Samir Ounzain – Joining the Dark Side
"seeing my basic academic research translate into real-world solutions for patients suffering with heart failure and supporting that process would bring incredible satisfaction and gratitude"
Dr Samir Ounzain is CEO and co-founder of precision medicine biotech HAYA Therapeutics, developing therapies to treat fibrotic diseases. Founded in 2019, HAYA are headquartered in Lausanne, Switzerland.
In the BHF's 60th Anniversary month, Samir tells us about his BHF-funded PhD project in the lab of our Medical Director, Professor Sir Nilesh Samani, the 'dark matter' and long non-coding RNAs that inspired the jump into industry, and how it felt to secure $20 million of seed funding for HAYA in early 2021...
What drew you to cardiovascular science; why the heart?
I was always fascinated by how your genome, and in particular the regulatory portion of it, controls development and disease. Unfortunately, I have, like many others, been touched personally by cardiovascular diseases. This was a driving force and motivation for me to try and decipher the regulatory genomes roles in cardiovascular disease and, ultimately, to try and find new therapeutic solutions by targeting your genomes ‘dark side’. This drew me to cardiovascular science, and the founding of HAYA Therapeutics. Can we, as a community, provide our loved ones with more effective, safe and accessible medicines for cardiovascular disease?
Finally, the heart as an organ has always fascinated me, both scientifically and emotionally. I think William Harvey [English Physician, 1578-1657] distilled this beautifully;`The heart of animals is the foundation of their life, the sovereign of everything within them, the sun of their microcosm, that upon which all growth depends, from which all power proceeds’.
Tell us about your BHF-funded PhD at the University of Leicester, and working with Professor Sir Nilesh Samani.
My PhD studies, led by Sir Nilesh Samani, represents where my academic career started and where my interest in the underlying science that led to HAYA Therapeutics was born.
Nilesh’s group had recently discovered a new gene linked to muscle development and function called Myocyte Stress 1 (MS1). My PhD project was to try to decipher the molecular mechanisms that governed its expression both in development and disease. This is where I truly became fascinated with the genomes ‘dark matter’. This is the portion of the genome that does not encode for proteins and was naively assumed to be ‘junk’, but what was realized is this portion of the genome is full of regulatory information and governs the expression of key genes, like MS1, in tissue, cell and disease specific ways. At the time, genome wide transcriptomic and epigenomic approaches were still nascent and I used a comparative genomics approach (looking for non-coding regions highly conserved between species) to identify the genetic switches that regulate MS1 expression in development and disease.
My time in the department also coincided with pioneering work from Sir Nilesh Samani using genome-wide association studies (GWAS) to identify genetic risk variants associated with coronary artery disease. These studies further highlighted and accelerated my interest in the genomes dark side as it was clear then that the vast majority of variants linked to common diseases were located in the genomes non-coding regulatory portion. This work also represented one of the first examples of the potential importance of long non-coding RNAs (i.e. ANRIL) in cardiovascular disease, the target molecule class that HAYA Therapeutics is now leveraging for first-in-class tissue and cell-selective anti-fibrotic therapeutics.
Following my PhD, I moved to London (UCL, Institute of Child Health, also a BHF funded project) to continue my post-doctoral work studying the roles of protein factors (transcription factors) that dictate the activity of the regulatory non-coding genome in cardiac development and disease.
You moved to Switzerland in 2011, working at Lausanne University Hospital, what motivated the move and what did you find when you got there?
Towards the end of my post-doctoral work in London it was becoming apparent that the genomes regulatory ‘dark side’ was more active than previously thought and was in fact being transcribed into a new class of regulatory RNA called long non-coding RNAs. Long non-coding RNAs are a class of molecules that can form complex structures to interact with both proteins and nucleic acids (DNA and RNA), thereby bridging the ‘digital’ and ‘analogue’ worlds of biomolecules within your cells controlling their fate and behaviour. At this time, it was unknown how this long non-coding RNA landscape behaved in the heart and this stimulated me to move to Lausanne, Switzerland. I was looking for an opportunity to profile this landscape in mammalian models of heart failure and was given the opportunity to move to the Experimental Cardiology Unit at the Lausanne University Hospital (CHUV). This department had outstanding pre-clinical experimental models of heart disease and heart failure coupled with an excellent supporting ecosystem with respect to the genomic, transcriptomic and bioinformatic competences required to conduct such an exploration.
Furthermore, excellent funding from the Swiss National Science Foundation allowed us to proceed with what, at the time, was a somewhat high risk and costly exploratory study delving into the genomes dark side in the heart. Fortunately, the project was a success and we proceeded to map and ultimately discover 100s of novel and functionally interesting lncRNAs with important roles in cardiovascular development (i.e. CARMEN, Meteor) and disease (i.e. Wisper).
When did you realise that you wanted to move from academic research to commercial therapeutics, and what did this journey feel like for you?
Early on during my post-doctoral work at the Lausanne University Hospital, it became strikingly apparent that these new regulatory RNAs we were discovering could have significant translational potential. They serve as the computational engine of your genome and had unprecedented tissue, cell and disease specific activity which rendered them very exciting potential targets for next-generation RNA-targeting therapies. Our pre-clinical data targeting these molecules supported this potential (i.e. blocking cardiac fibrosis by targeting the lncRNA Wisper) and that was ultimately what drove me to found HAYA Therapeutics and transition from academia into industry.
Basic scientific research is at the core of innovation and the development of future medicines. Realizing we had a real-world solution to an incredibly painful problem (heart failure associated with cardiac fibrosis) was a strong motivational force that drove me to make the jump.
How did it feel to secure $20 million of seed funding for HAYA Therapeutics?
It was extremely satisfying to be able to close our financing round and have the capital and support to take our therapeutic hypothesis to the next steps in pre-clinical development and, ultimately, towards the clinic. In addition to the capital, the calibre of our investors and advisors supporting our work and believing in our first-in-biology approach to solve this problem was particularly exciting and validating.
You’ve worked in research in the UK and Switzerland, and have started your commercial venture in Europe. Do you have any reflections on how the landscape is changing post-Brexit?
I would like to say, having spent time both in Switzerland and the UK, that basic academic research and translational commercial development of next generation therapies to halt and potentially cure heart failure is truly an international and global effort. Any barriers to collaboration and development will ultimately only delay innovation and the speed at which we can bring solutions to patients who desperately need new safe, effective and accessible medicines.
BHF Alumni connects our community all over the world. How have networks played a role in your journey?
My time in the UK both as a PhD student and as a post-doctoral researcher allowed me to form many relationships with talented and passionate colleagues in the cardiovascular domain, the majority of which were supported by the BHF. To this day this network allows me to gain insights and collaborations which play a significant role supporting HAYA’s mission in combatting cardiac fibrosis and ultimately providing new solutions to patients with heart failure.
What does the future hold for you, and for HAYA Therapeutics?
HAYA is now proceeding with pre-clinical large animal studies that will hopefully allow us to take our new approach to the clinic and provide patients with heart failure a truly targeted therapy that combats one of the underlying drivers of the disease, cardiac fibrosis.
On a personal note, seeing my basic academic research translate into real-world solutions for patients suffering with heart failure and supporting that process would bring incredible satisfaction and gratitude.
Is there a life mantra/motto/ethos that drives your career? What is it?
I think Nietzsche [Friedrich Nietzsche, German Philosopher, 1844-1900] had an interesting perspective that I tried to carry with me in my scientific career and now as I try to develop novel therapeutic approaches drugging the genomes dark matter; ‘Convictions are more dangerous foes of truth than lies’. Both in academia and in industry, we are often married to specific convictions which don’t necessarily reflect the counterintuitive nature of our biology and the implications this may have on countering disease. It is for this reason we should always try to stress-test our convictions and allow them to be challenged and ultimately changed if we want to discover and innovate in the life sciences sector.
Dr Samir Ounzain on Twitter
HAYA Therepeutics on Twitter