BCS Career Interviews – Prof. Ooi Eng Eong, SAB member of Arcturus Therapeutics

Published by Biotech Connection Singapore on

In this edition of the BCS career interviews, we have the privilege of speaking with Prof Ooi Eng Eong, a highly respected figure in the field of virology and infectious diseases research. Prof Ooi serves as a Scientific Advisory Board (SAB) member for Arcturus Therapeutics, a company specializing in messenger RNA medicines and vaccines. In this interview, BCS Communications Lead, Qian Yi Lee, discusses with Prof Ooi about his journey to become an SAB board member and the role the SAB plays in biotech start-ups. With his extensive background and expertise, particularly in the areas of dengue and COVID-19, Prof Ooi also offers invaluable insights into pandemic response strategies and the challenges faced by startups in the scientific industry. (Any opinions in this article are personal and do not reflect those of the interviewee’s employers)

 

QY: Hi Professor Ooi, thank you for taking time for this interview today. Could you tell us more about your background and how you became an SAB member at Arcturus Therapeutics?

Prof Ooi: I trained in medicine, and after my medical training, I decided to pursue a career in research. I did my PhD with Professor Chan Soh Ha at the Department of Microbiology in NUS. Around the time I was finishing my PhD in 1998, Singapore had a big dengue outbreak. The only dengue virologist in the country had retired a couple of years ago, so there was a pressing need to have someone working on dengue again. That was how I ended up working on dengue, and it is my research interest up to this day. 

During the COVID-19 outbreak, I was approached by EDB to see if I was willing to collaborate with Arcturus Therapeutics to develop a vaccine against COVID. I was not looking for developmental work on vaccines at that time, but when I heard it was a self-amplifying mRNA vaccine, I thought, okay, this is something I might be able to contribute, since this vaccine construct is based on a RNA virus

So, we then collaborated with Arcturus Therapeutics to develop the vaccine from preclinical stage, all the way through to phase one and two trials here in Singapore. That was the earlier version of the vaccine, which eventually led to the development of ARCT154, which became the vaccine that was licensed for use in Japan, and hopefully soon globally, as a booster shot to prevent COVID-19.

That was how I got into this field to work with Arcturus Therapeutics. And because of all the collaborations we did, they eventually invited me to be on the SAB.  

 

QY: Would you mind explaining a bit more about the self-amplifying mRNA vaccine? How is that different from regular vaccines?

Prof Ooi: Sure! The conventional mRNA vaccine, like the ones developed by Pfizer and Moderna that many of us received, is at its core a spike gene mRNA. When it goes into the cell, the cell then translates that into the spike protein, which allows the immune system to learn how to recognize that spike protein on a virus. So, when we do get infected with the virus, our immune response against the virus is much faster than if we have never seen the spike protein before.  

The self-amplifying mRNA vaccine goes one step further. Unlike the conventional mRNA vaccine, where what you put into the body is all that you have, a self-amplifying mRNA will multiply a little when it is administered. Now, when I say multiply, it’s not like a virus where it multiplies and spreads throughout the body.  The self-amplifying mRNA only multiplies in the cells that you put it into, in this case, the immune cells in your arm, and only for a very limited period. Then the immune cells bring the mRNA back to the lymph nodes, where all the immune memory gets developed. So with a self-amplifying mRNA vaccine, you can administer it at a much lower dose compared to regular mRNA and get more bang for your buck.

 

QY: What does a position as an SAB member encompass?

Prof Ooi: The advisory board serves in exactly that capacity – as an advisor. So, whenever the company feels that they need scientific advice, they will convene an advisory board to hear the different views. We are not like the board of directors, that has oversight over the company in terms of their operations, finance, strategy, etc. 

 

QY: In your opinion, what are the most critical factors for success in biotech, particularly in Singapore?

Prof Ooi: From a science perspective, any product that you want to develop should be grounded in good science. That’s fundamental. If the scientific basis for that product is uncertain, then there are going to be a lot of pitfalls along the way. And that is partly why companies want to hear views from the SAB members, so they know what are the latest trends in the field, and whether they (the SAB members) are supportive of the path forward or if they are saying, hold on a minute, be very careful about going down this path.

 

QY: That makes a lot of sense. Based on your experience, what are some common pitfalls or mistakes that biotech companies tend to make, and how can they be avoided?

Prof Ooi: If it is based on direct experience in a start-up, then I have only really been involved in one startup so far. I cannot say I have a success story to share there, but there were a lot of lessons I have learned from that experience. 

I think that, besides the science, the way you run a business is something that founders that come from an academic setting often neglect. Although the science can be a complete showstopper, if the business model is wrong, then you are essentially going to be wasting money. Even if the science is strong, you will also need someone who can manage the company well to bring it to success. 

At least one of the pitfalls I have encountered is that the company becomes unfocused and tries to do too many things, causing them to burn through their financial resources too quickly. In academia, we are often driven by curiosity, whereas in a biotech, the focus should be on product development. You kind of need both, but there’s a role for academia to fill, and there’s a role for biotech to fill. And sometimes you just have to let go of pursuit of knowledge for product development.

So, we need to ensure that there is good management of the financial resources and hire the best people to make sure things are well managed and the operations are as efficient as possible.

 

QY: What do you see as the most significant challenges in RNA therapeutics and vaccines today?

Prof Ooi: From a therapeutics perspective, mRNA works very well if it’s a liver disease. Because when you deliver the mRNA to the body, quite a bit of it ends up in the liver. But for other organs, then it becomes a little bit trickier. Because then, how do you make sure that that RNA, which is supposed to act as a drug, will end up in the cells that you want it to go to instead of the liver? So that would be an area we need to watch and see how that develops.

Regarding RNA vaccines…even beyond mRNA vaccines, we have recently been seeing a spike in vaccine hesitancy and the anti-vax movement. This is something that we probably need to do a better job of overcoming. There is nothing much we can do about people that are staunchly anti-vax, but we need to reach out a bit more to groups that are just hesitant because they don’t understand. I am not a social scientist, so I am probably not the best person to come up with solutions to this, but we do need to do a far better job of educating and promoting vaccinations.

The second issue is specifically regarding mRNA vaccines. It was particularly helpful in COVID, but I don’t think it will succeed in all viral infections. Everyone seems to be a bit overly enamoured with mRNA vaccines because of the success with COVID-19, but I think we got a bit lucky there. Had the pandemic been caused by a virus that’s more similar to dengue, I think we’ll still be struggling to get a vaccine today. 

 

QY: Why do you say it is not applicable to other viruses though? 

Prof Ooi: There are two parts to generating vaccines that can evoke immune response. First is the neutralizing antibodies generated against the virus, and second is the T cells recognizing a foreign virus. The ways antibodies and T cells recognize a virus are very different. The first recognizes the three dimensional structure while the second is seeing the components of that structure. In the COVID-19 coronavirus, we were very fortunate that the spike protein generated by the mRNA vaccines is recognized by both the neutralizing antibodies and the T-cells. But for viruses like dengue, it does not work like that. The parts that are targeted by the antibodies are not the parts that are targeted by T cells. So yes, mRNA vaccines are good. We have seen how fast it can be developed and manufactured. But it also has limitations. 

 

QY: I am curious regarding mRNA vaccine, it is actually quite different from how traditional vaccines were developed. What do you think made RNA vaccine succeed? 

Prof Ooi: I think the idea of using nucleic acids as a vaccine has been around for a long time. The most effective form of vaccine so far has been a live attenuated vaccine, which are live viruses that carry mutations that weaken them and prevent them from causing disease. The reason why they are good is because they still deliver their nucleic acid genome in the form of DNA or RNA into the cells which then translate the viral proteins and gives you the whole breadth of immune response.

So the idea therefore is that if instead of giving the whole virus, can we just give the nucleic acids containing the genes? People have tried DNA vaccines for a long time, but DNA vaccines, while they work well with small animals, the efficacy drops drastically with higher order mammals. It’s problematic, partly I think because the DNA needs to get into the cells, through the cytoplasm and into the nucleus, which is a lot of hurdles to jump through. 

Then the idea of just delivering mRNA came up, because it just needs to be delivered into the cytoplasm. This was helped by the two ground-breaking technologies. The first was nanoparticle technology, which allows RNA to be delivered across the plasma membrane into cells. The second were the discoveries by Nobel Laureates Kariko and Weissman on nucleoside modifications that prevent the cells from recognizing the RNA vaccines as foreign particles and getting rid of them. 

 

QY: Can you share any memorable success stories or lessons learned from your previous involvement with startup ventures?

Prof Ooi: I have only had one of my own start-up ventures. It was a company I started with Prof Ram Sasisekharan from MIT, called Tychan. He was an expert at engineering antibodies, and we thought we could apply this to antiviral therapeutics against viral viruses. We managed to get a monoclonal antibody against the Zika virus during the outbreak in South America, and another against Yellow Fever during the 2018 outbreak in Brazil. There is currently no treatment for both Zika and Yellow Fever. There are vaccines available for Yellow Fever, but it is not enough to be supplied globally. The concern at that time was that Yellow Fever might spread to other countries, including in Singapore, since the mosquitoes that spread Yellow Fever are the same as the ones that spread Dengue, and it would be a devastating epidemic since we have no population immunity against Yellow Fever.

So, the goal of the company was to help develop antiviral therapeutics quickly in response to an epidemic. Zika and Yellow Fever were two areas of focus for us, and we took both antibodies into Phase I trials, which showed good safety profiles. In the case of Yellow Fever, we even managed to show good proof of concept that it could prevent an infection using the live yellow fever vaccine to simulate an infection. 

Unfortunately, the investors decided that they wanted to turn their attention elsewhere. 

 

QY: That is very unfortunate because those could be life-saving therapies.

Prof Ooi: Yeah. But it’s one of the things – how do you make a company that is, in some ways, preparing to get ready for the next epidemic or pandemic sustainable? Because if the epidemic never happens, where’s the revenue, right?

 

QY: Do you think public funding might be more appropriate for this kind of company? 

Prof Ooi: Yes, I think you’re right. This might be something for the Ministries of Health to consider banding together to support. I think it will not make sense for just one country to try and support, because your domestic market isn’t always big enough to support commercial viability.

That’s why I say, I think that having good science is a necessary start, but having someone savvy with the business development is also critical to really consider what would be a good business model to support this kind of therapeutics.

 

QY: What advice would you give to aspiring entrepreneurs or startup founders?

Prof Ooi: Don’t be afraid to try. If you think you have a great idea, then follow your instincts. Make sure the science is well grounded, and then follow your instincts and find partners who can support you, or bring in partners with different skill sets that compliment yours and then go for it.

 

QY: What are your hopes for biotech in Singapore?

Prof Ooi: I hope that it will grow. I mean, I hope that we will have a very vibrant biotech scene. Certainly, from the science perspective, I think there are a lot of good ideas. There is a lot of new and exciting data. And I dare say that the research that is happening in Singapore is really at the forefront, and we are right up there with the very best right?

But we are still a far cry from the Boston and Silicon Valley kind of scene in terms of start-ups, and I think that there’s probably multiple factors. One is that I think the investors do need to see a little bit more track record from Singapore. But then it becomes a chicken and egg issue, because if they don’t invest, they’re not going to see this track record develop itself. But I think we have the science. Do we have people that are willing to take risks? I think we do, but maybe not as many as you would find in the Boston area or the Silicon Valley area.

So yeah, I think we just need to get one or two companies off the ground. And when they start to, people can see that, Hey, if they can do it, so can we, and then it will grow. 

Biotech Connection Singapore (BCS) is part of an international network of non-profit organizations, that aims to promote the transfer of ideas from theory to real world applications by providing a platform for fostering interaction between academia, industry and businesses.