Ori Rotstein Lecture in Translational Research

Ori Rotstein Lecture in Translational Research

By Laura Best and Alexa Desimone

It was summer 2019. Across the desk sat Vasu Venkateswaran, smiling after catching me up on the current status of the Ori Rotstein Lecture in Translational Research. She looked at me and asked “Ok, given the title of the lecture, what do you want the panel discussion to be about?” The lecture title was long, daunting even, and clinically specific, but what stood out to us were the first two words: “my journey”.

One of the most cliché phrases my mother imparted on me was that life is not about the destination, but the journey. As a child who followed the common progression from elementary to university, this wisdom had very little meaning. My academic life existed separately from my personal life, serving the sole purpose of getting me to my future career. Life used to function more like a checklist than a journey. Yet, somewhere along the way this changed. Unexpected obstacles and opinions made me rethink previous decisions, predetermined timelines extended and shrank, priorities shifted as new people and opportunities presented themselves. However, this is common and rarely do students embark on a linear track that leads them to their predetermined finish line without turns or hurdles. These twists and hurdles often make one stronger and more innovative. I learned that this is the journey, and that is what we wanted to be the focal theme of this year’s Ori Rotstein Lecture.

On October 4th, 2019, the Institute of Medical Science (IMS) held their annual Ori Rotstein Lecture in Translational Research, and for the first time, us as students were involved in the planning. We had the pleasure of hosting surgeon-scientist and IMS alumnus Dr. David Hackam as our keynote speaker, followed by a panel discussion highlighting journeys through research. Dr. Hackam is the Chief of Paediatric Surgery and Paediatric Surgeon-in-Chief at Johns Hopkins Children’s Centre, but truthfully, he should consider a side career in comedy.

“In this business we are invited to give talks often, but it is rare that you get to speak with family, in front of those who played a huge role in getting me to where I am today” – Dr. David J. Hackam

Surrounded by a number of mentors, the talk began with a full-circle story. A quote from Dr. Rotstein, “I’ll make you famous, come and work for me”, initiated Dr. Hackam’s journey from a struggling graduate student to a surgeon-scientist working at a world-renowned hospital. After completing his residency and doctoral studies, Dr. Hackam began his paediatric fellowship at the University of Pittsburgh. It was there, where he met a family whose son, Freddy, was diagnosed with necrotizing enterocolitis (NEC). This clinical encounter inspired his life’s research focus: a cure for this devastating disease.

Photo by IMS Office

In 2014, Dr. Hackam was recruited to Johns Hopkins Hospital as Chief of Paediatric Surgery and Co-Director of the Children’s Centre and began to dive deeper into his research focus. NEC is one of the most common fatal diseases of the gastrointestinal tract, affecting 2-15% of premature infants. Originally, scientists thought NEC was caused by immune system dysfunction secondary to prematurity. However, Dr. Hackam and his surgical colleagues focused on the intestines and the bacteria-endothelium interaction. After the discovery of toll-like receptor 4 (TLR4) on the endothelium of premature babies, they hypothesized that this immune receptor, when exposed to bacteria, overreacts, leading to cell death and the decay of the intestines.

Dr. Hackam considered why the developing gut would have a receptor that had such devastating impacts if it didn’t function properly. The answer lies in the fact that the premature baby is exposed to an abnormal environment. In-utero, TLR4 acts as a critical gut development regulator, but when TLR4 continues to be expressed postnatally it becomes a destructive inflammatory receptor. Fortunately, breast milk is known to be protective against NEC development; various molecules within breast milk are able to reverse NEC through inhibition of TLR4, which prompted Dr. Hackam to explore if medications could do the same. A TLR4 inhibitor was the first approach, and him and his team identified a molecular compound, C34, which effectively inhibits TLR4 in NEC animal models.

When patients survive NEC, they are typically left with long-term cognitive deficits. Dr. Hackam has identified the underlying mechanism demonstrating TLR4’s control of these deficits. He has shown that TLR4 in the gut leads to the release of molecules that activate microglia in the brain, leading to cell death and demyelination. A novel formulation which contains complexes to directly distribute TLR4 antagonists to the brain is a therapeutic strategy that he is currently pursuing.

Ultimately, being in an institution such as Johns Hopkins, with an abundance of resources available, Dr. Hackam had the opportunity to carry out his research to its full potential. Dr. Rotstein said, “You take the first job, to get the second job”, and this rang true for Dr. Hackam as pivotal advice in his career trajectory. If it wasn’t for Pittsburgh and meeting Freddy, Johns Hopkins would not have recruited him, and he would not have, over 20 years, developed five possible therapies for the treatment of NEC.

Photo by IMS Office

Following the keynote, the panel discussion was moderated by Dr. Ori Rotstein himself, and featured Dr. Shelley Boyd, Dr. Samantha Anthony, Dr. Sunit Das, Laura Best and Dr. David Hackam. Diversity of experience was the intention behind panelist selection, yet a commonality between panelists and audience members alike was a passion for science and research. This common ground led to an inclusive environment and dynamic conversation between panelists and students.

The discussion began with an invitation for each panelist to talk about their own journey including a hurdle or pivotal moment. Dr. Boyd, an entrepreneur and ophthalmologist at St. Michael’s Hospital, is the founder of biotech company Translatum Medicus Inc, and previously worked in the pharmaceutical industry at Novartis. Dr. Anthony, an IMS alumnus and clinician-scientist at SickKids, shared her experience forging the path as Canada’s first clinician-scientist with training in social work. Dr. Das, a neurosurgeon at St. Michael’s Hospital, shared the benefits of innovative thinking and cross-disciplinary training with his degrees in english literature and philosophy. Laura Best, a current PhD student in IMS, has held numerous leadership positions, sits on the board of a charity for women’s brain health, and is striving to learn all she can during her time in IMS.

Photo by IMS Office

2019 was the first year the Ori Rotstein Lecture in Translational Research was organized by IMS students

Students in the audience asked a variety of questions to the panelists, ranging from advice for navigating an early career in science to the panelists’ favourite books. When the discussion reluctantly came to an end, Dr. Rotstein shared some of the commonalities he heard amongst the journeys: (1) Incredible optimism and persistence are essential characteristics to success. (2) To a certain extent, many of the panelists’ experiences were not preplanned, instead they followed their noses to see what worked for them. (3) You have to like what you do because life is long. (4) Work hard, but balance is important. (5) Finding the right role model or mentor can be a game changer.

As graduate students ourselves, we are still in the process of learning and exploring our fields. Our experiences differ as we consider our unique perspectives and circumstances. What is common, though, is the existence of unpredictable influences on these experiences and that our unique strengths help us navigate our own journeys. For us, one thing we know is that planning the Ori Rotstein Lecture was not in the original plan, but it was definitely an impactful chapter in our journey here at IMS.

IMS writer Laura Best is currently a PhD student with Dr. Isabelle Boileau at CAMH. Her work uses neuroimaging to investigate the involvement of the endogenous cannabinoid system in alcohol use disorder. Check out this issue’s student spotlight to learn more about her work and time with IMS!