research
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KAIST Research Team Creates the Scent of Jasmine from Microorganisms
The fragrance of jasmine and ylang-ylang, used widely in the manufacturing of cosmetics, foods, and beverages, can be produced by direct extraction from their respective flowers. In reality, this makes it difficult for production to meet demand, so companies use benzyl acetate, a major aromatic component of the two fragrances that is chemically synthesized from raw materials derived from petroleum.
On February 26, a KAIST research team led by Research Professor Kyeong Rok Choi from the BioProcess Engineering Research Center and Distinguished Professor Sang Yup Lee from the Department of Chemical and Biomolecular Engineering revealed the development of the first microbial process to effectively produce benzyl acetate, an industrially useful compound, from renewable carbon sources such as glucose. The results were published in their paper titled “A microbial process for the production of benzyl acetate”.
< Figure 1. Production of benzyl acetate through co-culture of upstream and downstream strains harboring the benzoic acid-dependent pathway. >
The team, led by Distinguished Professor Lee, aimed to produce benzyl acetate through an environmentally friendly and sustainable method, and developed an Escherichia coli strand to convert glucose into benzyl acetate through system metabolic engineering*.
*System metabolic engineering: a field of research founded by Distinguished Professor Lee to effectively develop microbial cell plants, a core component of the bio-industry that will replace the existing chemical industry, which is highly dependent on petroleum.
The research team developed a metabolic pathway that biosynthesizes benzyl acetate from benzoic acid derived from glucose, and successfully produced benzyl acetate by co-culturing** the strain.
**co-culture: simultaneously synthesizing two or more types of microorganisms in a mixture
However, it has been confirmed that the enzyme used to convert benzoic acid into benzyl acetate in this co-culturing technique acts non-specifically on an intermediate product during benzoic acid biosynthesis, producing a by-product called cinnamyl acetate. This process consumes the intermediate product needed for benzoic acid biosynthesis, thereby reducing the production efficiency of the target compound, benzyl acetate.
To overcome this problem, Distinguished Professor Lee and his team devised a delayed co-culture method, where they first produced benzoic acid in the earlier stages of fermentation by only culturing the top strain that produces benzoic acid from glucose, and later inoculated the bottom strain to convert the accumulated benzoic acid in the culture medium into benzyl acetate.
By applying this co-culture technique, the team suppressed the formation of by-products without further strain improvement or applying additional enzymes, and multiplied the concentration of the target compound by 10 times, producing 2.2 g/L of benzyl acetate. In addition, the team confirmed its potential for the commercial production of benzyl acetate through a technical economic analysis on this microbial process.
< Figure 2. Delayed co-culture of the Bn1 and Bn-BnAc3 strains for improved production of benzyl acetate through the benzoic acid-independent pathway.>
Research Professor Keyong Rok Choi, who was the first author of this paper, said, “This work is significant in that we have developed an effective microbial process to produce the industrially useful compound benzyl acetate, and also in that we have suggested a new approach to overcome the target chemical efficiency diminution and by-product formation issues caused commonly through non-specific enzyme activities during metabolic engineering.”
Distinguished Professor Lee said, “If we can increase the variety and number of microbial processes that produce useful chemicals through sustainable methods and at the same time develop effective strategies to solve chronic and inevitable problems that arise during microbial strain development, we will be able to accelerate the transition from the petrochemical industry into the eco-friendly and sustainable bio-industry.
This work was published online in Nature Chemical Engineering, issued by Nature.
This research was supported by the ‘Implementation of Intelligent Cell Factory Technology (PI: Distinguished Professor Sang Yup Lee) Project by the Ministry of Science and ICT, and the ‘Development of Protein Production Technology from Inorganic Substances through Microbiological Metabolic System Control’ (PI: Research Professor Kyeong Rok Choi) by the Agricultural Microbiological Project Group at the Rural Development Administration.
2024.03.05 View 5228 -
KAIST to begin Joint Research to Develop Next-Generation LiDAR System with Hyundai Motor Group
< (From left) Jong-Soo Lee, Executive Vice President at Hyundai Motor, Sang-Yup Lee, Senior Vice President for Research at KAIST >
The ‘Hyundai Motor Group-KAIST On-Chip LiDAR Joint Research Lab’ was opened at KAIST’s main campus in Daejeon to develop LiDAR sensors for advanced autonomous vehicles.
The joint research lab aims to develop high-performance and compact on-chip sensors and new signal detection technology, which are essential in the increasingly competitive autonomous driving market. On-chip sensors, which utilize semiconductor manufacturing technology to add various functions, can reduce the size of LiDAR systems compared to conventional methods and secure price competitiveness through mass production using semiconductor fabrication processes.
The joint research lab will consist of about 30 researchers, including the Hyundai-Kia Institute of Advanced Technology Development research team and KAIST professors Sanghyeon Kim, Sangsik Kim, Wanyeong Jung, and Hamza Kurt from KAIST’s School of Electrical Engineering, and will operate for four years until 2028.
KAIST will be leading the specialized work of each research team, such as for the development of silicon optoelectronic on-chip LiDAR components, the fabrication of high-speed, high-power integrated circuits to run the LiDAR systems, and the optimization and verification of LiDAR systems.
Hyundai Motor and Kia, together with Hyundai NGV, a specialized industry-academia cooperation institution, will oversee the operation of the joint research lab and provide support such as monitoring technological trends, suggesting research directions, deriving core ideas, and recommending technologies and experts to enhance research capabilities.
A Hyundai Motor Group official said, "We believe that this cooperation between Hyundai Motor Company and Kia, the leader in autonomous driving technology, and KAIST, the home of world-class technology, will hasten the achievement of fully autonomous driving." He added, "We will do our best to enable the lab to produce tangible results.”
Professor Sanghyeon Kim said, "The LiDAR sensor, which serves as the eyes of a car, is a core technology for future autonomous vehicle development that is essential for automobile companies to internalize."
2024.02.27 View 7320 -
A Korean research team develops a new clinical candidate for fatty liver disease
A team of Korean researchers have succeeded in developing a new drug candidate for the treatment of non-alcoholic fatty liver disease (NAFLD) acting on peripheral tissues. To date, there has not been an optimal treatment for non-alcoholic steatohepatitis (NASH), and this discovery is expected to set the grounds for the development of new drugs that can safely suppress both liver fat accumulation and liver fibrosis at the same time.
A joint research team led by Professor Jin Hee Ahn from Gwangju Institute of Science and Technology (GIST) and Professor Hail Kim from the KAIST Graduate School of Medical Science and Engineering developed a new chemical that can suppress disease-specific protein (HTR2A) through years of basic research. The team also revealed to have verified its efficacy and safety through preclinical tests (animal tests) at JD Bioscience Inc., a start-up company founded by Professor Ahn.
Although NAFLD has a prevalence rate as high as 20-30%, and about 5% of the global adult population suffers from NASH, there are no commercial drugs targeting them to date. NAFLD is a chronic disease that starts from the fatty liver and progresses into steatohepatitis, fibrosis, cirrhosis, and liver cancer. The mortality rate of patients increases with accompanied cardiovascular diseases and liver-related complications, and appropriate treatment in the early stage is hence necessary.
< Figure 1. Strategy and history of 5HT2A antagonists. Library and rational design for the development of compound 11c as a potent 5HT2A antagonist. Previous research efforts were discontinued due to limited oral absorption and safety. A therapeutic candidate to overcome this problem was identified and phase 1 clinical trials are currently in progress. >
The new synthetic chemical developed by the joint GIST-KAIST research is an innovative drug candidate that shows therapeutic effects on NASH based on a dual action mechanism that inhibits the accumulation of fat in the liver and liver fibrosis by suppressing the serotonin receptor protein 5HT2A.
The research team confirmed its therapeutic effects in animal models for NAFLD and NASH, in which hepatic steatosis and liver fibrosis* caused by fat accumulation in the liver were suppressed simultaneously by 50-70%.
*fibrosis: stiffening of parts of the liver, also used as a major indicator to track the prognosis of steatosis
The research team explained that the material was designed with optimal polarity and lipid affinity to minimize its permeability across the blood-brain barrier. It therefore does not affect the brain, and causes little side effects in the central nervous system (CNS) such as depression and suicidal ideations, while demonstrating excellent inhibition on its target protein present in tissues outside brain (IC50* = 14 nM). The team also demonstrated its superior efficacy in improving liver fibrosis when compared to similar drugs in the phase 3 clinical trial.
*IC50 (half maximal inhibitory concentration): the concentration at which a chemical suppresses 50% of a particular biological function
< Figure 2. GM-60106 (11c)'s effect on obesity: When GM-60106 was administered to an obese animal model (mice) for 2 months, body weight, body fat mass, and blood sugar were significantly reduced (a-d). In addition, the steatohepatitis level (NAFLD Activity Score) and the expression of genes of the treated mice involved in adipogenesis along with blood/liver fat decreased (e-h) >
Based on the pharmacological data obtained through preclinical trials, the team evaluated the effects of the drug on 88 healthy adults as part of their phase 1 clinical trial, where the side effects and the safe dosage of a drug are tested against healthy adults. Results showed no serious side effects and a good level of drug safety.
In addition, a preliminary efficacy evaluation on eight adults with steatohepatitis is currently underway.
Professor Jin Hee Ahn said, “The aim of this research is to develop a treatment for NASH with little side effects and guaranteed safety by developing a new target. The developed chemical is currently going through phase 1 of the global clinical trial in Australia through JD Bioscience Inc., a bio venture company for innovative drug development.” he added, “The candidate material the research team is currently developing shows not only a high level of safety and preventative effects by suppressing fat accumulation in the liver, but also a direct therapeutic effect on liver fibrosis. This is a strength that distinguishes our material from other competing drugs.”
< Figure 3. Efficacy of GM-60106 (11c) on liver fibrosis: When GM-60106 was administered to a steatohepatitis model (mice) for 3 months, the expression of genes associated with tissue fibrosis was significantly reduced (b-c). As a result of a detailed analysis of the tissues of the animal model, it was confirmed that the rate of tissue fibrosis was reduced and the expression rate of genes related to tissue fibrosis and inflammation was also significantly reduced (e-h). >
Professor Hail Kim from KAIST said, “Until now, this disease did not have a method of treatment other than weight control, and there has been no attempt to develop a drug that can be used for non-obese patients.” He added, “Through this research, we look forward to the development of various treatment techniques targeting a range of metabolic diseases including NASH that do not affect the weight of the patient.”
This study, conducted together by the research teams led by Professor Ahn from GIST and Professor Kim from KAIST, as well as the research team from JD Bioscience Inc., was supported by the Ministry of Science and ICT, and the National New Drug Development Project. The results of this research were published by Nature Communications on January 20.
The team also presented the results of their clinical study on the candidate material coded GM-60106 targeting metabolic abnormality-related MASH* at NASH-TAG Conference 2024, which was held in Utah for three days starting on January 4, which was selected as an excellent abstract.
*MASH (Metabolic Dysfunction-Associated Steatohepatitis): new replacement term for NASH
2024.02.21 View 6888 -
KAIST Research Team Develops Sweat-Resistant Wearable Robot Sensor
New electromyography (EMG) sensor technology that allows the long-term stable control of wearable robots and is not affected by the wearer’s sweat and dead skin has gained attention recently. Wearable robots are devices used across a variety of rehabilitation treatments for the elderly and patients recovering from stroke or trauma.
A joint research team led by Professor Jae-Woong Jung from the KAIST School of Electrical Engineering (EE) and Professor Jung Kim from the KAIST Department of Mechanical Engineering (ME) announced on January 23rd that they have successfully developed a stretchable and adhesive microneedle sensor that can electrically sense physiological signals at a high level without being affected by the state of the user’s skin.
For wearable robots to recognize the intentions behind human movement for their use in rehabilitation treatment, they require a wearable electrophysiological sensor that gives precise EMG measurements. However, existing sensors often show deteriorating signal quality over time and are greatly affected by the user’s skin conditions. Furthermore, the sensor’s higher mechanical hardness causes noise since the contact surface is unable to keep up with the deformation of the skin. These shortcomings limit the reliable, long-term control of wearable robots.
< Figure 1. Design and working concept of the Stretchable microNeedle Adhesive Patch (SNAP). (A) Schematic illustration showing the overall system configuration and application of SNAP. (B) Exploded view schematic diagram of a SNAP, consisting of stretchable serpentine interconnects, Au-coated Si microneedle, and ECA made of Ag flakes–silicone composite. (C) Optical images showing high mechanical compliance of SNAP. >
However, the recently developed technology is expected to allow long-term and high-quality EMG measurements as it uses a stretchable and adhesive conducting substrate integrated with microneedle arrays that can easily penetrate the stratum corneum without causing discomfort. Through its excellent performance, the sensor is anticipated to be able to stably control wearable robots over a long period of time regardless of the wearer’s changing skin conditions and without the need for a preparation step that removes sweat and dead cells from the surface of their skin.
The research team created a stretchable and adhesive microneedle sensor by integrating microneedles into a soft silicon polymer substrate. The hard microneedles penetrate through the stratum corneum, which has high electrical resistance. As a result, the sensor can effectively lower contact resistance with the skin and obtain high-quality electrophysiological signals regardless of contamination. At the same time, the soft and adhesive conducting substrate can adapt to the skin’s surface that stretches with the wearer’s movement, providing a comfortable fit and minimizing noise caused by movement.
< Figure 2. Demonstration of the wireless Stretchable microNeedle Adhesive Patch (SNAP) system as an Human-machine interfaces (HMI) for closed-loop control of an exoskeleton robot. (A) Illustration depicting the system architecture and control strategy of an exoskeleton robot. (B) The hardware configuration of the pneumatic back support exoskeleton system. (C) Comparison of root mean square (RMS) of electromyography (EMG) with and without robotic assistance of pretreated skin and non-pretreated skin. >
To verify the usability of the new patch, the research team conducted a motion assistance experiment using a wearable robot. They attached the microneedle patch on a user’s leg, where it could sense the electrical signals generated by the muscle. The sensor then sent the detected intention to a wearable robot, allowing the robot to help the wearer lift a heavy object more easily.
Professor Jae-Woong Jung, who led the research, said, “The developed stretchable and adhesive microneedle sensor can stability detect EMG signals without being affected by the state of a user’s skin. Through this, we will be able to control wearable robots with higher precision and stability, which will help the rehabilitation of patients who use robots.”
The results of this research, written by co-first authors Heesoo Kim and Juhyun Lee, who are both Ph.D. candidates in the KAIST School of EE, were published in Science Advances on January 17th under the title “Skin-preparation-free, stretchable microneedle adhesive patches for reliable electrophysiological sensing and exoskeleton robot control”.
This research was supported by the Bio-signal Sensor Integrated Technology Development Project by the National Research Foundation of Korea, the Electronic Medicinal Technology Development Project, and the Step 4 BK21 Project.
2024.01.30 View 6202 -
KAIST presents strategies for environmentally friendly and sustainable polyamides production
- Provides current research trends in bio-based polyamide production
- Research on bio-based polyamides production gains importance for achieving a carbon-neutral society
Global industries focused on carbon neutrality, under the slogan "Net-Zero," are gaining increasing attention. In particular, research on microbial production of polymers, replacing traditional chemical methods with biological approaches, is actively progressing.
Polyamides, represented by nylon, are linear polymers widely used in various industries such as automotive, electronics, textiles, and medical fields. They possess beneficial properties such as high tensile strength, electrical insulation, heat resistance, wear resistance, and biocompatibility. Since the commercialization of nylon in 1938, approximately 7 million tons of polyamides are produced worldwide annually. Considering their broad applications and significance, producing polyamides through bio-based methods holds considerable environmental and industrial importance.
KAIST (President Kwang-Hyung Lee) announced that a research team led by Distinguished Professor Sang Yup Lee, including Dr. Jong An Lee and doctoral candidate Ji Yeon Kim from the Department of Chemical and Biomolecular Engineering, published a paper titled "Current Advancements in Bio-Based Production of Polyamides”. The paper was featured on the cover of the monthly issue of "Trends in Chemistry” by Cell Press.
As part of climate change response technologies, bio-refineries involve using biotechnological and chemical methods to produce industrially important chemicals and biofuels from renewable biomass without relying on fossil resources. Notably, systems metabolic engineering, pioneered by KAIST's Distinguished Professor Sang Yup Lee, is a research field that effectively manipulates microbial metabolic pathways to produce valuable chemicals, forming the core technology for bio-refineries. The research team has successfully developed high-performance strains producing a variety of compounds, including succinic acid, biodegradable plastics, biofuels, and natural products, using systems metabolic engineering tools and strategies.
The research team predicted that if bio-based polyamide production technology, which is widely used in the production of clothing and textiles, becomes widespread, it will attract attention as a future technology that can respond to the climate crisis due to its environment-friendly production technology. In this study, the research team comprehensively reviewed the bio-based polyamide production strategies. They provided insights into the advancements in polyamide monomer production using metabolically engineered microorganisms and highlighted the recent trends in bio-based polyamide advancements utilizing these monomers. Additionally, they reviewed the strategies for synthesizing bio-based polyamides through chemical conversion of natural oils and discussed the biodegradability and recycling of the polyamides. Furthermore, the paper presented the future direction in which metabolic engineering can be applied for the bio-based polyamide production, contributing to environmentally friendly and sustainable society.
Ji Yeon Kim, the co-first author of this paper from KAIST, stated "The importance of utilizing systems metabolic engineering tools and strategies for bio-based polyamides production is becoming increasingly prominent in achieving carbon neutrality."
Professor Sang Yup Lee emphasized, "Amid growing concerns about climate change, the significance of environmentally friendly and sustainable industrial development is greater than ever. Systems metabolic engineering is expected to have a significant impact not only on the chemical industry but also in various fields."
< [Figure 1] A schematic overview of the overall process for polyamides production >
This paper by Dr. Jong An Lee, PhD student Ji Yeon Kim, Dr. Jung Ho Ahn, and Master Yeah-Ji Ahn from the Department of Chemical and Biomolecular Engineering at KAIST was published in the December issue of 'Trends in Chemistry', an authoritative review journal in the field of chemistry published by Cell. It was published on December 7 as the cover paper and featured review.
※ Paper title: Current advancements in the bio-based production of polyamides
※ Author information: Jong An Lee, Ji Yeon Kim, Jung Ho Ahn, Yeah-Ji Ahn, and Sang Yup Lee
This research was conducted with the support from the development of platform technologies of microbial cell factories for the next-generation biorefineries project and C1 gas refinery program by Korean Ministry of Science and ICT.
< [Figure 2] Cover paper of the December issue of Trends in Chemistry >
2023.12.21 View 5532 -
KAIST introduces eco-friendly technologies for plastic production and biodegradation
- A research team under Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering published a paper in Nature Microbiology on the overview and trends of plastic production and degradation technology using microorganisms.
- Eco-friendly and sustainable plastic production and degradation technology using microorganisms as a core technology to achieve a plastic circular economy was presented.
Plastic is one of the important materials in modern society, with approximately 460 million tons produced annually and with expected production reaching approximately 1.23 billion tons in 2060. However, since 1950, plastic waste totaling more than 6.3 billion tons has been generated, and it is believed that more than 140 million tons of plastic waste has accumulated in the aquatic environment. Recently, the seriousness of microplastic pollution has emerged, not only posing a risk to the marine ecosystem and human health, but also worsening global warming by inhibiting the activity of marine plankton, which play an important role in lowering the Earth's carbon dioxide concentration.
KAIST President Kwang-Hyung Lee announced on December 11 that a research team under Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering had published a paper titled 'Sustainable production and degradation of plastics using microbes', which covers the latest technologies for producing plastics and processing waste plastics in an eco-friendly manner using microorganisms.
As the international community moves to solve this plastic problem, various efforts are being made, including 175 countries participating to conclude a legally binding agreement with the goal of ending plastic pollution by 2024. Various technologies are being developed for sustainable plastic production and processing, and among them, biotechnology using microorganisms is attracting attention.
Microorganisms have the ability to naturally produce or decompose certain compounds, and this ability is maximized through biotechnologies such as metabolic engineering and enzyme engineering to produce plastics from renewable biomass resources instead of fossil raw materials and to decompose waste plastics.
Accordingly, the research team comprehensively analyzed the latest microorganism-based technologies for the sustainable production and decomposition of plastics and presented how they actually contribute to solving the plastic problem. Based on this, they presented limitations, prospects, and research directions of the technologies for achieving a circular economy for plastics.
Microorganism-based technologies for various plastics range from widely used synthetic plastics such as polyethylene (PE) to promising bioplastics such as natural polymers derived from microorganisms (polyhydroxyalkanoate (PHA)) that are completely biodegradable in the natural environment and do not pose a risk of microplastic generation. Commercialization statuses and latest technologies were also discussed. In addition, the technology to decompose these plastics using microorganisms and their enzymes and the upcycling technology to convert them into other useful compounds after decomposition were introduced, highlighting the competitiveness and potential of technology using microorganisms.
First author So Young Choi, a research assistant professor in the Department of Chemical and Biomolecular Engineering at KAIST, said, “In the future, we will be able to easily find eco-friendly plastics made using microorganisms all around us,” and corresponding author Distinguished Professor Sang Yup Lee said, “Plastic can be made more sustainable. It is important to use plastics responsibly to protect the environment and simultaneously achieve economic and social development through the new plastics industry, and we look forward to the improved performance of microbial metabolic engineering technology.”
This paper was published on November 30th in the online edition of Nature Microbiology.
※ Paper Title : Sustainable production and degradation of plastics using microbes
Authors: So Young Choi, Youngjoon Lee, Hye Eun Yu, In Jin Cho, Minju Kang & Sang Yup Lee
2023.12.11 View 5559 -
KAIST-UCSD researchers build an enzyme discovering AI
- A joint research team led by Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering and Bernhard Palsson of UCSD developed ‘DeepECtransformer’, an artificial intelligence that can predict Enzyme Commission (EC) number of proteins.
- The AI is tasked to discover new enzymes that have not been discovered yet, which would allow prediction for a total of 5,360 types of Enzyme Commission (EC) numbers
- It is expected to be used in the development of microbial cell factories that produce environmentally friendly chemicals as a core technology for analyzing the metabolic network of a genome.
While E. coli is one of the most studied organisms, the function of 30% of proteins that make up E. coli has not yet been clearly revealed. For this, an artificial intelligence was used to discover 464 types of enzymes from the proteins that were unknown, and the researchers went on to verify the predictions of 3 types of proteins were successfully identified through in vitro enzyme assay.
KAIST (President Kwang-Hyung Lee) announced on the 24th that a joint research team comprised of Gi Bae Kim, Ji Yeon Kim, Dr. Jong An Lee and Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering at KAIST, and Dr. Charles J. Norsigian and Professor Bernhard O. Palsson of the Department of Bioengineering at UCSD has developed DeepECtransformer, an artificial intelligence that can predict the enzyme functions from the protein sequence, and has established a prediction system by utilizing the AI to quickly and accurately identify the enzyme function.
Enzymes are proteins that catalyze biological reactions, and identifying the function of each enzyme is essential to understanding the various chemical reactions that exist in living organisms and the metabolic characteristics of those organisms. Enzyme Commission (EC) number is an enzyme function classification system designed by the International Union of Biochemistry and Molecular Biology, and in order to understand the metabolic characteristics of various organisms, it is necessary to develop a technology that can quickly analyze enzymes and EC numbers of the enzymes present in the genome.
Various methodologies based on deep learning have been developed to analyze the features of biological sequences, including protein function prediction, but most of them have a problem of a black box, where the inference process of AI cannot be interpreted. Various prediction systems that utilize AI for enzyme function prediction have also been reported, but they do not solve this black box problem, or cannot interpret the reasoning process in fine-grained level (e.g., the level of amino acid residues in the enzyme sequence).
The joint team developed DeepECtransformer, an AI that utilizes deep learning and a protein homology analysis module to predict the enzyme function of a given protein sequence. To better understand the features of protein sequences, the transformer architecture, which is commonly used in natural language processing, was additionally used to extract important features about enzyme functions in the context of the entire protein sequence, which enabled the team to accurately predict the EC number of the enzyme. The developed DeepECtransformer can predict a total of 5360 EC numbers.
The joint team further analyzed the transformer architecture to understand the inference process of DeepECtransformer, and found that in the inference process, the AI utilizes information on catalytic active sites and/or the cofactor binding sites which are important for enzyme function. By analyzing the black box of DeepECtransformer, it was confirmed that the AI was able to identify the features that are important for enzyme function on its own during the learning process.
"By utilizing the prediction system we developed, we were able to predict the functions of enzymes that had not yet been identified and verify them experimentally," said Gi Bae Kim, the first author of the paper. "By using DeepECtransformer to identify previously unknown enzymes in living organisms, we will be able to more accurately analyze various facets involved in the metabolic processes of organisms, such as the enzymes needed to biosynthesize various useful compounds or the enzymes needed to biodegrade plastics." he added.
"DeepECtransformer, which quickly and accurately predicts enzyme functions, is a key technology in functional genomics, enabling us to analyze the function of entire enzymes at the systems level," said Professor Sang Yup Lee. He added, “We will be able to use it to develop eco-friendly microbial factories based on comprehensive genome-scale metabolic models, potentially minimizing missing information of metabolism.”
The joint team’s work on DeepECtransformer is described in the paper titled "Functional annotation of enzyme-encoding genes using deep learning with transformer layers" written by Gi Bae Kim, Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering of KAIST and their colleagues. The paper was published via peer-review on the 14th of November on “Nature Communications”.
This research was conducted with the support by “the Development of next-generation biorefinery platform technologies for leading bio-based chemicals industry project (2022M3J5A1056072)” and by “Development of platform technologies of microbial cell factories for the next-generation biorefineries project (2022M3J5A1056117)” from National Research Foundation supported by the Korean Ministry of Science and ICT (Project Leader: Distinguished Professor Sang Yup Lee, KAIST).
< Figure 1. The structure of DeepECtransformer's artificial neural network >
2023.11.24 View 4656 -
An intravenous needle that irreversibly softens via body temperature on insertion
- A joint research team at KAIST developed an intravenous (IV) needle that softens upon insertion, minimizing risk of damage to blood vessels and tissues.
- Once used, it remains soft even at room temperature, preventing accidental needle stick injuries and unethical multiple use of needle.
- A thin-film temperature sensor can be embedded with this needle, enabling real-time monitoring of the patient's core body temperature, or detection of unintended fluid leakage, during IV medication.
Intravenous (IV) injection is a method commonly used in patient’s treatment worldwide as it induces rapid effects and allows treatment through continuous administration of medication by directly injecting drugs into the blood vessel. However, medical IV needles, made of hard materials such as stainless steel or plastic which do not mechanically match the soft biological tissues of the body, can cause critical problems in healthcare settings, starting from minor tissue damages in the injection sites to serious inflammations.
The structure and dexterity of rigid medical IV devices also enable unethical reuse of needles for reduction of injection costs, leading to transmission of deadly blood-borne disease infections such as human immunodeficiency virus (HIV) and hepatitis B/C viruses. Furthermore, unintended needlestick injuries are frequently occurring in medical settings worldwide, that are viable sources of such infections, with IV needles having the greatest susceptibility of being the medium of transmissible diseases. For these reasons, the World Health Organization (WHO) in 2015 launched a policy on safe injection practices to encourage the development and use of “smart” syringes that have features to prevent re-use, after a tremendous increase in the number of deadly infectious disease worldwide due to medical-sharps related issues.
KAIST announced on the 13th that Professor Jae-Woong Jeong and his research team of its School of Electrical Engineering succeeded in developing the Phase-Convertible, Adapting and non-REusable (P-CARE) needle with variable stiffness that can improve patient health and ensure the safety of medical staff through convergent joint research with another team led by Professor Won-Il Jeong of the Graduate School of Medical Sciences.
The new technology is expected to allow patients to move without worrying about pain at the injection site as it reduces the risk of damage to the wall of the blood vessel as patients receive IV medication. This is possible with the needle’s stiffness-tunable characteristics which will make it soft and flexible upon insertion into the body due to increased temperature, adapting to the movement of thin-walled vein. It is also expected to prevent blood-borne disease infections caused by accidental needlestick injuries or unethical re-using of syringes as the deformed needle remains perpetually soft even after it is retracted from the injection site.
The results of this research, in which Karen-Christian Agno, a doctoral researcher of the School of Electrical Engineering at and Dr. Keungmo Yang of the Graduate School of Medical Sciences participated as co-first authors, was published in Nature Biomedical Engineering on October 30. (Paper title: A temperature-responsive intravenous needle that irreversibly softens on insertion)
< Figure 1. Disposable variable stiffness intravenous needle. (a) Conceptual illustration of the key features of the P-CARE needle whose mechanical properties can be changed by body temperature, (b) Photograph of commonly used IV access devices and the P-CARE needle, (c) Performance of common IV access devices and the P-CARE needle >
“We’ve developed this special needle using advanced materials and micro/nano engineering techniques, and it can solve many global problems related to conventional medical needles used in healthcare worldwide”, said Jae-Woong Jeong, Ph.D., an associate professor of Electrical Engineering at KAIST and a lead senior author of the study.
The softening IV needle created by the research team is made up of liquid metal gallium that forms the hollow, mechanical needle frame encapsulated within an ultra-soft silicone material. In its solid state, gallium has sufficient hardness that enables puncturing of soft biological tissues. However, gallium melts when it is exposed to body temperature upon insertion, and changes it into a soft state like the surrounding tissue, enabling stable delivery of the drug without damaging blood vessels. Once used, a needle remains soft even at room temperature due to the supercooling phenomenon of gallium, fundamentally preventing needlestick accidents and reuse problems.
Biocompatibility of the softening IV needle was validated through in vivo studies in mice. The studies showed that implanted needles caused significantly less inflammation relative to the standard IV access devices of similar size made of metal needles or plastic catheters. The study also confirmed the new needle was able to deliver medications as reliably as commercial injection needles.
< Photo 1. Photo of the P-CARE needle that softens with body temperature. >
Researchers also showed possibility of integrating a customized ultra-thin temperature sensor with the softening IV needle to measure the on-site temperature which can further enhance patient’s well-being. The single assembly of sensor-needle device can be used to monitor the core body temperature, or even detect if there is a fluid leakage on-site during indwelling use, eliminating the need for additional medical tools or procedures to provide the patients with better health care services.
The researchers believe that this transformative IV needle can open new opportunities for wide range of applications particularly in clinical setups, in terms of redesigning other medical needles and sharp medical tools to reduce muscle tissue injury during indwelling use. The softening IV needle may become even more valuable in the present times as there is an estimated 16 billion medical injections administered annually in a global scale, yet not all needles are disposed of properly, based on a 2018 WHO report.
< Figure 2. Biocompatibility test for P-CARE needle: Images of H&E stained histology (the area inside the dashed box on the left is provided in an expanded view in the right), TUNEL staining (green), DAPI staining of nuclei (blue) and co-staining (TUNEL and DAPI) of muscle tissue from different organs. >
< Figure 3. Conceptual images of potential utilization for temperature monitoring function of P-CARE needle integrated with a temperature sensor. >
(a) Schematic diagram of injecting a drug through intravenous injection into the abdomen of a laboratory mouse (b) Change of body temperature upon injection of drug (c) Conceptual illustration of normal intravenous drug injection (top) and fluid leakage (bottom) (d) Comparison of body temperature during normal drug injection and fluid leakage: when the fluid leak occur due to incorrect insertion, a sudden drop of temperature is detected.
This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT.
2023.11.13 View 7694 -
KAIST proposes alternatives to chemical factories through “iBridge”
- A computer simulation program “iBridge” was developed at KAIST that can put together microbial cell factories quickly and efficiently to produce cosmetics and food additives, and raw materials for nylons
- Eco-friendly and sustainable fermentation process to establish an alternative to chemical plants
As climate change and environmental concerns intensify, sustainable microbial cell factories garner significant attention as candidates to replace chemical plants. To develop microorganisms to be used in the microbial cell factories, it is crucial to modify their metabolic processes to induce efficient target chemical production by modulating its gene expressions. Yet, the challenge persists in determining which gene expressions to amplify and suppress, and the experimental verification of these modification targets is a time- and resource-intensive process even for experts. The challenges were addressed by a team of researchers at KAIST (President Kwang-Hyung Lee) led by Distinguished Professor Sang Yup Lee.
It was announced on the 9th by the school that a method for building a microbial factory at low cost, quickly and efficiently, was presented by a novel computer simulation program developed by the team under Professor Lee’s guidance, which is named “iBridge”. This innovative system is designed to predict gene targets to either overexpress or downregulate in the goal of producing a desired compound to enable the cost-effective and efficient construction of microbial cell factories specifically tailored for producing the chemical compound in demand from renewable biomass.
Systems metabolic engineering is a field of research and engineering pioneered by KAIST’s Distinguished Professor Sang Yup Lee that seeks to produce valuable compounds in industrial demands using microorganisms that are re-configured by a combination of methods including, but not limited to, metabolic engineering, synthetic biology, systems biology, and fermentation engineering.
In order to improve microorganisms’ capability to produce useful compounds, it is essential to delete, suppress, or overexpress microbial genes. However, it is difficult even for the experts to identify the gene targets to modify without experimental confirmations for each of them, which can take up immeasurable amount of time and resources.
The newly developed iBridge identifies positive and negative metabolites within cells, which exert positive and/or negative impact on formation of the products, by calculating the sum of covariances of their outgoing (consuming) reaction fluxes for a target chemical. Subsequently, it pinpoints "bridge" reactions responsible for converting negative metabolites into positive ones as candidates for overexpression, while identifying the opposites as targets for downregulation.
The research team successfully utilized the iBridge simulation to establish E. coli microbial cell factories each capable of producing three of the compounds that are in high demands at a production capacity that has not been reported around the world. They developed E. coli strains that can each produce panthenol, a moisturizing agent found in many cosmetics, putrescine, which is one of the key components in nylon production, and 4-hydroxyphenyllactic acid, an anti-bacterial food additive. In addition to these three compounds, the study presents predictions for overexpression and suppression genes to construct microbial factories for 298 other industrially valuable compounds.
Dr. Youngjoon Lee, the co-first author of this paper from KAIST, emphasized the accelerated construction of various microbial factories the newly developed simulation enabled. He stated, "With the use of this simulation, multiple microbial cell factories have been established significantly faster than it would have been using the conventional methods. Microbial cell factories producing a wider range of valuable compounds can now be constructed quickly using this technology."
Professor Sang Yup Lee said, "Systems metabolic engineering is a crucial technology for addressing the current climate change issues." He added, "This simulation could significantly expedite the transition from resorting to conventional chemical factories to utilizing environmentally friendly microbial factories."
< Figure. Conceptual diagram of the flow of iBridge simulation >
The team’s work on iBridge is described in a paper titled "Genome-Wide Identification of Overexpression and Downregulation Gene Targets Based on the Sum of Covariances of the Outgoing Reaction Fluxes" written by Dr. Won Jun Kim, and Dr. Youngjoon Lee of the Bioprocess Research Center and Professors Hyun Uk Kim and Sang Yup Lee of the Department of Chemical and Biomolecular Engineering of KAIST. The paper was published via peer-review on the 6th of November on “Cell Systems” by Cell Press.
This research was conducted with the support from the Development of Platform Technologies of Microbial Cell Factories for the Next-generation Biorefineries Project (Project Leader: Distinguished Professor Sang Yup Lee, KAIST) and Development of Platform Technology for the Production of Novel Aromatic Bioplastic using Microbial Cell Factories Project (Project Leader: Research Professor So Young Choi, KAIST) of the Korean Ministry of Science and ICT.
2023.11.09 View 6470 -
A KAIST Research Team Produces Eco-Friendly Nylon with Engineered Bacterium
With worsening climate change and environmental issues, in recent years, there has been increased interest in the eco-friendly production of polymers like nylon.
On August 10, Dr. Taehee Han from a KAIST research team led by Distinguished Professor Sang Yup Lee in the Department of Chemical and Biomolecular Engineering revealed the successful development of a microbial strain that produces valerolactam, a monomer of nylon-5.
Valerolactam is an important monomer that constitutes nylon-5 and nylon-6,5. Nylon is the oldest synthetic polymer, and nylon-5 is one of its derivatives composed of monomers with five carbons, while nylon-5,6 is composed of two types of monomers with either five or six carbons. They not only have excellent processability, but are also light and tough, which allows them to be applied in a wide range of industrial sectors including clothing, badminton rackets, fishing nets, tents, and gear parts. Monomers are materials that can be built into polymers, and synthetic processes are what connects them into a polymer.
The chemical production of valerolactam, however, is based on petrochemistry, where extreme reaction conditions are required and toxic waste is produced. To solve these problems, efforts are being made to develop environmentally friendly and highly efficient microbial cell factories for lactam production. Systems metabolic engineering, a key strategy for effective microbial strain development, is a research field pioneered by Professor Sang Yup Lee.
Professor Lee’s team used metabolic engineering, a technique for manipulating microbial metabolic pathways, to construct a synthetic metabolic pathway for valerolactam production in Corynebacteriam glutamicum, a bacterium commonly used for amino acid production. With this, they successfully developed a microbial strain that utilizes biomass-derived glucose as a carbon source to produce high-value valerolactam.
In 2017, the team suggested a novel method that metabolically manipulates Escherichia coli to produce valerolactam. However, there were several limitations at the time including low producibility and the generation of harmful byproducts.
< Figure 1. Schematic graphical representation of the development of microorganisms that produce valerolactam, a nylon-5 monomer >
In this research, the team improved valerolactam producibility and incorporated an additional systems metabolic strategy to the developed microbial strain while eliminating the harmful byproducts. By removing the gene involved in the production of the main byproduct and through gene screening, the team successfully converted 5-aminovaleric acid, a byproduct and a precursor, into valerolactam.
Furthermore, by employing a strategy where the 5-aminovaleric acid-converting gene is inserted multiple times into the genome, the team strengthened the metabolic flux for valerolactam production. As a result, they reached a world-record concentration of 76.1 g/L, which is 6.17 times greater than what was previously reported.
This study was published in Metabolic Engineering on July 12, under the title, “Metabolic engineering of Corynebacterium glutamicum for the high-level production of valerolactam, a nylon-5 monomer”.
Dr. Taehee Han, the first author of the paper, said, “The significance of this research lies in our development of an environmentally friendly technology that efficiently produces monomer lactam for nylon production using microorganisms.” She added, “Through this technology, we will be able to take a step forward in replacing the petrochemical industry with a microorganism-based biopolymer industry.”
This work was supported by the “Development of Next-Generation Biofinery Platform Technologies for Leading Bio-based Chemicals Industry Project” funded by the Korean Ministry of Science and ICT.
2023.08.24 View 5079 -
KAIST Research Team Develops World’s First Humanoid Pilot, PIBOT
In the Spring of last year, the legendary, fictional pilot “Maverick” flew his plane in the film “Top Gun: Maverick” that drew crowds to theatres around the world. This year, the appearance of a humanoid pilot, PIBOT, has stolen the spotlight at KAIST.
< Photo 1. Humanoid pilot robot, PIBOT >
A KAIST research team has developed a humanoid robot that can understand manuals written in natural language and fly a plane on its own. The team also announced their plans to commercialize the humanoid pilot.
< Photo 2. PIBOT on flight simulator (view from above) >
The project was led by KAIST Professor David Hyunchul Shim, and was conducted as a joint research project with Professors Jaegul Choo, Kuk-Jin Yoon, and Min Jun Kim. The study was supported by Future Challenge Funding under the project title, “Development of Human-like Pilot Robot based on Natural Language Processing”. The team utilized AI and robotics technologies, and demonstrated that the humanoid could sit itself in a real cockpit and operate the various pieces of equipment without modifying any part of the aircraft. This is a fundamental difference that distinguishes this technology from existing autopilot functions or unmanned aircrafts.
< Photo 3. PIBOT operating a flight simulator (side) >
The KAIST team’s humanoid pilot is still under development but it can already remember Jeppeson charts from all around the world, which is impossible for human pilots to do, and fly without error. In particular, it can make use of recent ChatGPT technology to remember the full Quick Reference Handbook (QRF) and respond immediately to various situations, as well as calculate safe routes in real time based on the flight status of the aircraft, with emergency response times quicker than human pilots.
Furthermore, while existing robots usually carry out repeated motions in a fixed position, PIBOT can analyze the state of the cockpit as well as the situation outside the aircraft using an embedded camera. PIBOT can accurately control the various switches in the cockpit and, using high-precision control technology, it can accurately control its robotic arms and hands even during harsh turbulence.
< Photo 4. PIBOT on-board KLA-100, Korea’s first light aircraft >
The humanoid pilot is currently capable of carrying out all operations from starting the aircraft to taxiing, takeoff and landing, cruising, and cycling using a flight control simulator. The research team plans to use the humanoid pilot to fly a real-life light aircraft to verify its abilities. Prof. Shim explained, “Humanoid pilot robots do not require the modification of existing aircrafts and can be applied immediately to automated flights. They are therefore highly applicable and practical. We expect them to be applied into various other vehicles like cars and military trucks since they can control a wide range of equipment. They will particularly be particularly helpful in situations where military resources are severely depleted.”
This research was supported by Future Challenge Funding (total: 5.7 bn KRW) from the Agency for Defense Development. The project started in 2022 as a joint research project by Prof. David Hyunchul Shim (chief of research) from the KAIST School of Electrical Engineering (EE), Prof. Jaegul Choo from the Kim Jaechul Graduate School of AI at KAIST, Prof. Kuk-Jin Yoon from the KAIST Department of Mechanical Engineering, and Prof. Min Jun Kim from the KAIST School of EE. The project is to be completed by 2026 and the involved researchers are also considering commercialization strategies for both military and civil use.
2023.08.03 View 12624 -
KAIST presents a microbial cell factory as a source of eco-friendly food and cosmetic coloring
Despite decades of global population growth, global food crisis seems to be at hand yet again because the food productivity is cut severely due to prolonged presence of abnormal weather from intensifying climate change and global food supply chain is deteriorated due to international conflicts such as wars exacerbating food shortages and nutritional inequality around the globe. At the same time, however, as awareness of the environment and sustainability rises, an increase in demand for more eco-friendly and high-quality food and beauty products is being observed not without a sense of irony. At a time like this, microorganisms are attracting attention as a key that can handle this couple of seemingly distant problems.
KAIST (President Kwang-Hyung Lee) announced on the 26th that Kyeong Rok Choi, a research professor of the Bioprocess Research Center and Sang Yup Lee, a Distinguished Professor of the Department of Chemical and Biomolecular Engineering, published a paper titled “Metabolic Engineering of Microorganisms for Food and Cosmetics Production” upon invitation by “Nature Reviews Bioengineering” to be published online published by Nature after peer review.
※ Paper title: Systems metabolic engineering of microorganisms for food and cosmetics production
※ Author information: Kyeong Rok Choi (first author) and Sang Yup Lee (corresponding author)
Systems metabolic engineering is a research field founded by Distinguished Professor Sang Yup Lee of KAIST to more effectively develop microbial cell factories, the core factor of the next-generation bio industry to replace the existing chemical industry that relies heavily on petroleum. By applying a systemic metabolic engineering strategy, the researchers have developed a number of high-performance microbial cell factories that produce a variety of food and cosmetic compounds including natural substances like heme and zinc protoporphyrin IX compounds which can improve the flavor and color of synthetic meat, lycopene and β-carotene which are functional natural pigments that can be widely used in food and cosmetics, and methyl anthranilate, a grape-derived compound widely used to impart grape flavor in food and beverage manufacturing.
In this paper written upon invitation by Nature, the research team covered remarkable cases of microbial cell factory that can produce amino acids, proteins, fats and fatty acids, vitamins, flavors, pigments, alcohols, functional compounds and other food additives used in various foods and cosmetics and the companies that have successfully commercialized these microbial-derived materials Furthermore, the paper organized and presents systems metabolic engineering strategies that can spur the development of industrial microbial cell factories that can produce more diverse food and cosmetic compounds in an eco-friendly way with economic feasibility.
< Figure 1. Examples of production of food and cosmetic compounds using microbial cell factories >
For example, by producing proteins or amino acids with high nutritional value through non-edible biomass used as animal feed or fertilizer through the microbial fermentation process, it will contribute to the increase in production and stable supply of food around the world. Furthermore, by contributing to developing more viable alternative meat, further reducing dependence on animal protein, it can also contribute to reducing greenhouse gases and environmental pollution generated through livestock breeding or fish farming.
In addition, vanillin or methyl anthranilate, which give off vanilla or grape flavor, are widely added to various foods, but natural products isolated and refined from plants are low in production and high in production cost, so in most cases, petrochemicals substances derived from vanillin and methylanthranilic acid are added to food. These materials can also be produced through an eco-friendly and human-friendly method by borrowing the power of microorganisms.
Ethical and resource problems that arise in producing compounds like Calmin (cochineal pigment), a coloring added to various cosmetics and foods such as red lipstick and strawberry-flavored milk, which must be extracted from cochineal insects that live only in certain cacti. and Hyaluronic acid, which is widely consumed as a health supplement, but is only present in omega-3 fatty acids extracted from shark or fish livers, can also be resolved when they can be produced in an eco-friendly way using microorganisms.
KAIST Research Professor Kyeong Rok Choi, the first author of this paper, said, “In addition to traditional fermented foods such as kimchi and yogurt, foods produced with the help of microorganisms like cocoa butter, a base ingredient for chocolate that can only be obtained from fermented cacao beans, and monosodium glutamate, a seasoning produced through microbial fermentation are already familiar to us”. “In the future, we will be able to acquire a wider variety of foods and cosmetics even more easily produced in an eco-friendly and sustainable way in our daily lives through microbial cell factories.” he added.
< Figure 2. Systems metabolic engineering strategy to improve metabolic flow in microbial cell factories >
Distinguished Professor Sang Yup Lee said, “It is engineers’ mission to make the world a better place utilizing science and technology.” and added, “Continuous advancement and active use of systems metabolic engineering will contribute greatly to easing and resolving the problems arising from both the food crisis and the climate change."
This research was carried out as a part of the “Development of Protein Production Technology from Inorganic Substances through Control of Microbial Metabolism System Project” (Project Leader: Kyeong Rok Choi, KAIST Research Professor) of the the Center for Agricultural Microorganism and Enzyme (Director Pahn-Shick Chang) supported by the Rural Development Administration and the “Development of Platform Technologies of Microbial Cell Factories for the Next-generation Biorefineries Project” (Project Leader: Sang Yup Lee, KAIST Distinguished Professor) of the Petroleum-Substitute Eco-friendly Chemical Technology Development Program supported by the Ministry of Science and ICT.
2023.07.28 View 7193