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Haiqing Bai on Understanding and Treating Influenza

The Humans of the Wyss (HOW) series features members of the Wyss community discussing their work, the influences that shape them as scientists, and their collaborations at the Wyss Institute and beyond. 

Haiqing Bai is motivated by his curiosity and desire to answer scientific questions. This inquisitive spirit led to the serendipitous, accidental discovery of a broad-spectrum RNA therapeutic that could be used against viruses like influenza and SARS-CoV-2. Learn more about Haiqing and his work in this month’s Humans of the Wyss.

What are you working on?

Haiqing Bai on Understanding and Treating Influenza
Haiqing Bai, Postdoctoral Fellow. Credit: Wyss Institute at Harvard University

I primarily work on using human Lung Chips, including the Lung Alveolus Chip and the human Airway Chip, to study influenza. We’re modeling the disease and trying to identify better therapeutic treatments. During the pandemic, we were able to quickly shift our focus to identify existing drugs and test their efficacy in treating COVID-19. This work was done as part of the drug repurposing pipeline set up by the Wyss in collaboration with the Icahn School of Medicine at Mount Sinai and the University of Maryland School of Medicine.

At the same time, Longlong Si, a colleague in Don Ingber’s lab, and I have been working on a broad-spectrum RNA therapeutic. Our discovery of this technology was pretty unexpected. In the human genome, only a small number of our genes actually code for proteins. Most of our DNA and RNA is non-coding. Scientists used to think of this as “junk,” but now we realize that many of these sequences are important, though we don’t know much about their function.

Initially, Longlong and I intended to use CRISPR technology to screen the non-coding RNAs involved in influenza infections and then use small interfering RNA (siRNA) to validate the top candidates. During the process, we serendipitously found that certain  siRNAs, which are double-stranded, can induce a type 1 interferon response, which is the body’s first line of defense against viruses. We couldn’t believe it, because these RNAs are purposely designed to avoid such an effect. So, we performed more experiments to find out what novel sequence features enable the siRNAs to become immunostimulatory RNAs (isRNAs). Then we used human Organ Chips to validate their efficacy. We also worked with our collaborators at Icahn School of Medicine at Mt. Sinai and University of Maryland School of Medicine to test these isRNAs against other pathogens like SARS, MERS, and SARS-CoV-2 and we found that they were very effective for all viruses tested, so they could be used as a broad-spectrum antiviral therapeutic.

What real world problem does this solve?

Haiqing Bai on Understanding and Treating Influenza
Haiqing and his colleagues working in the lab. Credit: Wyss Institute at Harvard University

In general, my research using Organ Chips and other technologies to better mimic respiratory diseases like influenza will be beneficial in ending this pandemic sooner and making us better prepared for potential pandemics in the future. The double-stranded RNA technology will have a more immediate effect. It can enable better design of siRNA, which are being used as a type of gene therapy to treat many diseases. The novel sequence we discovered that can induce the type 1 interferon response will provide insights for those who will use isRNAs to develop immunotherapies for cancer. We have also demonstrated that isRNAs can be used broadly as a therapeutic against viruses like influenza and SARS-CoV-2.

What inspired you to get into this field?

During my Ph.D. I studied a disease called acute respiratory distress syndrome, or ARDS. It’s a severe lung disease where fluid enters the lung, and the patient has difficulty breathing. Often the patients die from multiple organ failure. There is an approximately 40% mortality rate. ARDS has become somewhat more well-known recently because it is the primary cause of death for COVID-19 infections. When doing research during my Ph.D., I used a lot of primary cells, in vitro models, and some animal models to study ARDS, but I realized there were many limitations. For example, traditional in vitro models are too simple to capture the complexity of diseases, while data from mouse models is often inaccurate when translating it to humans. I read Dr. Ingber’s research about human Organ Chips and thought they could be a transformative tool to study respiratory diseases. So, I was inspired to email him about a postdoctoral fellow position in his lab.

What continues to motivate you?

I think it would be curiosity. In the research world, you start out with a hypothesis, but most of the time your results are completely different from what you expected. When that happens, it gives rise to more questions. You try to figure out why and how you got the outcomes you did. Our double-stranded RNA project is a great example of this. That element of uncertainty and discovery keeps me motivated on a daily basis.

What excites you the most about your work?

Haiqing Bai on Understanding and Treating Influenza
Haiqing and some of his colleagues with diverse backgrounds at the 2018 Wyss Retreat. Credit: Wyss Institute at Harvard

The opportunity to work and collaborate with people from different backgrounds is exciting. When I say that, I mean both in terms of different countries, regions, and cultures, but also scientifically. This is especially true at the Wyss. I got my Ph.D. in pathology, but I interact with molecular biologists, cell biologists, engineers, and people with expertise in data science. Working with such a variety of people is so rewarding – I learn something new every day.

What are some of the challenges that you face?

The biggest challenge is how to balance everything that you’re working on and focus enough on something to push it forward. As you advance in your career, you begin to contribute to more projects at one time. This is especially true at the Wyss because along with your main project, you have many great opportunities to collaborate. The difficulty is that each project lead has their own schedule and deadlines. It can be difficult sometimes to advance each project towards the next milestone, whether it’s writing a patent or a manuscript, while managing the different timelines.

What is unique about the Wyss and how has that impacted your work?

The resources available at the Wyss are unimaginable. Not only is there a lot of different equipment and materials, but the people are also an invaluable asset. There is talent coming from a variety of backgrounds. What’s also unique is that we’re not separated into departments – people with different specialties sit right next to you. If you don’t know something, chances are there will be someone who does, and you can easily go and talk to them. It makes it easy to establish collaborations.

Scientists tend to focus on how to finish a paper, but a publication and a translational path are not incompatible. In fact, I think that keeping the application in mind helps to push the science further.

Haiqing Bai

Another unique feature of the Wyss is the translational path. Everybody’s mindset, even before a paper comes out, is whether we can move this forward into something useful, and if so, how can we do it? This mindset is pretty rare in academic settings, but it’s useful. Scientists tend to focus on how to finish a paper, but a publication and a translational path are not incompatible. In fact, I think that keeping the application in mind helps to push the science further.

How has your previous experience shaped your approach to your work today?

I got my Ph.D. at the University of Rochester Medical School. It was a unique program in that they put biomedical scientists and physicians in the same building. You might have a doctor’s office in one room and a research lab in the next. That really affected my mindset. I’m always thinking about how the biology I’m researching can be applied to a disease. When I got to the Wyss in September 2018, Organ Chips were already commercialized, and we were at the point where we could use this well-established technology to understand more about the pathophysiology of various diseases and come up with better diagnostics and therapeutics. My background in the cell biology of diseases fit in perfectly, and my focus on the end-user meshes well with the Wyss culture.

When you’re not at the lab, and you’re not social distancing, what do you like to do?

I enjoy cooking. With COVID-19, I’ve had more time to cook. Hot pot is one of my favorite things to cook because my hometown, Sichuan, China is where hot pot started. Before I moved to Boston, I liked fishing, but I haven’t had the chance since I got here.

I also enjoy taking photos. When I was getting my Ph.D. in upstate New York I used to photograph waterfalls. After joining the Wyss, I took photos for the Wyss soccer team.

If you had to choose an entirely different career path, what would it be?

From a really young age I knew I wanted to do something related to science and nature. In high school, my top choice to study in college was physics, but I ended up majoring in systems biology. So, I think my alternative career path would be a physical engineer.

What does it feel like to be working on cutting-edge technology that has the potential to have a real and significant impact on people’s lives and society?

It’s gradual, incremental progress that we don’t think about regularly, but getting the COVID-19 vaccine made me realize that over time our work has the potential to impact people’s daily lives at a dramatic scale.

Haiqing Bai

On a daily basis, I don’t really think about this. But, the other day, when I got my first COVID-19 vaccine, I thought about how that technology is something amazing that we as a scientific community have achieved over the past 20-30 years. One hundred years ago, when the 1918 flu pandemic hit, it took almost 12 years for people to understand that the pathogen causing the pandemic was a virus, not a bacteria. Now, in about a year, we’ve identified the virus, sequenced it, and developed a vaccine. There have been amazing improvements in science over the last 100 years. It’s gradual, incremental progress that we don’t think about regularly, but getting the vaccine made me realize that over time our work has the potential to impact people’s daily lives at a dramatic scale.

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