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CHEMICAL BIOLOGY

Big Science and Blowing Bubbles
Jim Rothman's unique approach just may revolutionize drug discovery

Jim Rothman
To Jim Rothman, one of Columbia's newest faculty members, modern biology is drowning in detail. Scientific papers are filled with so many three-letter words for molecules unique to that field that whenever Dr. Rothman reads a research paper outside his own field, he feels "like shouting four-letter words because I can hardly remember all the three-letter words."

Not that Dr. Rothman has let himself off the hook. He's contributed plenty of three-letter words to the scientific literature as he revealed the details of the secretory pathway: how vesicles are made inside cells, how they move through the cell, and how they fuse with the cell membrane to ship proteins like serotonin or insulin out of the cell. Somebody else must have understood all these three-letter words since in 2002 the work earned Dr. Rothman and his colleague Dr. Randy Schekman the Lasker Award, often considered a precursor to the Nobel Prize.

Now Dr. Rothman is looking for a lifeboat to make sense of all the countless processes that go on in a living cell. What's needed, he says, is "big science approach" — something increasingly being called chemical biology or chemical genomics. On a practical level, such an approach would allow researchers to screen 50,000 drugs in one day to find the rare ones that may alleviate disease. But on a broader scientific level he believes the approach will eventually reveal a higher, and simpler, level of organization in the cell that we currently cannot see.

In Vivo's Susan Conova sat down with Dr. Rothman, professor of physiology and cellular biophysics, to see how this visionary's plan is going to change science.

Is that a silhouette of you blowing bubbles?

Yes, I had a portrait taken by a photographer and she asked me to do something that epitomized my life and I thought blowing bubbles seemed like the perfect analogy. First of all, I'm a cell biologist and a bubble connotes a spherical object like a cell. And I've been working most intensively on how vesicles within cells fuse to the cell membrane, and that's very similar to how soap bubbles coalesce. You know, when you blow a bunch of bubbles and the little bubbles stick to and merge with other little bubbles to make bigger bubbles. Plus, blowing bubbles is fun.

What does blowing bubbles have to do with "big science" chemical biology?

What I found absolutely amazing about the secretory pathway is that the same molecular machinery underlies the release of cargo from all cells, from yeast to man. The principle is very general but the use of the pathway is very different from cell to cell. If the cell is a neuron, a packet of neurotransmitters is released; if it's a pancreatic beta cell, insulin is released.

The next step is to try to figure out what regulates the pathway in these different cell types and, of course, how misregulation results in disease. Type 2 diabetes, for example, is in many respects a disease of the secretory pathway.

That led me to start thinking about how to go about understanding regulation by taking advantage of the full scope of big science biology in an approach that's increasingly called chemical biology or chemical genomics.

Why do you need "big science" to understand how cellular processes are regulated?

Can you imagine taking a radio apart, jumbling all the parts, and then handing it so somebody and asking, "So, how does it work?" That's what we biologists are trying to do.

In a case like this, the engineer would grab each part and ramp the strength of that component up and down. If the part is a capacitor in the tuning circuit, you get a big change because you're listening to WABC one moment and WCBS the next. On the other hand, if the part is in the volume circuit, the volume goes up a little but the change is not as dramatic. The point is that the engineer tries to find the components that, when you change them, have a big impact on the device's output.

Pharmacologists do the exact same thing with a cell. They alter the strength of each component with chemicals. When you throw all of chemistry at a cellular system one chemical at a time, occasionally you're going to hit an ultra-sensitive control point like that capacitor in the tuning circuit.

Until now that sort of screening to find control points has been very low throughput. The chemical genomics approach promises to very efficiently yield all them. And every one of these control points is a target for therapeutic intervention.

How will it work?

There have been some huge technological advances in the past few years that we can capitalize on. One of the major advances has been in fluorescent cell imaging, so we have very recently purchased an instrument that is essentially a microscope run at an enormous speed by a computer. It allows us to carry out 50,000 detailed microscopic cell culture experiments in a single day. This power can be harnessed to test 50,000 different potential drugs to see which rare ones have potentially beneficial effects on the disease.

The other major technological advance is the human genome. There are 30,000 to 40,000 genes in the human genome so there's a very interesting correspondence in numbers. This means that in theory you can test every gene in the human genome to see what its impact would be on a cellular process in a single day by putting each gene or an interfering RNA into one culture at a time.

In five years we would like to be in a position to take a pathophysiological process, interrogate it with tens of thousands of chemical compounds, identify those few that are potential drugs, and do all that in a single day.

On the second day, we'd take those compounds and figure out in an automated way what component of the cell they're targeting. Knowing the identity of the target will greatly facilitate research and drug development. This is now where the major roadblock is, so that's essentially the problem we're trying to solve.

It's a tall order and we very well may not succeed in five years but the reward for doing so is very substantial, so that's why I'm taking on the challenge.

Every department from surgery to pathology is happy to have you here – what prompted you to come to Columbia and how will others here benefit from your presence?

I'd been at Memorial Sloan-Kettering Cancer Center for 13 years and it's a great place but it's very specialized in cancer. I feel this work I'm embarking on has a reach that goes way beyond cancer and I wanted to be in a place where I could find collaborators, including chemists, I should add. Here we have an entire department of great chemists.

What I'm taking the responsibility to do here is build up the big science infrastructure for cellular screening, bringing together the kinds of chemical resources that are needed. Many, if not most, of the labs at Columbia could take advantage of this technology.

As the technology develops I intend to seek out collaborations with the many different labs here that specialize in one biological process or another. Most disease processes can now be recapitulated in an in vitro model, and that in vitro model can be subjected to interrogation with genes and chemicals in this high throughput and comprehensive way.

So I would love to see the day in a couple of years when investigators can come here and say, "We've found the most remarkable thing in our model of disease X. Will you help us discover what genes are required, what potential drugs can perturb the process, and how can we focus our future basic and therapeutic research?"

I'd love to be in a position to have our center interact with a wide range of investigators on that basis because it has great promise for patients. Right now we're at the beginning with a lot of dreams and hopes.


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