During every second of every day, untold millions of messages course through your body-- within cells, between cells, or from different parts of your body to your brain. This remarkably complex communications system uses signals of all different kinds, from electrical, to chemical, to the purely physical. It is this last kind of signalling that interests Dr. Cathy Morris, as one of the two areas to which she devotes intense study is the mechanical status of cells.

Something as simple as the stretching of a membrane can result in a message being sent. A readily graspable example is the discomfort we feel when the skin of the bladder is stretched. On a microscopic level, the stretching of a cell's plasma membrane can turn on or off the channels through which ions pass. These stretch-activated channels occur in highly specialized mechanoreceptor cells, but Dr. Morris intends to locate and characterize the mechanosensitive channel in common cells, such as those in the liver or the heart. In the current phase of this project, Dr. Morris is working to clone the mechanosensitive channel in an oocyte. The knowledge she gains from this effort will allow her to determine how such channels are used to regulate the functions that result in good health or disease.

One discovery Dr. Morris and her team have made through biophysical and cell physiological studies of these stretch-activated ion channels is that the more injury a cell sustains, the more mechanosensitive its channels become. In other words, the more trauma you inflict on a cell, the more likely it is that these channels will open. The reason for this is not yet clear, but there are obvious medical implications. Dr. Morris hopes that once she has pinpointed the mechanosensitive channel in common cells, and determined how it functions, she will be able to suggest ways to deactivate it when it malfunctions. This will be particularly important in improving treatments for diseases like muscular dystrophy, a disorder in which the mechanosensitive channels in muscle cells operate out of control. Another area that will benefit is the treatment of stroke and any other general cellular trauma in which an energy imbalance causes cells to swell.

In her quest to understand these stretch-activated channels, Dr. Morris has stumbled across what appears to be a profound piece of basic cell biology. As a consequence of manipulating cells to swell or shrink, Dr. Morris has discovered what she believes is a system that alters the amount of plasma membrane around a cell in response to membrane tension. When a cell is induced to swell, its membrane must enlarge, in order to prevent a rupture, as even a tiny tear in the membrane means death to the cell. When a cell shrinks, the membrane is again rearranged, this time to take up the slack.

This is the kind of observation that seems almost self-evident once it is pointed out--and therein lies much of its elegance. As science has gained the ability to study smaller and smaller particles, many-- like the cell, or the atom--have been revealed to be infinitely more complex than was once believed. It appears that this observation may add a significant piece of the puzzle in refining the way we think of cells. Contrary to what was only recently taught in high school biology courses, cells are not perfect spheres. That would mean that the volume of a cell would be contained by only the minimum amount of membrane possible, which would mean that its shape would be fixed. Because a cellular membrane is virtually inelastic, cells formed like perfect spheres would be unable to accommodate different shapes if even slight pressure were applied, and they would burst. A better mental image for a cell is something like a breast implant, which can take on different shapes without bursting, while maintaining a fixed surface-to-volume ratio, because it has a membrane large enough to accommodate different positions without being stretched. Theoretically, this membrane could be stretched, perhaps if the implant were to be placed on a table with a weight on top. But that would simultaneously thin the membrane-- something that can't be done with a biological membrane. Yet the fact that many biological cells migrate into different positions and orientations indicates that they can change surface-to-volume ratio. Local tension, Dr. Morris believes, is the best stimulus for this--which is entirely supported by her observation of mechanosensitive membranes. Now that she has published her initial work on this question, feedback indicates that this phenomenon has been observed in other types of cells, like muscle cells, but has never before been identified. Therefore, some of Dr. Morris's current projects are designed to prove her hypothesis, using electrophysiology, microscopy, and confocal microscopy with special dyes, to keep track of the amount of membrane a cell has at a given point in time.

If Dr. Morris's theory of mechanosensitive membranes proves to be the exciting discovery it seems, the treatment of stroke could be a direct beneficiary. If brain cells are to survive the swelling that results, they must reduce their membranes to get back into shape upon recovery. But the implications go far beyond that, as this hypothesis may answer several basic questions that have never been adequately explained, such as how the outgrowth of neurons (nerve cells) is organized.

Dr. Morris's other area of concentration is quite different, as it revolves around the problem of multidrug resistance. This difficulty arises in the realm of cancer chemotherapy, wherein an ancient ability of cells to excrete a wide variety of toxic substances becomes enhanced, and actually counteracts the cancer treatment. As it happens, cells have evolved mechanisms to pump out of their interiors a number of the very same organic compounds that we now use as drugs. Tumors treated with some of these compounds generally regress at first. But if one tumor cell that is overexpressing this multidrug pump survives, subsequent tumors are invariably resistant not only to the first drug but to any other drug that can be introduced. That is one reason that cancers treated with chemotherapy often show a resurgence of growth after an initial regression, because the course of treatment itself is subjecting the cells of the tumor to huge Darwinian pressure.

Dr. Morris's interest in this area began with the blood/brain barrier in insects. As she explains it, present-day insects and plants are the result of millions of years of coevolutionary wars between them. As insects eat plants, plants evolve to produce slightly toxic compounds to protect themselves. In response, the insects develop mechanisms like the multidrug pump so that they can benefit from the plant's nutritional value without succumbing to the poison--and so it continues. Interestingly, this process is where we get most of our pharmaceutical drugs from, as well as a dangerous toxin that our society consumes in enormous quantities--nicotine.

Most insects cannot eat tobacco because of the nicotine it contains. This very small, very membrane-permeable substance crosses the blood-brain barrier--both in insects and in humans--with ease. One insect whose brain should be susceptible to nicotine, but is not, is the tobacco hornworm. At the outset of her work with hornworms, Dr. Morris hypothesized that they might have multidrug pumps at the blood-brain barrier. She and her team have now demonstrated this to be the case. At this stage in their research, they are working to clone this system, and to characterize it at the molecular level.

Dr. Morris's confirmation of her initial hypothesis increases the likelihood that the multidrug pump exists at the blood/brain barrier in humans, as well, although perhaps in a less efficient form. That is something that Dr. Morris believes may work to the advantage of the tobacco companies. A person addicted to cigarettes requires a certain level of nicotine to reach a certain portion of their brain. If the blood/brain barrier opposes that, the natural consequence is that the addicted smoker smokes more. If there is a 10% effect, that might be small and hard to detect, but it becomes quite significant if it means a 10% increase in cigarette sales.

Not only will Dr. Morris's work in this area expand our understanding of nicotine addiction and multidrug resistance in tumors, but it will add to our knowledge of several other related problems. Similar systems are at work in the resistance many strains of bacteria are developing to antibiotics--something that many fear may soon become a major problem in treating routine infections- -and the resistance to treatment of the plasmodia that cause malaria. Another potential application that particularly interests Dr. Morris is the problem of cross-resistance to insecticides. Rather than loading up our fruits and vegetables with toxins, it's certainly preferable--from both health and economic standpoints--to use insecticides judiciously. Therefore, we must understand what will produce resistance to these products in the pests that would destroy the crops.

A particularly significant result of Dr. Morris's research on these questions is her fortuitous discovery of a drug that's particularly toxic to drug-resistant cancer cells. Not only is this compound not toxic to humans, the plant in which it is found is a common food. Needless to say, Dr. Morris is hard at work on developing this significant discovery. Stay tuned--she should have some very exciting results to announce in the near future.