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The Simple Goals of Complex Systems: Nobel Laureate James E. Rothman Talks About Nanomachines, Cutting Through the Fog, Personalized Medicine and the Benefits of Becoming Fish Wrap

On October 7, biologist James E. Rothman received the 2013 Nobel Prize in Physiology and Medicine together with colleagues Randy W. Schekman and Thomas C. Südhof. Rothman is a professor of biomedical sciences at Yale. Over the last decade he has served as a senior advisor to GE Global Research in Niskayuna, NY. He is also a former chief scientist at GE Healthcare. GE Reports managing editor Tomas Kellner talked to Rothman last week about his discovery, innovation, and GE.

Nobel laureate James Rothman worked as chief scientist at GE Healthcare. “In the university we talk a lot about collaboration, discovery through bringing together disciplines,” he says. “I have never seen it work anywhere as well as at GE Global Research.”

The Nobel committee is known in the U.S. for what may be the world’s most exhilarating wake up call. Where were you when you learned the news that you won a Nobel?

I was at home and I was in bed. The phone rang and there was a very pleasant Swedish voice bringing good news. It turned out that I had met the gentleman who was calling, Göran Hansson, at a scientific conference a couple of years ago. He is the Secretary of the Nobel Assembly at the Karolinska Institute in Stockholm.

The Nobel committee recognized you and your two colleagues for “solving the mystery” of how cells transport molecules like insulin to the right place in the cell and at the right time. Why is that important?

The body is made up of many different types of cells that make up your muscle, your liver or the nerve cells in your brain. These cells need to communicate with each other, otherwise they get out of synch and the liver won’t function like a liver.

Adding even more complexity, the different organs need to talk to each other. For example, when you eat a meal, your intestines are digesting the food and producing sugar that goes into the blood. The pancreas is detecting the sugar and secreting insulin to control and distribute the sugar throughout the body. There have to be signals or information flowing between the components of the system in order for it to function in a coherent way. Every electrical engineer will understand this. The work we have done has elucidated how those signals are produced and passed between cells.

It is interesting that you mention engineering. Your Nobel is in physiology and medicine, you studied medicine, but you left medical school and trained as a physicist.

I am not a physicist in any professional sense. But like many people at GE who are engineers, my initial education was in math and physics. I later moved toward molecular biology.

You said in an interview that what attracted you to molecular biology was the opportunity to find simplicity. Can you explain it? Biology seems inherently messy.

I’ve observed that biologists fall into two camps. There are those who seek simplicity and find it, and then there are those who seek complexity and revel in it. I know that sounds a little odd, but I think it’s true.

The goal of a complex system can actually be very simple. Its core function could be almost mechanical, like a little machine. In fact, we found that this is the case. Most of cell biology is carried out by proteins that are very complex on one level, but when you look at them through an electron microscope, they behave just like little nanomachines. So you have something than can be very complex, involving interactions of tens of thousands of atoms in multiple combinations and a complex interface between two proteins, or it can be conceptualized for example as a hammer hitting a nail, because one of the proteins looks like a hammer and the other looks like a nail.

You cannot get a simpler system than that.

If you have orientation to physics, where you always expect some simplicity and generality as distinct from the way biology is usually approached, it’s possible to make better progress in a complex field and cut through the fog more easily.

You could use these simple building blocks to create a much more complex picture and gain a deeper understanding.

That’s exactly right. The very complex behaviors of healthy and diseased organs are now being modeled increasingly using tools similar to what electrical engineers use. This approach extracts the essence and represents a profound simplification. This so called systems biology is becoming an important tool for example in the pharmaceutical industry. It will be an important clinical tool down the road for qualifying patients for treatments.

Such personalized medicine is a goal that GE is also pursuing. When did you start working at GE?

My history with GE goes back to early 2000s when GE acquired Amersham. That company brought to GE a great strength in life sciences. This truly differentiates GE from major industrial companies. I served for several years as chief scientist at GE Healthcare, which was then a new business formed by the combination of Amersham and GE’s imaging unit, GE Medical. I also started working in a high-level advisory role at GE Global Research (GRC). We essentially moved the Amersham research group from New Jersey to GRC and we’ve seen so many rewards from that move over the years.

Why was this move so important?

At first, the biologists were out in the left field and the GRC engineers didn’t really know how to relate to them even. They were working on two completely different sets of projects. But over the years we’ve seen the biology culture infuse and inform almost every aspect of research across the healthcare business. The development of digital pathology is an important example. Ten years ago we were not in digital pathology at all. If you think about it, that’s kind of interesting, because GE is a predominant company in the imaging space.

Can you explain the connection between medical imaging and pathology?

Pathologists use a microscope, rather than an MRI or ultrasound machine, to analyze a large numbers of cells. It’s subjective, it’s not digital, it’s qualitative, it’s all the things that radiology is not. But we were able to develop digital pathology because of the infusion of biology in the engineering.

Is digital pathology a tool that could help us advance personalized medicine?

Digital pathology paves the road for digitizing the pathology department. Once the environment is digital, data are created and stored in an archive in instantly manageable and accessible forms. This creates the platform for personalized medicine.

But this is just the first step. Step two is the development of molecular pathology at GRC, and that still continues. The acquisition of Clarient a few years ago was a major step in this direction. This is a big deal in clinical medicine and, eventually, cancer treatment. While digital pathology purely concerns capturing and storing microscope images of samples like tumor biopsies, molecular pathology images numerous potential cancer causing genes within the tumor, allowing pinpoint diagnoses and targeted treatments.

How often do you visit GRC?

I am usually in Niskayuna two days a month. I work very closely with the scientists and the advanced technology there, particularly John Burczak and Nadeem Ishaque, who are great leaders. I have the privilege of working with a great number of very talented people, including Mike Idelchik [vice president for advanced technologies] and Mark Little [GE senior vice president and chief technology officer], whose leadership is really quite extraordinary.

You have a busy academic career as chair of the cell biology department at Yale. What makes you go back to GRC?

Having had the experience of working with other companies as an adviser, I can tell you that there is no greater company in the world. It is absolutely my privilege to be a part of GE. The value system, the business focus, the innovation that goes on at GRC are all astonishing.

In the university we talk a lot about collaboration, discovery through bringing together disciplines. I have never seen it work anywhere as well as at GRC. The needs of the various business segments way outside of healthcare are appreciated by the people at GRC through the very nature of the lab. That sort of non-quantifiable knowledge has a way of leveraging across the whole of GE.

People who do not really understand GE describe us as a conglomerate. Sure, we are very broadly based. But what I see from the standpoint of GE Global Research is a company that has technology platforms that add enormous value that goes way beyond the conglomerate [label]. I see it every time I am at GRC and it excites me because I learn so much from my colleagues there.

How do you compare university research, or blue-sky research, and the type of research that goes on at GRC, which is looking for commercial applications? Are there benefits to having a product in mind?

Absolutely. GE does that so impressively.

Academia is largely supported by the public because of what you call the blue-sky aspect, with the hope that some of that will translate it into outcomes that benefit the society broadly. That of course happens.

GE Global Research has many, many tentacles and connections into the academia. GRC has labs all over the world and we have excellent relationship with excellent investigators at the top universities. We go to meetings, we publish, and we are understood to be leaders. That’s very important because it gives us visibility and it gives us access. It allows us to be part of the ecosystem in the way that we function, which is synthesizing the blue sky developments, the best of them, that occur anywhere in the world.

We take those developments, the best of them and we infuse them with the shorter term needs of the various businesses. Out of that ferment emerge projects that have perhaps a longer term timeline than what the business would ordinarily be excited about. It’s very powerful. I am not aware of any other large industrial that has the kind of leverage that we have.

Have you started working on your Nobel lecture? Do you have a topic in mind?

That’s a good question. The ceremony is scheduled for early December in Stockholm. I have not started working on my Nobel Lecture, which is a special lecture of more than average importance. This week there has been a lot of interest from the press. I trust that it will go away by next week as we become fish wrap.

I am also trying to get some sleep. I’ve been going on three to four hours of sleep all week. If I conveyed any measure of coherence today, that in itself should be worth of a Nobel Prize.

Thank you for your time.

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