10 December 2018

Fate Decisions ‒ Paving the Way to Scientific Success, an Interview with Anant Mamidi

Nature paper

An interview with Assistant Professor Anant Mamidi, Co-first author of a Nature paper: ‘Mechanosignaling via integrins directs pancreatic progenitor fate decisions’

Story by postdocs Abigail Jackson and Ulf Tiemann

Scientists from the Semb group in DanStem have discovered how fate decisions in the developing pancreas are determined by the immediate environment that progenitor cells are exposed to. The study has identified specific factors in the matrix surrounding naive pancreatic cells (progenitors) that act to maintain the ‘gatekeeper’ protein YAP. When the progenitor cells are exposed to an alternative matrix factor, they lose YAP and commit toward a mature cell identity with the potential to become cells that produce insulin in response to glucose. The results, published last month in “Nature”*, are likely to facilitate the production of functional insulin-producing cells from human stem cells for future diabetes therapies. We interviewed Anant Mamidi who, together with Christy Prawiro, implemented the study.

Anant, who were your role models as you grew up and what was your motivation to become a scientist?

My father was a pharmacist and I used to spend a lot of time in his pharmacy during my childhood in Southern India. I was always fascinated when patients with severe diseases could be treated back to health with a single pill. I really wanted to know what was behind this and I dreamt of making new discoveries myself, like the invention of penicillin by Alexander Fleming. So I decided to become a scientist ‒ even though my father was hoping I would go for a career in medicine!

You moved to Europe for your PhD. how was that experience for you?

It was a great opportunity given by my former supervisor Rakesh Mishra, who, in 2005 was organizing an EMBO conference.  He recommended me to an invited speaker - Stefano Piccolo - who was recruiting young scientists for his newly established lab. He offered me a 2-week visit to Italy that led to a PhD position in his group. Moving to Europe was a big change for me, since I had never been outside of India before, but luckily my fellow lab members helped me to overcome the cultural differences.

After your time in the Piccolo lab you moved from Cancer Biology to Stem Cell Biology, what prompted this change, which then led you to DanStem?

After 5 publications in the cancer field I was offered a prestigious industrial ‘presidential Post-doc’ in cancer research at Novartis in California. At the same time I learned my father had developed type 2 diabetes, with retinopathy complications and this motivated me to change my focus to pancreas and stem cell research with the hope of contributing to diabetes cures. When Yamanaka published his ground breaking development of reprogrammed stem cells in 2006, my dream using cell replacement therapies seemed achievable.

The paper’s findings are a culmination of diverse collaborative experiments, what enabled such a productive interaction in the project?

I think it’s extremely important to credit my co-authors but also DanStem as the department’s integrative environment made the project a success. Christy and myself benefited from the collaboration mutually: she worked extremely hard to establish the single cell culture system and I related the findings in vivo. Our collaboration with the Serup group – Palle, Phil and Kristian – was initiated after a department presentation. It was their Notch expertise that helped tie the project together. DanStem is a nurturing environment that prides itself on collaborations and its important to take advantage of this unique opportunity. 

Your unique insight into how a naive pancreas cell’s physical environment can instruct its maturation opens up many new avenues of research, how do you plan to follow up on such a novel finding?

The Nature paper has demonstrated that effective cell differentiation requires a permissive environment.  A naive cell receives instructions from signals in the media but also from exposure to the right surface. My ultimate dream is to translate this knowledge to medical research and be part of clinical trials that aim to use cellular therapies to treat diabetes.

Research, especially using mice and human embryonic stem cells as model organisms, requires dedication over many years, what kept you motivated?

I think a common driving force for every scientist is the hope that our discoveries may benefit society, for example by treating patients. Most importantly I could not have achieved my goals without the support of my wife Swetha Kancharla. She has always followed my dreams and it is because of her that I could keep motivated over all this time. Reaching these achievements are also a result of the support and guidance I have  received from Professor Henrik Semb, who I thank very much. 

Looking back on what you have achieved, what advice would you give to a junior scientists just starting out on their scientific journey?

Have belief in your project and in yourself, even in the face of frustration and pressure! And discuss your results with other scientists, be it inside your own group or on retreats, conferences etc. This will give you new ideas and can open the door for multidisciplinary collaborations, so don’t be shy!

*Anant Mamidi, Christy Prawiro (equal contribution), Philip A. Seymour, Kristian Honnens de Lichtenberg, Abigail Jackson, Palle Serup, and Henrik Semb. Mechanosignalling via integrins directs fate decisions of pancreatic progenitors. Nature. 2018 Nov 28. doi: 10.1038/s41586-018-0762-2.

The work was supported by a 2-year postdoctoral fellowship from the Lundbeck Foundation and by grants from the Novo Nordisk Foundation to Henrik Semb, the corresponding author. 

Anant Mamidi and Henrik Semb are inventors of international patent (WO2016170067A1), which is based on this work.

Anant began his career in the field of microbiology in India. He changed his interest to developmental biology and studied Hox gene regulatory mechanisms in the fruit fly embryo when he worked as a research fellow with Rakesh Mishra at the CCMB institute in Hyderabad. He then did his PhD and a short postdoc in Stefano Piccolo’s lab in Padua (Italy), where he studied TGFbeta and Wnt signalling pathways in the context of frog embryonic development and human cancer cells. Since the start of the DanStem center in 2011, Anant has been part of the Semb research group as a postdoctoral fellow and later as an assistant professor, where he studies pancreas development in mice and in human stem cells.