Nobel Prize-winning science from llamas to rejections

Brian Kobilka of Stanford University won the Nobel Prize in Chemistry in 2012 for work on G protein-coupled receptors (GPCRs), which are main targets for making new drugs. GPCRs sit on cell walls and are involved in conveying chemical messages from outside the cell to the inside. If cells gets the message wrong, it may cause disease, which could be fixed if drugs can manipulate GPCRs.

In a 2007 paper in the journal Nature, Kobilka published the structure of GPCRs after decades of effort. To do that he had to use a molecule from the immune system of llamas. Ashutosh Jogalekar and I got a chance to ask him about llamas, stardom and the difficulties of doing curiosity-driven science today.

 

Ashutosh Jogalekar, Brian Kobilka and Akshat Rathi.

So how come a llama got involved in Nobel Prize-winning science?

It was partly by luck. From early 2000s, I’ve been trying every method available to crystallise GPCRs. We never were able to find something that could stabilise them on the extracellular surface. A lot of my friends knew that I was searching for a new antibody. At the Gordon conference, Jan Steyaert suggested antibodies from llama and within months  the idea worked.

Young scientists seem less keen today to stay in research. There are fewer jobs and they seems less inspired to take the harder route. What do you think can be done?

Lack of inspiration might be partly due to the fact that young scientists were in graduate school during a time when their mentors were having funding difficulties. And that meant the mentors did not have the resources to do the most interesting science. Strictly speaking, to get a grant for your research, you have to have done some of the work that you propose to do.

The problem is that only highly innovative projects get funded, but such projects are also risky. You have to provide them evidence that it will work, so the project then is probably not innovative. I feel that young scientists are not just worried about the funding situation, but that they have done their research at a time when their mentors have struggled.

How do you pitch to a grant committee something like crystallising a protein, which sounds like a fishing expedition because the chances of success are very small?

Of course, I’m given more credibility now that I was given a few years ago. My first grant to crystallise GPCRs, as you can imagine, was turned down. Somehow because we managed to get poorly diffracting crystals, we were eventually able to convince the committee. 

But, interestingly, it also depends on the study section within the grant body that the application goes to. Our application that was accepted didn’t go to a crystallography section but to the signalling section. The tolerance for risk is very different among different study sections. When I pitch for grants today, I’m given the benefit of doubt because of my work. Sadly, I don’t think that researchers starting out today will get that. 

There is strategy in navigating the system of achieving grants, but one also needs a lot of luck.

How could the current system be fixed?

Probably the best system may be a merit-based system. Like the Howard Hughes Medical Institute (HHMI), which gives grants based on a researcher’s previous work. But that wouldn’t work for current graduate students and post-doctoral researchers, so I don’t know. 

I should also note that I had HHMI funding, but they weren’t happy with my progress so they terminated it after a number of years. I had it from 1990 to 2002. I had a sense of what they expected from me, but I was more interested in doing what I wanted to do, even though that wasn’t working very well.

Another issue that researchers face today is that they are being driven to do application-focused research rather than curiosity-driven work. Have you felt this in your career in the last 30 years and how do we fix that?

I’ve been lucky in that I can always rationalise that the work I do is relevant to human disease and drug discovery. Even though that is not my active target, you always have to sell what you’re doing. I’ve been able to do that because in my area of research it is relatively easy.

You started a company called ConformetRx. What was the reason behind it?

My wife and I started a company because we were missing out on opportunities on working with industry. Before that I tried a number of times to initiate a collaboration, but in order to do so at a university that receives public funding you need really strict agreements set out by lawyers to deal with conflict of interest issues. It was never a priority for industry lawyers and they have tremendous impact over what happens in pharma. It was also not a high priority for Stanford. 

So it used to happen that they couldn’t agree at all or it would take too long. Industry has interest in a particular project only for so long, before they move on. 

We were missing out on opportunities for our work in the lab that had practical applications. The company started with very little input from us and it has grown slowly. It has helped us fund projects that we would not have been able to do otherwise.

This is your first Lindau meeting. Could you tell us a little bit about your experience so far?

Before getting the prize, I had no idea what the Lindau meeting was. I got little information before I came, so I wasn’t expecting so many students. It is also a little bit reminiscent of Stockholm because I have car as soon as I step out of a building, if I want to go somewhere. You get treated very well. That doesn’t happen at home. My wife treats me well but there’s nothing special about a Nobel Prize at Stanford University.

How have you dealt with the publicity? Has it annoyed you? Has it affected your research?

Initially the publicity is quite disruptive. Since January that has gone, but there is still a problem that I get a lot more emails with invitations, requests for letters, applications to work in my lab. And I haven’t been able to deal with them. I’m always lagging behind. I find it hard to say no. 

I feel this had some negative impact on the lab. Fortunately, my students were at a stage in their work where they could get on with less attention from me. Unfortunately, I can’t keep up with it all. So now I’ve decided that if anyone is going to suffer from my inability to manage everything, then it’s not my lab or my family but everybody else.

What do you do to relax?

I run, cycle and swim. It helps to live in a part of the world where the weather is great to do all that.

 

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