the detrimental effects.

"There is actually a lot of work being done on developing inhibitors of the sodium-hydrogen exchanger protein," says Fliegel. "The hope is that someday there'll be drugs derived from these inhibitors to treat heart diseases."

Fliegel's work could have potential implications in heart disease and conditions involving cell growth such as cancer metastasis.

Dr. Joe Casey: Cell Basic

Dr. Joe Casey studies anion exchanger proteins which, like the sodium-hydrogen exchanger, help keep the cell's pH level at a certain point. But unlike the sodium-hydrogen exchanger, anion exchangers work to make cells more acidic, moving out substances that would make the cell too alkaline.

Casey explains, "It's really important to maintain the cell's pH and volume, because events can happen to change both. For example, during a heart attack, cells can acidify and cause a whole chain of events that would kill off heart cells. I'm trying to determine whether anion exchangers play a role in this chain of events, particularly since they are found in heart cells."

Casey sees membrane proteins as the very tools of life and death. "The membrane interface is so important because we have to control what goes into and out of cells. If we can't control what goes on, keeping the inside and outside of cells different, we are dead."

Dr. Marek Michalak is a Heritage Senior Scholar and a professor in the Faculty of Medicine and Oral Health Sciences. He was recently awarded a Senior Scientist Award from the Medical Research Council.

Dr. Larry Fliegel is a Heritage Senior Scholar and associate professor of Pediatrics in the Faculty of Medicine and Oral Health Sciences.

Dr. Joe Casey is a Heritage Scholar and an assistant professor of Physiology at the Faculty of Medicine and Oral Health Sciences.

relevant Internet site: Introduction to Cell Biology

http://lenti.med.umn.edu/~med/cell_www/cell_intro.htm/

U of A's Membrane Group:

http://www.biochem.ualberta.ca/biochem/dept/groups/mbmp/mbmphome.html

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