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How do you do? A bold challenge to open the future, SDF Diary. Recently, there have been days full of the freshness of May. Looking at the leaves outside the window, some people have imagined that in Korea, a "petrochemical powerhouse" that does not produce a drop of oil, the leaves can become raw materials for energy and plastic. Lee Sang-yup, Distinguished Professor of Biochemical Engineering at KAIST[5], has been leading the world in the field of science with the slightly strange name of 'metabolic engineering'.

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< fresh May recording. Mokdong>

In this period of transition, especially in the era of so-called tech-politics, where what strategic technology a country has affects its security and alliances, there is a renewed interest in scientists who have been working on cutting-edge technologies.

I met Professor Lee Sang-yup in Daejeon.

[1] Distinguished Professor is the highest honorary position on campus selected by KAIST from among professors on campus who have achieved world-class research and educational achievements and lead their fields of expertise. It is allowed to select within 3% of the total number of professors, and if selected as a distinguished professor, special incentives are given and privileges are given to continue working as non-tenure after the retirement age.

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It was the first time in 2010 years that I met Professor Lee Sang-yup, who was our SDF speaker in 13 under the title "Plastics from Blades of Grass: Challenging Industrial Bio and Petrochemical Industries".

I had previously heard the good news that Professor Lee Sang-yup and Professor Binnari Kim of Seoul National University were selected as the first Korean scientists of the Royal Society, a 2021-year-old institution with Isaac Newton, Charles Darwin, Albert Einstein, and Stephen Hawking in 360.

Q. Hello Professor. How have you been? I remember when you came as a speaker at our forum in 2010, I was curious to hear that you were taking on the challenge of making plastic from leaves. What kind of research do you focus on these days?

I've been researching metabolic engineering all my life. Biotechnology[2] and engineering[3] overlap. Objects can be all living things, and I've limited my research to "bacteria" that are ethically problematic and safe, that is, where we can put them in tanks or something, raise them, and kill them completely if necessary, with engineering to do research that can be done to fix them.

Usually, bacteria are in our skin, in our intestines, and all over the place. But the reason they are there is to feed themselves, grow up, and reproduce. But then I discovered that bacteria make so-called antibiotics and anticancer drugs. However, since we make so small quantities, how can we mass-produce it with science and benefit the current 80 billion people?

[2] Biotechnology is biotechnology, biotechnology. It is a general term for a technology that uses living organisms such as living microorganisms to change one organic substance into another or several substances.
[3] Engineering refers to engineering, the study of discovering technical problems and proposing technical solutions.

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<SDF2010 'Plastic from a Blade of Grass' session presented by Professor Lee Sang-yup>

'Irreplaceable technology' starts
from the search for solutions to the problems facing mankind!

The research I've been doing falls into three main categories. The first is that we are now too dependent on fossil fuels to get energy and chemicals. But in the climate crisis, the problem of resource depletion, that is, crude oil is produced over hundreds of millions of years, and we have dragged it out at a tremendous rate for the last 50~60 years. So it's out of balance. Therefore, we set a goal to produce petrochemicals from bio-renewable raw materials.

You know it's obligatory to make gasoline into bio for the first time in the world, and then to mix it with biodiesel for the first time in the world, and then in the case of diesel? [4] However, biodiesel is based on sustainable vegetable oils such as palm oil. But this palm oil is a very important food in Southeast Asia. So, as the population grows and consumption continues, the dilemma of whether to use it for food or fuel may arise. So I thought, 'We need to make biomass [5] from raw materials that even diesel can't eat,' so we developed a few years ago to make diesel very efficiently from glucose obtained from non-edible biomass such as waste wood. Even now it's being upgraded, and gasoline, which we showed academically, but not anymore. There are two reasons, one is that the efficiency is not as high as I thought. For example, if we put gasoline in at a gas station and it costs 2500 million won per liter, who can put it in? It's the price of the car (laughs) and the other thing is that we're already switching to electric cars anyway, so we're not doing it. Diesel must be used anyway in places where heavy duty [6] is required, such as cargo transportation, so we continue to research it.

[4] Since 2006, the government has launched a pilot project to blend biodiesel with diesel, and since 2015, it has introduced mandatory renewable fuel blending (RFS), which has increased the biodiesel blending rate to 2.5%. In 2018, the rate rose to 3.0 percent, and now it is 3.5 percent, increasing by 0.5 percent annually, aiming to increase by 2030 percent by 8.
[5] 'Biomass' was originally an ecological term for "biomass", but is now used to mean the amount of organism that can be converted into energy. Green plants receive solar energy, use water and carbon dioxide gas to synthesize starch, sugar, or fiber, which they store in plants. Animals feed on plants, and animals and plants are eventually decomposed into inorganic substances such as carbon dioxide gas and water by microorganisms to form a circular process. All the "organisms" involved in the cycle of these ecosystems are called biomass, and the largest of these are plant resources.
[6] The dictionary meaning of heavy duty is to be sturdy and to work in harsh environments.

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And the other thing is that plastic is very important in petrochemicals, and there are a lot of different types of plastics. Some plastics are stronger than steel, others are just used and thrown away, like PET bottles, and what SDF announced was mainly about "biodegradable plastics[7]." There are places where it should be used, but "biodegradable plastic" is not universally used. For example, cinematographer, I use a camera made of 'biodegradable plastic' to save the environment, so I bought it for 5 million won, but after a week, it rotted, so you can't do that.

[7] 'Biodegradable plastic' refers to plastics that can be degraded by bacteria or living organisms.

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There are five characteristics of plastic: lightweight, with excellent physical properties, inexpensive, non-perishable, and the processing is the way we want it to be. However, the main reason why plastic is the main cause of environmental pollution is that it emits greenhouse gases while making it from fossil fuels, and it is a problem because it does not rot when it is cheapened, used a lot, and discarded insignificantly. That's why we've been researching for the past 15 years to replace plastics with bio-based plastics.

We don't get various petroleum raw materials from petrochemicals, we get them from bios like glucose. We doted on it ignorantly in such research. We have created so many of them that a few years ago, Nature, a British scientific journal considered the oldest and most prominent in the world, said, "Let's summarize the metabolism that occurs in living organisms and the chemicals that we can make through metabolic reactions," so we created what we call a Google Map of bio-based chemicals.

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<Google Maps of biobased chemicals working with Nature, 2019>

So far, we've talked about bio-based chemistry to move to so-called "carbon neutrality" to respond to the climate crisis. Another important issue is the "health" of people.

For example, antioxidants are important to protect against skin aging, and it's better to eat tomatoes than to apply a million won cream. But to be effective, I had to eat a few truckloads of tomatoes, and I made a huge amount of lycopene, a bacterium that gives tomatoes a red color. Normally, tomatoes take 100 days to grow, but we made them in a fermenter within 50 hours, and we made them in a 48-ton truckload of tomatoes. So let's refine it and make it something like a pill so that it can have a big effect all at once, and we do this kind of research. The two antioxidant two-headed wagons are lycopene and astaxanthin, the orange color of krill. It was also difficult to make, but we produced it efficiently by fermentation a few years ago. After all, I'm always saying that everything starts with a problem.

And then I went one step further and started to pay attention not only to the big problems, but also to the small issues that were related to life. When I was on a business trip to the United States, I happened to go shopping for medicine and saw cold medicine for my children, and the scent I usually put in to make them eat well was grape flavor, but it was a chemical made from petroleum. We were feeding our kids oil without knowing it. So this is not what I want to make it even fermented. It's easier said than done, but it's not easy, and I made it after 5 years of research.

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<Professor Lee Sang-yup writing his name on the charter at the Royal Society membership ceremony, 2022 /
Newton's signature on the charter is also seen. (c) Royal Society>

In our lab, we have a wet team that does experiments and an insilico team that does only computers, and when the corona outbreak broke out, we called the head of the insilico team and asked him to help us with an algorithm, so we looked into it, and usually people over 65 take an average of five different drugs a day. These are all clinically approved drugs, but the problem is that there are not many results on whether it can be mixed together. They say that 1,10 people a year die from that issue in the United States alone. So, when we collected the global adverse event data with artificial intelligence, it turned out to be 14,240. But even if you mix the two, there are 14.240 million interactions. But now, Paxroids, which are effective treatments for corona, are usually given to people with underlying medical conditions or older people. They already have medication. So, after training 48,86 side effects with deep learning, we added all <>.<> million combinations, sprayed <>,<> side effects into <> side effect types, and applied them to Paxroid and presented them. We're scientists, so we can't do clinical trials, but if you predict that if you eat it, you're more likely to have cardiotoxicity, so it's better to eat it in a combination that you don't think will have such side effects. They wanted it to be a reference for doctors to prescribe.

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<Study on Drug Presentation that Can Have Side Effects When Eaten with Paxroids, a Corona Drug, 2023,
Professor Lee Sang-yup's research team>

Q. I think that's great. How far is the actual commercialization?

That's the key issue. After more than 30 years of research, academically, I have contributed to the extent that Korea's "metabolic engineering" is at the top. We have raised many great disciples and are active in all walks of life. When I think about what I want to do for the rest of the year, I want to see one or two of them go back to the factory with what I made, and I'm focusing on that even if I don't.

In the past, there were 100 new discoveries and research that were just being dragged out, but now it's about 70. Our students are already the first in the world and the best in the world, so we have to do that, but we still have to do research that we need to build a factory for about 30. We do it as a company project, we cooperate with industry and academia, and we receive national projects. The advantage of crude oil is that it has such a good structure and can be obtained at such a low price. Bio is a weed and this kind of thing seems free, but it also has to be collected, and it takes quite a bit of money to decompose it and make glucose. The reason why commercialization is not fast is because the price is not competitive. I think that if we maximize the performance of the microbial factory and somehow get close to the crude oil, consumers will naturally use it if it is so smart and helpful to the global environment.

Among the things we do, polyester and then analogues of PET[8] are the best in the world. The bio-based plastics that I talked about at SDF at that time were also made and commercialized by CJ Cheil Jedang. It's not the same thing as mine, but I'm trying to commercialize it and expand it to 5,8 tons a year in Indonesia. Especially these days, "plastic regulations" are coming in mainly in Europe, and because of the carbon neutrality issue, carbon taxes, border taxes, etc., are all coming out as actions now. So now we can't afford not to switch to bio. So, in my room, students with master's and doctoral degrees are hitting the price.

[9] PET is polyethylene terephthalate (PET), a synthetic resin used in the manufacture of beverage bottles.

Q. Is there anything that is holding back such advanced research because regulation or the system has not yet kept up?

There are always a few things to look at when it comes to 'emerging technologies'[9]. One is when the technology is good but the business is failing and the house is in shambles, and the other is that it's not just bio because of regulations, it's often an issue. And the other one is called 'Dual Use', which is made to be used for good, but it can be abused. That's why our research and development people put a lot of emphasis on things like 'research ethics' and so-called 'biosafety'.

[<>] 'Emerging technology' is a developing technology that is expected to be put into practical use.

More "physician scientists" can create
new national wealth such as drug development

Q. In the past, there were a lot of "scientists" who wanted to be "scientists," but now they seem to want more "doctors." I'm curious to know how you see this situation.

KAIST has been emphasizing "pseudoscientists" for a very long time. A 'physician-scientist' doesn't do clinical work and see patients, but does science with medical knowledge. We make new drugs. Engineers like me don't know the mysteries of the human body, so they have to work with a doctor. If one person could do both, it would be much more efficient. That's why KAIST created the Graduate School of Medical Science a long time ago, and only when more "physician-scientists" are emitted from these places can Korea become a so-called "biomedical powerhouse." Most doctors do clinical services, so it is not easy to make drugs and contribute to the creation of new national wealth.

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<Source: Ministry of Science and ICT>

In particular, if we continue to rely on semiconductors alone, the future of the country can come and go like a lamp, so we need to secure at least one or two more strategic technologies, right? The government recently announced 12 strategic technologies, which also include "advanced biotechnology." Anyway, in summary, I'm not worried about it yet, but I think it's too much of a concern. I think parents, teachers, and the media should play a role in thinking more actively about what "job safety" means in this transitional period.

Q. Doing something new is not an easy path with no guarantee of success. The professor is also called an "alchemist", so how about making up the things you think are so exactly?

It's so much fun. It's fun because it's good, but in the meantime, would everything have been fine for me? If not, it's painful. The student is more distressed, and the student is more distressed... But when I dig more and do it, I get 10 times the joy. And if we can't, we take pride in saying that no one else in the world can do it, and when we do, we'll be the "first in the world." But when it really doesn't work, I veer around. Because we tackle such difficult topics, we sometimes turn to other things.

In fact, research in the fields that Korea is now pioneering is increasing. The government recently announced that it will support the task of "high risk, high return"[10] that challenges the limits while facilitating failure under the term "limit-challenging R&D". Even if we fail, if we gather what we have learned along the way, we can become a national competitiveness.

[10] 'High risk, high return' means that the greater the risk, the greater the reward.

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For the first time in a long time, we met the world's best scientist with great passion and pride, and we thought it was wonderful throughout the interview.

Finally, when I asked the professor what is a serious issue in the eyes of researchers, but what is still less interesting in our society, he said that if we look at the big topics first, the first is the "climate crisis," then the "health issue in the age of aging," and the biggest problem in the world, like the corona pandemic, is the "antibiotic resistance problem."

He emphasized that we should pay attention to 'irreplaceable technology' instead of non-fungible tokens (NFTs) so that a small country surrounded by a great power like ours will not be ignored. In a way, he argued, it is safe to say that they are now protected because if someone tries to attack, semiconductors around the world can be smashed.

So, after semiconductors, what should be the flagship strategic technology we need to cultivate? Now I even began to wonder if we were about to see an era where scientists would be in the limelight again.

(Text: Jeongae Lee, calee@sbs.co.kr)

**This article originally appeared in the 'SDF Diary', a newsletter sent out every Wednesday morning. 'SDF Diary' is written by members of the SBS News Division Future Team preparing for the SBS D Forum. We look ahead at the issues that our society should be interested in, and convey meaningful perspectives and attempts. If you want to stay ahead of the curve and learn about new knowledge and trends, please subscribe to SDF Diary. ▶ Click here to 'subscribe'!