Case study

Lalita RamakrishnanProfessor of Immunology and Infectious Diseases, University of CambridgePrincipal Research Fellowships

Getting Wellcome Trust funding

What attracted you to Wellcome and to this scheme?

I was settled in Seattle when out of the blue I got a letter from Ken Smith asking if I would be interested in relocating to Cambridge. My first thought was, ‘No, of course not.’ But when I looked into it I realised that Cambridge could offer a unique combination of resources. 

I went for a visit, and Ken and his colleagues suggested that a Wellcome Trust Principal Research Fellowship (PRF) might be the best option for supporting a move. Initially, I was uncertain, but the Cambridge people told me how prestigious PRFs were, and it became clear a PRF would enable me to expand my research.

What aspects of the Principal Research Fellowship funding are most useful to you?

The PRF status is nice, but the chance to upgrade the scale of my research was the major attraction. The funding is flexible – I have the freedom to go in new directions and take a few risks. Obviously, I’m accountable at the end of the funding period, but I like being able to decide what avenues to pursue. 

The funding is also well-suited to international relocations. There was a generous relocation allowance, for lab members as well as me. I brought a team of seven with me – it’s a big move for them too, so it’s good they’re also well taken care of. 

I had a few teething troubles after I arrived, and the Trust was really responsive in getting them resolved. It’s very engaged with fellows in a way that government funding bodies, such as the Medical Research Council (MRC) and National Institutes of Health (NIH), simply don’t have the capacity to match.

What do you think of Wellcome’s application process?

I phoned people at Wellcome and they were very encouraging. They were also flexible about deadlines, as we were putting everything together in a rush. The application form is fairly short considering the size of the funding. It focuses on your long-term goals and there’s not much space for details. I was fine with that, although some of the interview panel then suggested there wasn't enough detail in my application. I was selected for interview and flown over to the UK.

You get ten minutes and are allowed three slides. That’s really challenging – us professors aren’t used to such discipline. There was some pretty aggressive questioning after my presentation, which I expected. Overall, I was pleased with the way it went.

How challenging have you found it to secure funding?

There was some risk in going for the PRF – I had to make the decision to relocate before I knew if I had an interview. I got an NIH Director’s Pioneer Award at the third attempt. And although I got a postdoctoral fellowship from the Howard Hughes Medical Institute, I never managed to get an Investigator award. Whenever members of my team get a rejection, I tell them it happens to everyone – you just have to keep going.

What advice would you give to other applicants?

I’d recommend the PRF scheme to any senior scientists thinking about relocating to the UK. People at Wellcome understand what relocation involves, they’ve designed processes to make it as easy as possible and they offer a very competitive package. It’s a shame more people aren’t aware of the terrific opportunities. There’s probably a perception that UK funding is smaller and shorter term, but that’s certainly not the case with a PRF.

Career path

Career Summary

  • 2014 Wellcome Trust Principal Research Fellowship
  • 2014–present Professor of Immunology and Infectious Diseases, University of Cambridge
  • 2010 NIH Director’s Pioneer Award
  • 2005 Burroughs Wellcome Pathogenesis of Infectious Diseases Award
  • 2001–14 Professor of Microbiology and Medicine, Adjunct Professor of Immunology, University of Washington, Seattle, USA (appointed as assistant professor, promoted to professor)  
  • 1998–2000 Senior Research Scientist, Stanford University School of Medicine, USA
  • 1997 Second child born
  • 1993 First child born
  • 1992–98 Postdoctoral Fellow, Stanford University School of Medicine, USA
  • 1992 Howard Hughes Medical Institute Physician Postdoctoral Fellowship Award
  • 1991–92 Clinical Fellow in Infectious Diseases, University of California, San Francisco, USA
  • 1988–91 Resident in Medicine, New England Medical Center, Boston, USA
  • 1990 PhD, Tufts University, Boston, USA
  • 1984–88 Graduate Research Fellow, Tufts University School of Medicine, Boston, USA
  • 1983–84 Graduate student, State University of New York, USA
  • 1983 MBBS, Baroda Medical College, India

What have been the defining moments in your career so far?

It would be when I followed up on Stanley Falkow’s advice to use a surrogate mycobacterial pathogen that infects fish. I discovered Mycobacterium marinum in Bergey’s Manual of Systemic Bacteriology. As I read , I realised this had the potential to be a great model. 

Soon after, the consultant doctor I was working with as an infectious diseases fellow suggested I try the zebrafish as a natural host for Mycobacterium marinum. It took me years to get the system up to the point I could do it, but within three to four weeks of working with the fish larvae we knew we were on to a great system. I still remember the heady excitement when we stared in the microscope and realised we were seeing the tuberculous granuloma form in the zebrafish.

I’ve tended to be a bit impulsive in my career moves, and some have been challenging to organise. Moving to the UK is a big deal. It’s been great for my science, but my husband has had to find new work, my son has had to leave his friends and start a new school, my elderly father has come to England with us, and my university-going daughter has seen her childhood home in Seattle disappear. But we’re settling in now – definitely no regrets.

Research

What’s the key question you’re addressing?

My focus is on tuberculosis (TB) and how infection with Mycobacterium tuberculosis causes disease. I don’t have specific medical goals. I’m seeking a better understanding of the disease process. What we’ve learned so far has had practical spin-offs, leading to new clinical trials.

How are you going about answering this question?

Mainly I use zebrafish to study interactions between pathogen and host1. Zebrafish embryos are transparent, so you can watch infection occurring. And zebrafish genetics are very powerful – you can screen random mutations to find genes affecting susceptibility to infection or introduce changes into genes of interest. 

We also use other model organisms, cellular studies and work on human infections –whichever approach is most suitable to the scientific question we want to answer. 

What discoveries have you made?

One of our key recent discoveries was of a complex mechanism the bacterium uses to enter ‘permissive’ macrophages – those in which it can survive rather than be destroyed2. Also, that mycobacteria survive in organised structures called granuloma. These have been thought of as host protective structures, but we showed they provide a site in which the bacteria can reproduce3. TB has been considered a disease of failed immunity. But we’ve shown that some patients mount very vigorous inflammatory reactions4. We should be thinking about treating the disease differently according to the type of inflammatory responses being mounted by different individuals. Some of our findings provide ideal examples of precision medicine5.

References

  1. Ramakrishnan L. The zebrafish guide to tuberculosis immunity and treatment. Cold Spring Harb Symp Quant Biol 2013;78:179–92.
  2. Cambier CJ et al. Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature 2014;505(7482):218–22.
  3. Tobin DM et al. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 2012;148(3):434–46.
  4. Roca FJ, Ramakrishnan L. TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species. Cell 2013;153(3):521–34.
  5. Volkman HE et al. Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science 2010;327(5964):466–9.

More information

Find out more about Lalita's reseach on the University of Cambridge website.

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