November 2011: Building the right ensemble of imaging equipment was one of the most important decisions in setting up my lab — second only to getting the right students to join my group. One of the goals of establishing our lab at the Hebrew University was to strengthen the live cell imaging capabilities at the Silberman Institute of Life Sciences by developing sophisticated methods for both quantitative and phenomenological applications in cell biology.
We study highly dynamic cell biological processes such as protein folding and protein aggregation (biochemical processes that are highly relevant for understanding and treating neurodegenerative diseases), with an emphasis on studying these processes in the living cell in real time. The microscopy applications that we sought to develop therefore go hand-in-hand with the basic science questions that interest us. In choosing the right microscopy set-up my goal was twofold.
For sophisticated, quantitative imaging I wanted a microscope that would image rapidly at high resolution and in three dimensions. In effect, I wanted to be able to peek inside a living cell and watch as proteins interact, fold and move around. At the same time, I wanted to be able to simultaneously manipulate the proteins that I was watching — in a sense, to turn them on and off. Secondly, I also wanted to improve our phenomenological capabilities by developing imaging approaches that can increase our resolution down to single-molecule size.
There were a number of options from three competing companies. The decision took longer than any other decision I’ve ever had to make, and included a lot of testing, playing around with the microscopes, and even a trip to France to demo one of the microscopes that was not yet installed anywhere else.
A decision like this is both nerve-racking and exhilarating. No one wants to make a million-dollar mistake, and mistakes do happen — a microscope can be ill-suited for an application, the company team supporting it might be incapable of properly installing and maintaining the equipment, and the microscope could just plain not work. These are very complicated machines with many moving parts and optics relying on nanometer precision, so when you buy one you have to be absolutely sure that it works (and when you are one of the first people in the world buying it, that’s not a simple task).
It was also one of the most exciting decisions I've ever made. For someone who loves microscopes and imaging, and can generally spend tens of hours in a row playing with a ’scope, the opportunity to have a microscopy set-up like this in my own lab is a once-in-a-lifetime event.
All in all it took us about a year, start to finish, to do all the necessary research, negotiate with the companies, and iron out the exact details of the package we were going to purchase and the specifications of the microscopy system. In the end, once the decision was made, I had a gut feeling that it was the right one.
We were the first lab in Israel to buy this type of system from this particular company (Nikon), but weeks after we made our decisions a half dozen other labs decided to purchase the same or a similar microscope from them, so I think it was a good deal for all involved.
After a few months of assembling the various parts at the Nikon factory, the microscope started coming in. It’s not just “a microscope” as we typically think of it. The entire thing takes up two small rooms, and includes air tables, incubators, the scopes themselves, and various modules with lasers, optics, and detectors. It took about two weeks to assemble everything, and this is just half of the system so far (the half that will be doing the rapid, quantitative live-cell imaging).
We are still waiting for the other half, since it would be unfeasible to assemble everything simultaneously. From the day the first half of the system was operational, I have been using it almost non-stop, and now the students in the lab are also slowly getting to know it. I have to say that it exceeded my expectations — I have never seen the quality of images that we are getting from it (more on that later).
Now the challenge is to make all of the students in the lab experts in using this microscope. This is not as easy as it sounds — I’ve spent the last 10 years on various kinds of microscopes day and night, and there are still a million new things for me to learn about this type of imaging. For my students it will be like learning a new language and then using that language to get to know a person really well (in this case, the microscope is the person). It will take time, but we are already seeing amazing data from our new imaging system.
Harvard graduate Dr. Daniel Kaganovich, who joined the Hebrew University in 2010, is exploring protein folding and aggregation, a basic cellular process with profound implications for neurodegenerative diseases. Apart from getting the ‘ideal starting package’ with his own lab and highly specialized and costly equipment, he is benefitting from working with Israel’s best students.
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