Interview with Dr. Chris Beh

Associate Professor, Department of Molecular Biology & Biochemistry

Cholesterol Genetics and Genomics, Cell Polarization

It is easy to lose perspective about how dynamic biological cells are and instead see them merely as fixed building blocks of an organism. Activity and movement within a cell is ever-changing: molecules are on the move, going in every direction, all of the time, billions of them moving around every second. The orchestration of intracellular movement, the coordination of events toward purpose is what interests Dr. Chris Beh. How does a cell maintain what looks like a static balance with all that fantastic motion going on?

Do you consider yourself a basic researcher?
Absolutely, though my lab has projects that are translational and medically relevant as well. If you look at the recent Nobel prizes, most emphasize basic research. If you are doing applied science you can make fantastic discoveries to create valuable commercial products, but if you do something fabulous in basic research those ideas can establish entire new industries.

Why do you tackle your research questions using a yeast model?
With yeast cells we can remove genes, replace them with genes from humans or any other organism, and express those genes at any time. We can manipulate things in any way we want – the yeast system is a biotechnology marvel!

With yeast we are truly working with a clonal organism. When we delete a gene and compare it to its unmodified normal progenitor, the mutant is identical except for that one change we made. So we have precise control over the targeted changes we make and this gives us control over all of the molecular genetics experiments we conduct.

In contrast, making a knockout mouse to study the effect of a gene can take months or years, but sometimes you can ask the same questions using yeast and get answers in less than a week. For getting quick answers about fundamental processes common to all living cells, yeast is hard to beat.

Among yeast genetics researchers, what is your specialty?
We stand out by making elaborate and novel combinations of mutants. For example, using molecular genetics my lab has made complex combinations of gene deletions to examine the collective function of large gene families, including those encoding potential protein carriers for moving cholesterol around within cells. Our mutants allow us to manipulate all of these different genes in unison and observe the effect.

Further, we deleted a bunch of other genes that encode proteins that stick membranes together inside the cell. We found some fascinating, unanticipated contributions of these internal membrane contacts, including roles in regulating cellular metabolism and segregation of the DNA-containing nucleus during cell division. These surprising results are an example of what can happen by just following where experimental data leads.

Microscope image of two yeast cells with daughter cell buds.  The internal membrane of the cell is labeled using a red fluorescent membrane-associated protein. These cells have been genetically modified in the Beh lab to produce an "artificial staple" protein, as visualized by the green fluorescent spots, assembled from several proteins found in other organisms. The artificial staple shows up as discrete areas around the cell membrane. In mutant cells that lack the natural ability to tether the red internal membrane to the inner face of the outer cell membrane, the green artificial protein “staples” the internal and external membranes back together.

What projects are you working on right now?
We study how cells transport materials to and from different organelle membranes within the cell. Each organelle is a biochemically active machine, each with its own special environment, supporting different chemical processes – that's why these structures need to be compartmentalized.

We know a lot about how material is moved in the cell, but we don't understand much about how that movement is coordinated and balanced. Moving material and communicating with other organelles within a cell requires vesicles, small structures that are more or less bubbles of proteins, lipids and other components contained inside and on the vesicle membrane.

One of our more recent projects looks at how the cell balances the removal of old material with the import of new cargo at the cell surface. Coordinating the movement across the membrane preserves a balance that maintains a seemingly constant surface area and size of the cell. We discovered that this process is regulated by a protein that acts like a molecular switch. The protein moves within cells on vesicles to the inside face of the cell membrane and once there, it triggers an inward recycling of membrane, which we call ‘compensatory endocytosis’ – membrane in, membrane out.

What makes cholesterol transport so fascinating?
We know a lot about how cholesterol travels through our arterial passages, but we still don't know much about how cholesterol moves once it is within cells. Cholesterol is a fat that is not miscible in water, so it must have some way of moving through the watery environment of the cell to reach its destination, the outer cell membrane. One way is via vesicles, and my program is looking at another way, protein carriers for transporting cholesterol.  

It turns out that Mother Nature has cleverly devised multiple mechanisms that work together to transport cholesterol. We want to knock out all of these cholesterol transport mechanisms (i.e., the vesicles and protein carrier mechanisms) to understand how they work together.

You discovered that certain cholesterol binding proteins are involved in cell polarization and, furthermore, that their dysfunction is related to cancer. Did you expect cholesterol binding proteins to relate to cancer?
We found that regulatory proteins responsible for setting up the directionality of cell growth do not work correctly in cells that lack a particular class of supposed cholesterol transport proteins. We discovered that not all of these supposed cholesterol-binding proteins were specific for sterols; some of them actually bind to other lipids. The link to cancer is that some of the other lipids they transport help regulate aspects of cell division. So, the multiple targets of these carrier proteins mean that their functions are far more ubiquitous than we had thought.

These discoveries came about through an unanticipated result that we then pursued. Following the science is the hallmark of good basic research, to find what exactly is pertinent in an unbiased way. The excitement of having unanticipated results and not knowing where the research is going to take you is probably the most appealing part of my research.

What applied research do you do?
We are collaborating with a group in Engineering to make a biosensor to detect very small amounts of estrogens, to track hormone levels on a daily basis so women will know the best time to conceive. We envision using yeast, almost like a computer chip, for a biosensor that is cheap, fast and easy to use.

What do you look for in prospective group members?
I've been fortunate to have exceptional graduate students, which has led to increased research funding for my program, such as my recent NSERC Discovery Accelerator Supplement grant.

I look for a combination of personal motivation and interest in talking about the possibilities revealed by research results. The best student is not necessarily one who has perfect grades. An A+ student who has never dealt with failure can crumble, while a student who has had their ups and downs is often more equipped to roll with the punches, to move on and test the next hypothesis. Mother Nature doesn't always do what we think she should do, so research success requires a thick skin.

Is the recent change in government leadership in Canada affecting how science is conducted in the country?
I am delighted with the new appreciation shown by the new government in cultivating basic science and letting researchers explore topics in ways they think best. The previous government took a business approach to science, which has its limitations. In business, gains are realized in the short-term, in a matter of years, whereas for basic science the outlook is longer, and advances can take decades. For transformative discoveries, you have to be in it for the long-haul.

What contemporary scientific issue concerns you the most?
The dwindling enthusiasm for basic research is one of my biggest concerns. People think we've learned everything possible and now it's time to apply that knowledge. The truth is, basic research provides a pool of new ideas without which inspirations for new applications dry up. There is so much we do not understand; basic research provides a window into this wide and amazing territory of unknowns.

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 Read more: Dr. Beh’s profile on the Molecular Biology and Biochemistry website, the Beh lab site and the Featured Researchers page

Interview by Jacqueline Watson with Theresa Kitos