Discovery of Potential Therapeutic Drugs for Lung Disease

Discovery of Potential Therapeutic Drugs for Lung Disease

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By: Yekta Dowlati

Mingyao Liu, MD, MSc
Director,  Institute of Medical Science, University of Toronto
Professor, Department of Surgery, and Physiology, Faculty of Medicine, University of Toronto
Senior Scientist, Toronto General Research Institute, University Health Network

Dr. Mingyao Liu is a senior scientist at the Toronto General Hospital Research Institute, a full Professor of Surgery in the Departments of Physiology and Medicine, and the Director of the Institute of Medical Science (IMS) at the University of Toronto (U of T). His research interest is focused on ischemia-reperfusion induced lung injury in lung transplantation, and the cellular and molecular mechanisms of acute lung injury. I sat down with Dr. Liu to hear more about his passionate and successful scientific career in lung research, which will have substantial impact on treatment outcomes for patients with pulmonary diseases.

Could you tell us a little bit about your background, training, and the events that brought you to the University of Toronto?

I obtained my Medical Degree in 1983 and my Master of Science in 1986 in China. I completed two projects during my Master studies. For the first project, I designed precise evaluation equipment to measure the activity of lung surfactant, which was manufactured in collaboration with engineers and commercialized in China. For my second project, I tried to purify the surfactant from animal lungs and then prepared the surfactant as a drug for therapy. Later, after I left China, my colleagues commercialized that preparation and made it into a clinical drug.

In 1987, I moved to Buffalo, New York, as a visiting scholar. Half a year later, I got an appointment as a research assistant professor, continuing my work in surfactant related research. After three years, I immigrated to Canada. Dr. Martin Post, at the Hospital for Sick Children (SickKids), offered me a fellowship, which helped me learn about cellular molecular biology and intracellular signal transduction. In 1994, I got a faculty position at SickKids and later moved to Toronto General Hospital. Together with Dr. Shaf Keshavjee, we created a team that started [with] the two of us. Now, we have approximately 100 people working on acute lung injury in transplantation studies.

What inspired you to begin conducting research in respiratory disease?

When I was a medical student, I was selected to do research in my second year. I started working with a professor who was doing acute respiratory distress syndrome (ARDS) research, and got very interested in lung research. Since then, it never changed and I have been conducting research on the lung my entire life.

Please describe your most recent discoveries and research work.

Basically, my current research can be summarized in three different categories. First is the development of a translational pipeline. There are many potential therapies; however, if you look at clinical practice, doctors are still using the same treatments as three decades ago. There is no new drug that has been effectively translated into clinical practice. One particular challenge is that most of these studies are done in small animals, such as mice, rats, or, the largest, rabbits. But the human body is much bigger, and the hemodynamics, pharmacokinetics, and cell metabolism…are so different compared to small animals. Therefore, we need to verify that what we discovered in small animals in larger model organisms as a preclinical trial. If that works, then a lot of what we learned from animals could be translated to humans. Accordingly, we have developed this as a pipeline for drug discovery and delivery. We have two pig lung transplantation models. In one model, we sacrifice the animal four hours after lung transplantation in order to evaluate the therapeutic effects on ischemia-reperfusion injury. In the other model, we let the animal survive for 3-7 days to see if the therapeutic effects last. In addition, with Dr. Keshavjee and our team, we have developed a technique called the “ex-vivo lung perfusion system,” which intends to treat injured donor lungs before transplantation. We are using this to test the therapeutic effects on damaged human donor lungs. With this pipeline, we are exploring multiple therapeutic reagents for acute lung injury.

Second, most of the transplantation studies done so far are collected from animal studies or clinical observations, and the cellular molecular mechanisms are largely unknown. Moreover, when you do an animal study, for each drug you need to have control and therapy groups, at different dosing and timing; hence it’s not easy and you cannot test too many things. So as a cell molecular biologist, my lab developed a novel cell culture model to explore mechanisms at the cellular level. Of course, the cell culture model is too simple and we need to validate our finding with animal models.

Third, the clinical application of many developed drugs is limited by the absence of an efficient vehicle that allows their solubility in water. My lab used nanotechnology to make non-soluble drugs water-soluble; in other words, to formulate hydrophobic drugs, so they can be directly injected into the blood stream.

What are you hoping to see in the future as a result of your work?

We know translation of our research into clinical practice has a long way to go, and many people may get discouraged by high costs and the length of the pipeline studies. Our first approach is to collaborate with industry partners and pharmaceutical companies. For example, take a clinical drug that is used to treat emphysema. There is cumulative evidence that this drug has anti-inflammation and anti cell-death effects. We took this drug and ran it through our pipeline and now we are almost near the end of the tests, and will launch a clinical trial by next year. Based on our studies in cells, small [animals], and large animals, we think that the likelihood of this drug working is very high. As a result of our collaborations, we are also being chased by other companies to test their drugs in this pipeline. In my opinion, investigating old drugs for new applications is an excellent approach that can speed up translation and build up confidence for the availability of new drugs to the clinicians.

In addition, we leverage the technology and skill sets developed through collaboration with pharmaceutical companies to make this pipeline available for our own discovered drugs. I hope this pipeline will speed up our own drug discovery process, so I can see the day that our drugs can be used clinically.

Finally, I hope that the cellular molecular models to select and develop new drugs will be further developed by my junior faculty members and students in the future.

What are some of the challenges you are facing in your research?

The major challenge for me is the continuous evolution of knowledge and technology. I still remember, a long time ago, when I was a fellow at SickKids, someone came to the U of T to give a lecture about polymerase chain reactions (PCR). The [entire] U of T community was rushing to a big auditorium. But now, everyone knows about PCR. So, many new technologies and skills are continuously evolving; thus, we as professors are also learning all the time. Currently, as I have many administrative responsibilities, my students take a lead on their projects and they come back to teach me. So I say, “I am my students’ student.” This continued learning is challenging and at the same time very interesting as it keeps you young.

What is your best advice for graduate students?

Recently, the Faculty of Medicine introduced a training program for faculty members on how to help our students build an individual career development plan. In the past, our advice to our students was to work hard; but no matter how hard you are working, only 15-20% of people will eventually become professors. It does not mean that the other 80% of people did not work hard. Each graduate student, especially [those pursuing a PhD], has a personal interest and based on that, they have to gain the skills to reach their goal. For example, if one is interested in teaching, he or she needs to gain communication skills, and if one is interested in industry, he or she has to start getting connections early in graduate training. So if I need to give one piece of advice, it is this: “Prepare your career as early as possible, so [that] by preparing yourself, you will be more motivated and more successful.”