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Synthetic sRNAs to knockdown genes in medical and industrial bacteria
Bacteria are intimately involved in our daily lives. These microorganisms have been used in human history for food such as cheese, yogurt, and wine, In more recent years, through metabolic engineering, microorganisms been used extensively as microbial cell factories to manufacture plastics, feed for livestock, dietary supplements, and drugs. However, in addition to these bacteria that are beneficial to human lives, pathogens such as Pneumonia, Salmonella, and Staphylococcus that cause various infectious diseases are also ubiquitously present. It is important to be able to metabolically control these beneficial industrial bacteria for high value-added chemicals production and to manipulate harmful pathogens to suppress its pathogenic traits.
KAIST (President Kwang Hyung Lee) announced on the 10th that a research team led by Distinguished Professor Sang Yup Lee of the Department of Biochemical Engineering has developed a new sRNA tool that can effectively inhibit target genes in various bacteria, including both Gram-negative and Gram-positive bacteria. The research results were published online on April 24 in Nature Communications.
※ Thesis title: Targeted and high-throughput gene knockdown in diverse bacteria using synthetic sRNAs
※ Author information : Jae Sung Cho (co-1st), Dongsoo Yang (co-1st), Cindy Pricilia Surya Prabowo (co-author), Mohammad Rifqi Ghiffary (co-author), Taehee Han (co-author), Kyeong Rok Choi (co-author), Cheon Woo Moon (co-author), Hengrui Zhou (co-author), Jae Yong Ryu (co-author), Hyun Uk Kim (co-author) and Sang Yup Lee (corresponding author).
sRNA is an effective tool for synthesizing and regulating target genes in E. coli, but it has been difficult to apply to industrially useful Gram-positive bacteria such as Bacillus subtilis and Corynebacterium in addition to Gram-negative bacteria such as E. coli.
To address this issue, a research team led by Distinguished Professor Lee Sang Yup Lee of the Department of Chemical and Biomolecular Engineering at KAIST developed a new sRNA platform that can effectively suppress target genes in various bacteria, including both Gram-negative and positive bacteria. The research team surveyed thousands of microbial-derived sRNA systems in the microbial database, and eventually designated the sRNA system derived from 'Bacillus subtilis' that showed the highest gene knockdown efficiency, and designated it as “Broad-Host-Range sRNA”, or BHR-sRNA.
A similar well-known system is the CRISPR interference (CRISPRi) system, which is a modified CRISPR system that knocks down gene expression by suppressing the gene transcription process. However, the Cas9 protein in the CRISPRi system has a very high molecular weight, and there have been reports growth inhibition in bacteria. The BHR-sRNA system developed in this study did not affect bacterial growth while showing similar gene knockdown efficiencies to CRISPRi.
< Figure 1. a) Schematic illustration demonstrating the mechanism of syntetic sRNA b) Phylogenetic tree of the 16 Gram-negative and Gram-positive bacterial species tested for gene knockdown by the BHR-sRNA system. >
To validate the versatility of the BHR-sRNA system, 16 different gram-negative and gram-positive bacteria were selected and tested, where the BHR-sRNA system worked successfully in 15 of them. In addition, it was demonstrated that the gene knockdown capability was more effective than that of the existing E. coli-based sRNA system in 10 bacteria. The BHR-sRNA system proved to be a universal tool capable of effectively inhibiting gene expression in various bacteria.
In order to address the problem of antibiotic-resistant pathogens that have recently become more serious, the BHR-sRNA was demonstrated to suppress the pathogenicity by suppressing the gene producing the virulence factor. By using BHR-sRNA, biofilm formation, one of the factors resulting in antibiotic resistance, was inhibited by 73% in Staphylococcus epidermidis a pathogen that can cause hospital-acquired infections. Antibiotic resistance was also weakened by 58% in the pneumonia causing bacteria Klebsiella pneumoniae. In addition, BHR-sRNA was applied to industrial bacteria to develop microbial cell factories to produce high value-added chemicals with better production performance. Notably, superior industrial strains were constructed with the aid of BHR-sRNA to produce the following chemicals: valerolactam, a raw material for polyamide polymers, methyl-anthranilate, a grape-flavor food additive, and indigoidine, a blue-toned natural dye.
The BHR-sRNA developed through this study will help expedite the commercialization of bioprocesses to produce high value-added compounds and materials such as artificial meat, jet fuel, health supplements, pharmaceuticals, and plastics. It is also anticipated that to help eradicating antibiotic-resistant pathogens in preparation for another upcoming pandemic. “In the past, we could only develop new tools for gene knockdown for each bacterium, but now we have developed a tool that works for a variety of bacteria” said Distinguished Professor Sang Yup Lee.
This work was supported by the Development of Next-generation Biorefinery Platform Technologies for Leading Bio-based Chemicals Industry Project and the Development of Platform Technologies of Microbial Cell Factories for the Next-generation Biorefineries Project from NRF supported by the Korean MSIT.
2023.05.10 View 6748 -
KAIST gearing up to train physician-scientists and BT Professionals joining hands with Boston-based organizations
KAIST (President Kwang Hyung Lee) announced on the 29th that it has signed MOUs with Massachusetts General Hospital, a founding member of the Mass General Brigham health care system and a world-class research-oriented hospital, and Moderna, a biotechnology company that developed a COVID-19 vaccine at the Langham Hotel in Boston, MA, USA on the morning of April 28th (local time). The signing ceremony was attended by officials from each institution joined by others headed by Minister LEE Young of the Korean Ministry of SMEs and Startups (MSS), and Commissioner LEE Insil of the Korean Intellectual Property Office.
< Photo 1. Photo from the Signing of MOU between KAIST-Harvard University Massachusetts General Hospital and KAIST-Moderna >
Mass General is the first and largest teaching hospital of Harvard Medical School in Boston, USA, and it is one of the most innovative hospitals in the world being the alma mater of more than 13 Nobel Prize winners and the home of the Mass General Research Institute, the world’s largest hospital-based research program that utilizes an annual research budget of more than $1.3 billion.
KAIST signed a general agreement to explore research and academic exchange with Mass General in September of last year and this MOU is a part of its follow-ups.
Mass General works with Harvard and the Massachusetts Institute of Technology (MIT), as well as local hospitals, to support students learn the theories of medicine and engineering, and gain rich clinical research experience.
Through this MOU, KAIST will explore cooperation with an innovative ecosystem created through the convergence of medicine and engineering. In particular, KAIST’s goal is to develop a Korean-style training program and implement a differentiated educational program when establishing the science and technology-oriented medical school in the future by further strengthening the science and engineering part of the training including a curriculum on artificial intelligence (AI) and the likes there of.
Also, in order to foster innovative physician-scientists, KAIST plans to pursue cooperation to develop programs for exchange of academic and human resources including programs for student and research exchanges and a program for students of the science and technology-oriented medical school at KAIST to have a chance to take part in practical training at Mass General.
David F.M. Brown, MD, Mass General President, said, “The collaboration with KAIST has a wide range of potentials, including advice on training of physician-scientists, academic and human resource exchanges, and vitalization of joint research by faculty from both institutions. Through this agreement, we will be able to actively contribute to global cooperation and achieve mutual goals.”
Meanwhile, an MOU between KAIST and Moderna was also held on the same day. Its main focus is to foster medical experts in cooperation with KAIST Graduate School of Medical Science and Engineering (GSMSE), and plans to cooperate in various ways in the future, including collaborating for development of vaccine and new drugs, virus research, joint mRNA research, and facilitation of technology commercialization.
In over 10 years since its inception, Moderna has transformed from a research-stage company advancing programs in the field of messenger RNA (mRNA) to an enterprise with a diverse clinical portfolio of vaccines and therapeutics across seven modalities. The Company has 48 programs in development across 45 development candidates, of which 38 are currently in active clinical trials.
“We are grateful to have laid a foundation for collaboration to foster industry experts with the Korea Advanced Institute of Science and Technology, a leader of science and technology innovation in Korea,” said Arpa Garay, Chief Commercial Officer, Moderna. “Based on our leadership and expertise in developing innovative mRNA vaccines and therapeutics, we hope to contribute to educating and collaborating with professionals in the bio-health field of Korea.“
President Kwang Hyung Lee of KAIST, said, “We deem this occasion to be of grave significance to be able to work closely with Massachusetts General Hospital, one of the world's best research-oriented hospitals, and Moderna, one of the most influential biomedical companies.”
President Lee continued, "On the basis of the collaboration with the two institutions, we will be able to bring up qualified physician-scientists and global leaders of the biomedical business who will solve problems of human health and their progress will in turn, accelerate the national R&D efforts in general and diversify the industry."
2023.04.29 View 13161 -
KAIST Team Develops Highly-Sensitive Wearable Piezoelectric Blood Pressure Sensor for Continuous Health Monitoring
- A collaborative research team led by KAIST Professor Keon Jae Lee verifies the accuracy of the highly-sensitive sensor through clinical trials
- Commercialization of the watch and patch-type sensor is in progress
A KAIST research team led by Professor Keon Jae Lee from the Department of Materials Science and Engineering and the College of Medicine of the Catholic University of Korea has developed a highly sensitive, wearable piezoelectric blood pressure sensor.
Blood pressure is a critical indicator for assessing general health and predicting stroke or heart failure. In particular, cardiovascular disease is the leading cause of global death, therefore, periodic measurement of blood pressure is crucial for personal healthcare.
Recently, there has been a growing interest in healthcare devices for continuous blood pressure monitoring. Although smart watches using LED-based photoplethysmography (PPG) technology have been on market, these devices have been limited by the accuracy constraints of optical sensors, making it hard to meet the international standards of automatic sphygmomanometers.
Professor Lee’s team has developed the wearable piezoelectric blood pressure sensor by transferring a highly sensitive, inorganic piezoelectric membrane from bulk sapphire substrates to flexible substrates. Ultrathin piezoelectric sensors with a thickness of several micrometers (one hundredth of the human hair) exhibit conformal contact with the skin to successfully collect accurate blood pressure from the subtle pulsation of the blood vessels.
Clinical trial at the St. Mary’s Hospital of the Catholic University validated the accuracy of blood pressure sensor at par with international standard with errors within ±5 mmHg and a standard deviation under 8 mmHg for both systolic and diastolic blood pressure. In addition, the research team successfully embedded the sensor on a watch-type product to enable continuous monitoring of blood pressure.
Prof. Keon Jae Lee said, “Major target of our healthcare devices is hypertensive patients for their daily medical check-up. We plan to develop a comfortable patch-type sensor to monitor blood pressure during sleep and have a start-up company commercialize these watch and patch-type products soon.”
This result titled “Clinical validation of wearable piezoelectric blood pressure sensor for health monitoring” was published in the online issue of Advanced Materials on March 24th, 2023. (DOI: 10.1002/adma.202301627)
Figure 1. Schematic illustration of the overall concept for a wearable piezoelectric blood pressure sensor (WPBPS).
Figure 2. Wearable piezoelectric blood pressure sensor (WPBPS) mounted on a watch (a) Schematic design of the WPBPS-embedded wristwatch. (b) Block diagram of the wireless communication circuit, which filters, amplifies, and transmits wireless data to portable devices. (c) Pulse waveforms transmitted from the wristwatch to the portable device by the wireless communication circuit. The inset shows a photograph of monitoring a user’s beat-to-beat pulses and their corresponding BP values in real time using the developed WPBPS-mounted wristwatch.
2023.04.17 View 7420 -
KAIST research team develops a cheap and safe redox flow battery
Redox flow batteries, one of the potential replacements for the widely used lithium-ion secondary batteries, can be utilized as new and renewable energy as well as for energy storage systems (ESS) thanks to their low cost, low flammability, and long lifetime of over 20 years. Since the price of vanadium, the most widely used active material for redox flow batteries, has been rising in recent years, scientists have been actively searching for redox materials to replace it.
On March 23, a joint research team led by Professors Hye Ryung Byon and Mu-Hyun Baik from the KAIST Department of Chemistry, and Professor Jongcheol Seo from the POSTECH Department of Chemistry announced that they had developed a highly soluble and stable organic redox-active molecule for use in aqueous redox flow batteries.
The research team focused on developing aqueous redox flow batteries by redesigning an organic molecule. It is possible to control the solubility and electrochemical redox potential of organic molecules by engineering their design, which makes them a promising active material candidate with possibly higher energy storage capabilities than vanadium. Most organic redox-active molecules have low solubilities or have slow chemical stability during redox reactions. Low solubility means low energy storage capacity and low chemical stability leads to reduced cycle performance. For this research, the team chose naphthalene diimide (NDI) as their active molecule. Until now, there was little research done on NDI despite its high chemical stability, as it shows low solubility in aqueous electrolyte solutions.
Although NDI molecules are almost insoluble in water, the research team tethered four ammonium functionalities and achieved a solubility as high as 1.5M* in water. In addition, they confirmed that when a 1M solution of NDI was used in neutral redox flow batteries for 500 cycles, 98% of its capacity was maintained. This means 0.004% capacity decay per cycle, and only 2% of its capacity would be lost if the battery were to be operated for 45 days.
Furthermore, the developed NDI molecule can save two electrons per molecule, and the team proved that 2M of electrons could be stored in every 1M of NDI solution used. For reference, vanadium used in vanadium redox flow batteries, which require a highly concentrated sulfuric acid solution, has a solubility of about 1.6M and can only hold one electron per molecule, meaning it can store a total of 1.6M of electrons. Therefore, the newly developed NDI active molecule shows a higher storage capacity compared to existing vanadium devices.
*1M (mol/L): 6.022 x 1023 active molecules are present in 1L of solution
This paper, written by co-first authors Research Professor Vikram Singh, and Ph.D. candidates Seongyeon Kwon and Yunseop Choi, was published in the online version of Advanced Materials on February 7 under the title, Controlling π-π interactions of highly soluble naphthalene diimide derivatives for neutral pH aqueous redox flow batteries. Ph.D. Candidate Yelim Yi and Professor Mi Hee Lee’s team from the KAIST Department of Chemistry also contributed to the study by conducting electron paramagnetic resonance analyses.
Professor Hye Ryung Byon said, “We have demonstrated the principles of molecular design by modifying an existing organic active molecule with low solubility and utilizing it as an active molecule for redox flow batteries. We have also shown that during a redox reaction, we can use molecular interactions to suppress the chemical reactivity of radically formed molecules.”
She added, “Should this be used later for aqueous redox flow batteries, along with its high energy density and high solubility, it would also have the advantage of being available for use in neutral pH electrolytes. Vanadium redox flow batteries currently use acidic solutions, which cause corrosion, and we expect our molecule to solve this issue. Since existing lithium ion-based ESS are flammable, we must develop safer and cheaper next-generation ESS, and our research has shown great promise in addressing this.”
This research was funded by Samsung Research Funding & Incubation Center, the Institute for Basic Science, and the National Research Foundation.
Figure 1. (a) Structures of various NDI molecules. (b) Solubility of NDI molecules in water (black bars) and aqueous electrolytes including KCl electrolyte (blue bars). (c–d) Structural changes of the molecules as the developed NDI molecule stores two electrons. (c) Illustration of cluster combination and separation of NDI molecules developed during redox reaction and (d) Snapshot of the MD simulation. NDI molecules prepared from the left, formation of bimolecular sieve and tetramolecular sieve clusters after the first reductive reaction, and a single molecule with a three-dimensional structure after the second reduction.
Figure 2. Performance results of an aqueous redox flow battery using 1M of the developed NDI molecule as the cathode electrolyte and 3.1M of ammonium iodine as the anode electrolyte. Using 1.5 M KCl solution. (a) A schematic diagram of a redox flow battery. (b) Voltage-capacity graph according to cycle in a redox flow battery. (c) Graphs of capacity and coulombs, voltage, and energy efficiency maintained at 500 cycles.
2023.04.03 View 6124 -
A biohybrid system to extract 20 times more bioplastic from CO2 developed by KAIST researchers
As the issues surrounding global climate change intensify, more attention and determined efforts are required to re-grasp the issue as a state of “crisis” and respond to it properly. Among the various methods of recycling CO2, the electrochemical CO2 conversion technology is a technology that can convert CO2 into useful chemical substances using electrical energy. Since it is easy to operate facilities and can use the electricity from renewable sources like the solar cells or the wind power, it has received a lot of attention as an eco-friendly technology can contribute to reducing greenhouse gases and achieve carbon neutrality.
KAIST (President Kwang Hyung Lee) announced on the 30th that the joint research team led by Professor Hyunjoo Lee and Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering succeeded in developing a technology that produces bioplastics from CO2 with high efficiency by developing a hybrid system that interlinked the electrochemical CO2 conversion and microbial bio conversion methods together. The results of the research, which showed the world's highest productivity by more than 20 times compared to similar systems, were published online on March 27th in the "Proceedings of the National Academy of Sciences (PNAS)".
※ Paper title: Biohybrid CO2 electrolysis for the direct synthesis of polyesters from CO2
※ Author information: Jinkyu Lim (currently at Stanford Linear Accelerator Center, co-first author), So Young Choi (KAIST, co-first author), Jae Won Lee (KAIST, co-first author), Hyunjoo Lee (KAIST, corresponding author), Sang Yup Lee (KAIST, corresponding author)
For the efficient conversion of CO2, high-efficiency electrode catalysts and systems are actively being developed. As conversion products, only compounds containing one or up to three carbon atoms are produced on a limited basis. Compounds of one carbon, such as CO, formic acid, and ethylene, are produced with relatively high efficiency. Liquid compounds of several carbons, such as ethanol, acetic acid, and propanol, can also be produced by these systems, but due to the nature of the chemical reaction that requires more electrons, there are limitations involving the conversion efficiency and the product selection.
Accordingly, a joint research team led by Professor Hyunjoo Lee and Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering at KAIST developed a technology to produce bioplastics from CO2 by linking electrochemical conversion technology with bioconversion method that uses microorganisms.
This electrochemical-bio hybrid system is in the form of having an electrolyzer, in which electrochemical conversion reactions occur, connected to a fermenter, in which microorganisms are cultured. When CO2 is converted to formic acid in the electrolyzer, and it is fed into the fermenter in which the microbes like the Cupriavidus necator, in this case, consumes the carbon source to produce polyhydroxyalkanoate (PHA), a microbial-derived bioplastic.
According to the research results of the existing hybrid concepts, there was a disadvantage of having low productivity or stopping at a non-continuous process due to problems of low efficiency of the electrolysis and irregular results arising from the culturing conditions of the microbes.
In order to overcome these problems, the joint research team made formic acid with a gas diffusion electrode using gaseous CO2. In addition, the team developed a 'physiologically compatible catholyte' that can be used as a culture medium for microorganisms as well as an electrolyte that allows the electrolysis to occur sufficiently without inhibiting the growth of microorganisms, without having to have a additional separation and purification process, which allowed the acide to be supplied directly to microorganisms.
Through this, the electrolyte solution containing formic acid made from CO2 enters the fermentation tank, is used for microbial culture, and enters the electrolyzer to be circulated, maximizing the utilization of the electrolyte solution and remaining formic acid. In addition, a filter was installed to ensure that only the electrolyte solution with any and all microorganisms that can affect the electrosis filtered out is supplied back to the electrolyzer, and that the microorganisms exist only in the fermenter, designing the two system to work well together with utmost efficiency.
Through the developed hybrid system, the produced bioplastic, poly-3-hydroxybutyrate (PHB), of up to 83% of the cell dry weight was produced from CO2, which produced 1.38g of PHB from a 4 cm2 electrode, which is the world's first gram(g) level production and is more than 20 times more productive than previous research. In addition, the hybrid system is expected to be applied to various industrial processes in the future as it shows promises of the continuous culture system.
The corresponding authors, Professor Hyunjoo Lee and Distinguished Professor Sang Yup Lee noted that “The results of this research are technologies that can be applied to the production of various chemical substances as well as bioplastics, and are expected to be used as key parts needed in achieving carbon neutrality in the future.”
This research was received and performed with the supports from the CO2 Reduction Catalyst and Energy Device Technology Development Project, the Heterogeneous Atomic Catalyst Control Project, and the Next-generation Biorefinery Source Technology Development Project to lead the Biochemical Industry of the Oil-replacement Eco-friendly Chemical Technology Development Program by the Ministry of Science and ICT.
Figure 1. Schematic diagram and photo of the biohybrid CO2 electrolysis system.
(A) A conceptual scheme and (B) a photograph of the biohybrid CO2 electrolysis system. (C) A detailed scheme of reaction inside the system. Gaseous CO2 was converted to formate in the electrolyzer, and the formate was converted to PHB by the cells in the fermenter. The catholyte was developed so that it is compatible with both CO2 electrolysis and fermentation and was continuously circulated.
2023.03.30 View 9292 -
KAIST researchers devises a technology to utilize ultrahigh-resolution micro-LED with 40% reduced self-generated heat
In the digitized modern life, various forms of future displays, such as wearable and rollable displays are required. More and more people are wanting to connect to the virtual world whenever and wherever with the use of their smartglasses or smartwatches. Even further, we’ve been hearing about medical diagnosis kit on a shirt and a theatre-hat. However, it is not quite here in our hands yet due to technical limitations of being unable to fit as many pixels as a limited surface area of a glasses while keeping the power consumption at the a level that a hand held battery can supply, all the while the resolution of 4K+ is needed in order to perfectly immerse the users into the augmented or virtual reality through a wireless smartglasses or whatever the device.
KAIST (President Kwang Hyung Lee) announced on the 22nd that Professor Sang Hyeon Kim's research team of the Department of Electrical and Electronic Engineering re-examined the phenomenon of efficiency degradation of micro-LEDs with pixels in a size of micrometers (μm, one millionth of a meter) and found that it was possible to fundamentally resolve the problem by the use of epitaxial structure engineering.
Epitaxy refers to the process of stacking gallium nitride crystals that are used as a light emitting body on top of an ultrapure silicon or sapphire substrate used for μLEDs as a medium.
μLED is being actively studied because it has the advantages of superior brightness, contrast ratio, and lifespan compared to OLED. In 2018, Samsung Electronics commercialized a product equipped with μLED called 'The Wall'. And there is a prospect that Apple may be launching a μLED-mounted product in 2025.
In order to manufacture μLEDs, pixels are formed by cutting the epitaxial structure grown on a wafer into a cylinder or cuboid shape through an etching process, and this etching process is accompanied by a plasma-based process. However, these plasmas generate defects on the side of the pixel during the pixel formation process.
Therefore, as the pixel size becomes smaller and the resolution increases, the ratio of the surface area to the volume of the pixel increases, and defects on the side of the device that occur during processing further reduce the device efficiency of the μLED. Accordingly, a considerable amount of research has been conducted on mitigating or removing sidewall defects, but this method has a limit to the degree of improvement as it must be done at the post-processing stage after the grown of the epitaxial structure is finished.
The research team identified that there is a difference in the current moving to the sidewall of the μLED depending on the epitaxial structure during μLED device operation, and based on the findings, the team built a structure that is not sensitive to sidewall defects to solve the problem of reduced efficiency due to miniaturization of μLED devices. In addition, the proposed structure reduced the self-generated heat while the device was running by about 40% compared to the existing structure, which is also of great significance in commercialization of ultrahigh-resolution μLED displays.
This study, which was led by Woo Jin Baek of Professor Sang Hyeon Kim's research team at the KAIST School of Electrical and Electronic Engineering as the first author with guidance by Professor Sang Hyeon Kim and Professor Dae-Myeong Geum of the Chungbuk National University (who was with the team as a postdoctoral researcher at the time) as corresponding authors, was published in the international journal, 'Nature Communications' on March 17th. (Title of the paper: Ultra-low-current driven InGaN blue micro light-emitting diodes for electrically efficient and self-heating relaxed microdisplay).
Professor Sang Hyeon Kim said, "This technological development has great meaning in identifying the cause of the drop in efficiency, which was an obstacle to miniaturization of μLED, and solving it with the design of the epitaxial structure.“ He added, ”We are looking forward to it being used in manufacturing of ultrahigh-resolution displays in the future."
This research was carried out with the support of the Samsung Future Technology Incubation Center.
Figure 1. Image of electroluminescence distribution of μLEDs fabricated from epitaxial structures with quantum barriers of different thicknesses while the current is running
Figure 2. Thermal distribution images of devices fabricated with different epitaxial structures under the same amount of light.
Figure 3. Normalized external quantum efficiency of the device fabricated with the optimized epitaxial structure by sizes.
2023.03.23 View 6345 -
KAIST leads AI-based analysis on drug-drug interactions involving Paxlovid
KAIST (President Kwang Hyung Lee) announced on the 16th that an advanced AI-based drug interaction prediction technology developed by the Distinguished Professor Sang Yup Lee's research team in the Department of Biochemical Engineering that analyzed the interaction between the PaxlovidTM ingredients that are used as COVID-19 treatment and other prescription drugs was published as a thesis. This paper was published in the online edition of 「Proceedings of the National Academy of Sciences of America」 (PNAS), an internationally renowned academic journal, on the 13th of March.
* Thesis Title: Computational prediction of interactions between Paxlovid and prescription drugs (Authored by Yeji Kim (KAIST, co-first author), Jae Yong Ryu (Duksung Women's University, co-first author), Hyun Uk Kim (KAIST, co-first author), and Sang Yup Lee (KAIST, corresponding author))
In this study, the research team developed DeepDDI2, an advanced version of DeepDDI, an AI-based drug interaction prediction model they developed in 2018. DeepDDI2 is able to compute for and process a total of 113 drug-drug interaction (DDI) types, more than the 86 DDI types covered by the existing DeepDDI.
The research team used DeepDDI2 to predict possible interactions between the ingredients (ritonavir, nirmatrelvir) of Paxlovid*, a COVID-19 treatment, and other prescription drugs. The research team said that while among COVID-19 patients, high-risk patients with chronic diseases such as high blood pressure and diabetes are likely to be taking other drugs, drug-drug interactions and adverse drug reactions for Paxlovid have not been sufficiently analyzed, yet. This study was pursued in light of seeing how continued usage of the drug may lead to serious and unwanted complications.
* Paxlovid: Paxlovid is a COVID-19 treatment developed by Pfizer, an American pharmaceutical company, and received emergency use approval (EUA) from the US Food and Drug Administration (FDA) in December 2021.
The research team used DeepDDI2 to predict how Paxrovid's components, ritonavir and nirmatrelvir, would interact with 2,248 prescription drugs. As a result of the prediction, ritonavir was predicted to interact with 1,403 prescription drugs and nirmatrelvir with 673 drugs.
Using the prediction results, the research team proposed alternative drugs with the same mechanism but low drug interaction potential for prescription drugs with high adverse drug events (ADEs). Accordingly, 124 alternative drugs that could reduce the possible adverse DDI with ritonavir and 239 alternative drugs for nirmatrelvir were identified.
Through this research achievement, it became possible to use an deep learning technology to accurately predict drug-drug interactions (DDIs), and this is expected to play an important role in the digital healthcare, precision medicine and pharmaceutical industries by providing useful information in the process of developing new drugs and making prescriptions.
Distinguished Professor Sang Yup Lee said, "The results of this study are meaningful at times like when we would have to resort to using drugs that are developed in a hurry in the face of an urgent situations like the COVID-19 pandemic, that it is now possible to identify and take necessary actions against adverse drug reactions caused by drug-drug interactions very quickly.”
This research was carried out with the support of the KAIST New-Deal Project for COVID-19 Science and Technology and the Bio·Medical Technology Development Project supported by the Ministry of Science and ICT.
Figure 1. Results of drug interaction prediction between Paxlovid ingredients and representative approved drugs using DeepDDI2
2023.03.16 View 7470 -
The cause of disability in aged brain meningeal membranes identified
Due to the increase in average age, studies on changes in the brain following general aging process without serious brain diseases have also become an issue that requires in-depth studies. Regarding aging research, as aging progresses, ‘sugar’ accumulates in the body, and the accumulated sugar becomes a causative agent for various diseases such as aging-related inflammation and vascular disease. In the end, “surplus” sugar molecules attach to various proteins in the body and interfere with their functions.
KAIST (President Kwang Hyung Lee), a joint research team of Professor Pilnam Kim and Professor Yong Jeong of the Department of Bio and Brain Engineering, revealed on the 15th that it was confirmed that the function of being the “front line of defense” for the cerebrocortex of the brain meninges, the layers of membranes that surrounds the brain, is hindered when 'sugar' begins to build up on them as aging progresses.
Professor Kim's research team confirmed excessive accumulation of sugar molecules in the meninges of the elderly and also confirmed that sugar accumulation occurs mouse models in accordance with certain age levels. The meninges are thin membranes that surround the brain and exist at the boundary between the cerebrospinal fluid and the cortex and play an important role in protecting the brain. In this study, it was revealed that the dysfunction of these brain membranes caused by aging is induced by 'excess' sugar in the brain. In particular, as the meningeal membrane becomes thinner and stickier due to aging, a new paradigm has been provided for the discovery of the principle of the decrease in material exchange between the cerebrospinal fluid and the cerebral cortex.
This research was conducted by the Ph.D. candidate Hyo Min Kim and Dr. Shinheun Kim as the co-first authors to be published online on February 28th in the international journal, Aging Cell. (Paper Title: Glycation-mediated tissue-level remodeling of brain meningeal membrane by aging)
The meninges, which are in direct contact with the cerebrospinal fluid, are mainly composed of collagen, an extracellular matrix (ECM) protein, and are composed of fibroblasts, which are cells that produce this protein. The cells that come in contact with collagen proteins that are attached with sugar have a low collagen production function, while the meningeal membrane continuously thins and collapses as the expression of collagen degrading enzymes increases.
Studies on the relationship between excess sugar molecules accumulation in the brain due to continued sugar intake and the degeneration of neurons and brain diseases have been continuously conducted. However, this study was the first to identify meningeal degeneration and dysfunction caused by glucose accumulation with the focus on the meninges itself, and the results are expected to present new ideas for research into approach towards discoveries of new treatments for brain disease.
Researcher Hyomin Kim, the first author, introduced the research results as “an interesting study that identified changes in the barriers of the brain due to aging through a convergent approach, starting from the human brain and utilizing an animal model with a biomimetic meningeal model”.
Professor Pilnam Kim's research team is conducting research and development to remove sugar that accumulated throughout the human body, including the meninges. Advanced glycation end products, which are waste products formed when proteins and sugars meet in the human body, are partially removed by macrophages. However, glycated products bound to extracellular matrix proteins such as collagen are difficult to remove naturally. Through the KAIST-Ceragem Research Center, this research team is developing a healthcare medical device to remove 'sugar residue' in the body.
This study was carried out with the National Research Foundation of Korea's collective research support.
Figure 1. Schematic diagram of proposed mechanism showing aging‐related ECM remodeling through meningeal fibroblasts on the brain leptomeninges. Meningeal fibroblasts in the young brain showed dynamic COL1A1 synthetic and COL1‐interactive function on the collagen membrane. They showed ITGB1‐mediated adhesion on the COL1‐composed leptomeningeal membrane and induction of COL1A1 synthesis for maintaining the collagen membrane. With aging, meningeal fibroblasts showed depletion of COL1A1 synthetic function and altered cell–matrix interaction.
Figure 2. Representative rat meningeal images observed in the study. Compared to young rats, it was confirmed that type 1 collagen (COL1) decreased along with the accumulation of glycated end products (AGE) in the brain membrane of aged rats, and the activity of integrin beta 1 (ITGB1), a representative receptor corresponding to cell-collagen interaction. Instead, it was observed that the activity of discoidin domain receptor 2 (DDR2), one of the tyrosine kinases, increased.
Figure 3. Substance flux through the brain membrane decreases with aging. It was confirmed that the degree of adsorption of fluorescent substances contained in cerebrospinal fluid (CSF) to the brain membrane increased and the degree of entry into the periphery of the cerebral blood vessels decreased in the aged rats. In this study, only the influx into the brain was confirmed during the entry and exit of substances, but the degree of outflow will also be confirmed through future studies.
2023.03.15 View 7288 -
KAIST team develops smart immune system that can pin down on malignant tumors
A joint research team led by Professor Jung Kyoon Choi of the KAIST Department of Bio and Brain Engineering and Professor Jong-Eun Park of the KAIST Graduate School of Medical Science and Engineering (GSMSE) announced the development of the key technologies to treat cancers using smart immune cells designed based on AI and big data analysis. This technology is expected to be a next-generation immunotherapy that allows precision targeting of tumor cells by having the chimeric antigen receptors (CARs) operate through a logical circuit. Professor Hee Jung An of CHA Bundang Medical Center and Professor Hae-Ock Lee of the Catholic University of Korea also participated in this research to contribute joint effort.
Professor Jung Kyoon Choi’s team built a gene expression database from millions of cells, and used this to successfully develop and verify a deep-learning algorithm that could detect the differences in gene expression patterns between tumor cells and normal cells through a logical circuit. CAR immune cells that were fitted with the logic circuits discovered through this methodology could distinguish between tumorous and normal cells as a computer would, and therefore showed potentials to strike only on tumor cells accurately without causing unwanted side effects.
This research, conducted by co-first authors Dr. Joonha Kwon of the KAIST Department of Bio and Brain Engineering and Ph.D. candidate Junho Kang of KAIST GSMSE, was published by Nature Biotechnology on February 16, under the title Single-cell mapping of combinatorial target antigens for CAR switches using logic gates.
An area in cancer research where the most attempts and advances have been made in recent years is immunotherapy. This field of treatment, which utilizes the patient’s own immune system in order to overcome cancer, has several methods including immune checkpoint inhibitors, cancer vaccines and cellular treatments. Immune cells like CAR-T or CAR-NK equipped with chimera antigen receptors, in particular, can recognize cancer antigens and directly destroy cancer cells.
Starting with its success in blood cancer treatment, scientists have been trying to expand the application of CAR cell therapy to treat solid cancer. But there have been difficulties to develop CAR cells with effective killing abilities against solid cancer cells with minimized side effects. Accordingly, in recent years, the development of smarter CAR engineering technologies, i.e., computational logic gates such as AND, OR, and NOT, to effectively target cancer cells has been underway.
At this point in time, the research team built a large-scale database for cancer and normal cells to discover the exact genes that are expressed only from cancer cells at a single-cell level. The team followed this up by developing an AI algorithm that could search for a combination of genes that best distinguishes cancer cells from normal cells. This algorithm, in particular, has been used to find a logic circuit that can specifically target cancer cells through cell-level simulations of all gene combinations. CAR-T cells equipped with logic circuits discovered through this methodology are expected to distinguish cancerous cells from normal cells like computers, thereby minimizing side effects and maximizing the effects of chemotherapy.
Dr. Joonha Kwon, who is the first author of this paper, said, “this research suggests a new method that hasn’t been tried before. What’s particularly noteworthy is the process in which we found the optimal CAR cell circuit through simulations of millions of individual tumors and normal cells.” He added, “This is an innovative technology that can apply AI and computer logic circuits to immune cell engineering. It would contribute greatly to expanding CAR therapy, which is being successfully used for blood cancer, to solid cancers as well.”
This research was funded by the Original Technology Development Project and Research Program for Next Generation Applied Omic of the Korea Research Foundation.
Figure 1. A schematic diagram of manufacturing and administration process of CAR therapy and of cancer cell-specific dual targeting using CAR.
Figure 2. Deep learning (convolutional neural networks, CNNs) algorithm for selection of dual targets based on gene combination (left) and algorithm for calculating expressing cell fractions by gene combination according to logical circuit (right).
2023.03.09 View 8766 -
KAIST Holds 2023 Commencement Ceremony
< Photo 1. On the 17th, KAIST held the 2023 Commencement Ceremony for a total of 2,870 students, including 691 doctors. >
KAIST held its 2023 commencement ceremony at the Sports Complex of its main campus in Daejeon at 2 p.m. on February 27. It was the first commencement ceremony to invite all its graduates since the start of COVID-19 quarantine measures.
KAIST awarded a total of 2,870 degrees including 691 PhD degrees, 1,464 master’s degrees, and 715 bachelor’s degrees, which adds to the total of 74,999 degrees KAIST has conferred since its foundation in 1971, which includes 15,772 PhD, 38,360 master’s and 20,867 bachelor’s degrees.
This year’s Cum Laude, Gabin Ryu, from the Department of Mechanical Engineering received the Minister of Science and ICT Award. Seung-ju Lee from the School of Computing received the Chairman of the KAIST Board of Trustees Award, while Jantakan Nedsaengtip, an international student from Thailand received the KAIST Presidential Award, and Jaeyong Hwang from the Department of Physics and Junmo Lee from the Department of Industrial and Systems Engineering each received the President of the Alumni Association Award and the Chairman of the KAIST Development Foundation Award, respectively.
Minister Jong-ho Lee of the Ministry of Science and ICT awarded the recipients of the academic awards and delivered a congratulatory speech.
Yujin Cha from the Department of Bio and Brain Engineering, who received a PhD degree after 19 years since his entrance to KAIST as an undergraduate student in 2004 gave a speech on behalf of the graduates to move and inspire the graduates and the guests.
After Cha received a bachelor’s degree from the Department of Nuclear and Quantum Engineering, he entered a medical graduate school and became a radiation oncology specialist. But after experiencing the death of a young patient who suffered from osteosarcoma, he returned to his alma mater to become a scientist. As he believes that science and technology is the ultimate solution to the limitations of modern medicine, he started as a PhD student at the Department of Bio and Brain Engineering in 2018, hoping to find such solutions.
During his course, he identified the characteristics of the decision-making process of doctors during diagnosis, and developed a brain-inspired AI algorithm. It is an original and challenging study that attempted to develop a fundamental machine learning theory from the data he collected from 200 doctors of different specialties.
Cha said, “Humans and AI can cooperate by humans utilizing the unique learning abilities of AI to develop our expertise, while AIs can mimic us humans’ learning abilities to improve.” He added, “My ultimate goal is to develop technology to a level at which humans and machines influence each other and ‘coevolve’, and applying it not only to medicine, but in all areas.”
Cha, who is currently an assistant professor at the KAIST Biomedical Research Center, has also written Artificial Intelligence for Doctors in 2017 to help medical personnel use AI in clinical fields, and the book was selected as one of the 2018 Sejong Books in the academic category.
During his speech at this year’s commencement ceremony, he shared that “there are so many things in the world that are difficult to solve and many things to solve them with, but I believe the things that can really broaden the horizons of the world and find fundamental solutions to the problems at hand are science and technology.”
Meanwhile, singer-songwriter Sae Byul Park who studied at the KAIST Graduate School of Culture Technology will also receive her PhD degree.
Natural language processing (NLP) is a field in AI that teaches a computer to understand and analyze human language that is actively being studied. An example of NLP is ChatGTP, which recently received a lot of attention. For her research, Park analyzed music rather than language using NLP technology.
To analyze music, which is in the form of sound, using the methods for NLP, it is necessary to rebuild notes and beats into a form of words or sentences as in a language. For this, Park designed an algorithm called Mel2Word and applied it to her research.
She also suggested that by converting melodies into texts for analysis, one would be able to quantitatively express music as sentences or words with meaning and context rather than as simple sounds representing a certain note.
Park said, “music has always been considered as a product of subjective emotion, but this research provides a framework that can calculate and analyze music.”
Park’s study can later be developed into a tool to measure the similarities between musical work, as well as a piece’s originality, artistry and popularity, and it can be used as a clue to explore the fundamental principles of how humans respond to music from a cognitive science perspective.
Park began her Ph.D. program in 2014, while carrying on with her musical activities as well as public and university lectures alongside, and dealing with personally major events including marriage and childbirth during the course of years. She already met the requirements to receive her degree in 2019, but delayed her graduation in order to improve the level of completion of her research, and finally graduated with her current achievements after nine years.
Professor Juhan Nam, who supervised Park’s research, said, “Park, who has a bachelor’s degree in psychology, later learned to code for graduate school, and has complete high-quality research in the field of artificial intelligence.” He added, “Though it took a long time, her attitude of not giving up until the end as a researcher is also excellent.”
Sae Byul Park is currently lecturing courses entitled Culture Technology and Music Information Retrieval at the Underwood International College of Yonsei University.
Park said, “the 10 or so years I’ve spent at KAIST as a graduate student was a time I could learn and prosper not only academically but from all angles of life.” She added, “having received a doctorate degree is not the end, but a ‘commencement’. Therefore, I will start to root deeper from the seeds I sowed and work harder as a both a scholar and an artist.”
< Photo 2. From left) Yujin Cha (Valedictorian, Medical-Scientist Program Ph.D. graduate), Saebyeol Park (a singer-songwriter, Ph.D. graduate from the Graduate School of Culture and Technology), Junseok Moon and Inah Seo (the two highlighted CEO graduates from the Department of Management Engineering's master’s program) >
Young entrepreneurs who dream of solving social problems will also be wearing their graduation caps. Two such graduates are Jun-seok Moon and Inah Seo, receiving their master’s degrees in social entrepreneurship MBA from the KAIST College of Business.
Before entrance, Moon ran a café helping African refugees stand on their own feet. Then, he entered KAIST to later expand his business and learn social entrepreneurship in order to sustainably help refugees in the blind spots of human rights and welfare.
During his master’s course, Moon realized that he could achieve active carbon reduction by changing the coffee alone, and switched his business field and founded Equal Table. The amount of carbon an individual can reduce by refraining from using a single paper cup is 10g, while changing the coffee itself can reduce it by 300g.
1kg of coffee emits 15kg of carbon over the course of its production, distribution, processing, and consumption, but Moon produces nearly carbon-neutral coffee beans by having innovated the entire process. In particular, the company-to-company ESG business solution is Moon’s new start-up area. It provides companies with carbon-reduced coffee made by roasting raw beans from carbon-neutral certified farms with 100% renewable energy, and shows how much carbon has been reduced in its making. Equal Table will launch the service this month in collaboration with SK Telecom, its first partner.
Inah Seo, who also graduated with Moon, founded Conscious Wear to start a fashion business reducing environmental pollution. In order to realize her mission, she felt the need to gain the appropriate expertise in management, and enrolled for the social entrepreneurship MBA.
Out of the various fashion industries, Seo focused on the leather market, which is worth 80 trillion won. Due to thickness or contamination issues, only about 60% of animal skin fabric is used, and the rest is discarded. Heavy metals are used during such processes, which also directly affects the environment.
During the social entrepreneurship MBA course, Seo collaborated with SK Chemicals, which had links through the program, and launched eco-friendly leather bags. The bags used discarded leather that was recycled by grinding and reprocessing into a biomaterial called PO3G. It was the first case in which PO3G that is over 90% biodegradable was applied to regenerated leather. In other words, it can reduce environmental pollution in the processing and disposal stages, while also reducing carbon emissions and water usage by one-tenth compared to existing cowhide products.
The social entrepreneurship MBA course, from which Moon and Seo graduated, will run in integration with the Graduate School of Green Growth as an Impact MBA program starting this year. KAIST plans to steadily foster entrepreneurs who will lead meaningful changes in the environment and society as well as economic values through innovative technologies and ideas.
< Photo 3. NYU President Emeritus John Sexton (left), who received this year's honorary doctorate of science, poses with President Kwang Hyung Lee >
Meanwhile, during this day’s commencement ceremony, KAIST also presented President Emeritus John Sexton of New York University with an honorary doctorate in science. He was recognized for laying the foundation for the cooperation between KAIST and New York University, such as promoting joint campuses.
< Photo 4. At the commencement ceremony of KAIST held on the 17th, President Kwang Hyung Lee is encouraging the graduates with his commencement address. >
President Kwang Hyung Lee emphasized in his commencement speech that, “if you can draw up the future and work hard toward your goal, the future can become a work of art that you create with your own hands,” and added, “Never stop on the journey toward your dreams, and do not give up even when you are met with failure. Failure happens to everyone, all the time. The important thing is to know 'why you failed', and to use those elements of failure as the driving force for the next try.”
2023.02.20 View 17472 -
KAIST confers Honorary Doctorate of Science on NYU President Emeritus John Edward Sexton
< Photo 1. NYU President Emeritus John Edward Sexton posing with KAIST President Kwang Hyung Lee holding the Honorary Doctorate at the KAIST Commencement Ceremony >
KAIST (President Kwang Hyung Lee) announced that it conferred an honorary doctorate of science degree on NYU President Emeritus John Edward Sexton at the Commencement Ceremony held on the 17th.
An official from KAIST explained, "KAIST is conferring an honorary doctorate for President Sexton's longstanding leadership in higher education, and for his contributions to the process of establishing the groundwork for collaboration with NYU through which KAIST is to become a leading global value-creating university."
President Emeritus Sexton served as the president of NYU from 2002 to 2015, establishing two degree-granting campuses and several global academic sites of NYU around the world. Because of its steady rise in university rankings, such as its medical school earning the number two position in the United States, not only has NYU joined the ranks of first-class universities, but it has also achieved remarkable growth, with the number of students increasing dramatically from 29,000 to 60,000.
In addition, during his tenure as president at NYU, President Emeritus Sexton successfully expanded fundraising to support the University’s academic goals. During his 14-year tenure as president, he organized initiatives such as 'Raise $1 Million Every Day' and 'Call to Action' to raise $4.9 billion in donations, the largest in NYU history to date.
President Emeritus Sexton is famous for teaching full time even during his presidential tenure and for the anecdotes about his special care for students, addressing the school members as “family”. In particular, he is famous for giving hugs to all graduates at the commencement ceremony. Minister Park Jin of the Ministry of Foreign Affairs of Korea, who graduated from NYU School of Law in 1999 with a Master of Studies in Law, is one of the graduates who received President Sexton's hug.
President Emeritus Sexton, born in 1942, visited KAIST on the 17th to receive the honorary doctorate and to encourage the expedited development of the KAIST-NYU Joint Campus, for which he helped lay the foundation.
President Emeritus Sexton said, "I like the slogan, 'Onward and upward together,'" and added, "I look forward to having the two universities achieve their shared vision of becoming the world-class universities together through cooperation to establish the KAIST-NYU Joint Campus."
< Photo 2. NYU President Emeritus John Edward Sexton giving the acceptance speech at the KAIST Commencement Ceremony >
The US Ambassador to Korea, the Honorable Philip Goldberg, also attended the commencement ceremony at KAIST to congratulate President Emeritus Sexton on the conferment of the honorary doctorate. Ambassador Goldberg has been serving as the US Ambassador to Korea since July of last year.
President Kwang Hyung Lee said, “President Emeritus Sexton was a president best described as an innovator who promoted diversity in education and pursued academic excellence throughout his life.” He went on to say, “The KAIST-NYU Joint Campus, which will be completed on the foundation laid by President Emeritus Sexton, will serve as the focal point that will attract global talents flooding into New York by the driving force created from the synergy of the two universities as well as serving as a starting point for KAIST's outstanding talents to pursue their dreams toward the world.”
KAIST signed a cooperation agreement with NYU in June of 2022 to build a joint campus, and held a presentation of signage for the KAIST-NYU Joint Campus in September. Currently, about 60 faculty members are planning to begin joint research initiatives in seven fields, including robotics, AI, brain sciences, and climate change. In addition, cooperation in the field of education, including student exchange, minors, double majors, and joint degrees, is under discussion.
2023.02.17 View 8601 -
Prof. Austin Givens of KAIST Language Center receives Ministerial Commendation
< Professor Austin Givens posing with the Letter of Commendation by the Miniser Hwang-Keun Chung of the Ministry of Agriculture, Food and Rural Affairs at the Language Center >
Professor Austin Givens of our Language Center received a Ministerial Commendation from the Korean Ministry of Agriculture, Food and Rural Affairs dated December 21st, 2022 for his contribution for the development of the Korean Foodservices Industry through his active and prominent media presence.
Professor Austin Givens has been working with the KAIST Language Center since 2017, and has shown his passion for Korean food through his YouTube channel "Austin! Eating What is Given", introducing not only the food but also the culture of Korea and KAIST to his international viewers through the videos he shares of his candid reviews of the food and restaurants around town on the popular video streaming platform.
< Thumbnail introductions of Professor Givens' videos on his YouTube channel, "Austin! Eating What is Given" >
- KAIST Language Center
2023.02.09 View 7773