College+of+Engineering
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Repurposed Drugs Present New Strategy for Treating COVID-19
Virtual screening of 6,218 drugs and cell-based assays identifies best therapeutic medication candidates
A joint research group from KAIST and Institut Pasteur Korea has identified repurposed drugs for COVID-19 treatment through virtual screening and cell-based assays. The research team suggested the strategy for virtual screening with greatly reduced false positives by incorporating pre-docking filtering based on shape similarity and post-docking filtering based on interaction similarity. This strategy will help develop therapeutic medications for COVID-19 and other antiviral diseases more rapidly. This study was reported at the Proceedings of the National Academy of Sciences of the United States of America (PNAS).
Researchers screened 6,218 drugs from a collection of FDA-approved drugs or those under clinical trial and identified 38 potential repurposed drugs for COVID-19 with this strategy. Among them, seven compounds inhibited SARS-CoV-2 replication in Vero cells. Three of these drugs, emodin, omipalisib, and tipifarnib, showed anti-SARS-CoV-2 activity in human lung cells, Calu-3.
Drug repurposing is a practical strategy for developing antiviral drugs in a short period of time, especially during a global pandemic. In many instances, drug repurposing starts with the virtual screening of approved drugs. However, the actual hit rate of virtual screening is low and most of the predicted drug candidates are false positives.
The research group developed effective filtering algorithms before and after the docking simulations to improve the hit rates. In the pre-docking filtering process, compounds with similar shapes to the known active compounds for each target protein were selected and used for docking simulations. In the post-docking filtering process, the chemicals identified through their docking simulations were evaluated considering the docking energy and the similarity of the protein-ligand interactions with the known active compounds.
The experimental results showed that the virtual screening strategy reached a high hit rate of 18.4%, leading to the identification of seven potential drugs out of the 38 drugs initially selected.
“We plan to conduct further preclinical trials for optimizing drug concentrations as one of the three candidates didn’t resolve the toxicity issues in preclinical trials,” said Woo Dae Jang, one of the researchers from KAIST.
“The most important part of this research is that we developed a platform technology that can rapidly identify novel compounds for COVID-19 treatment. If we use this technology, we will be able to quickly respond to new infectious diseases as well as variants of the coronavirus,” said Distinguished Professor Sang Yup Lee.
This work was supported by the KAIST Mobile Clinic Module Project funded by the Ministry of Science and ICT (MSIT) and the National Research Foundation of Korea (NRF). The National Culture Collection for Pathogens in Korea provided the SARS-CoV-2 (NCCP43326).
-PublicationWoo Dae Jang, Sangeun Jeon, Seungtaek Kim, and Sang Yup Lee. Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay. Proc. Natl. Acad. Sci. U.S.A. (https://doi/org/10.1073/pnas.2024302118)
-ProfileDistinguished Professor Sang Yup LeeMetabolic &Biomolecular Engineering National Research Laboratoryhttp://mbel.kaist.ac.kr
Department of Chemical and Biomolecular EngineeringKAIST
2021.07.08 View 10423 -
Alumni Professor Cho at NYU Endows Scholarship for Female Computer Scientists
Alumni Professor Kyunghyun Cho at New York University endowed the “Lim Mi-Sook Scholarship” at KAIST for female computer scientists in honor of his mother.
Professor Cho, a graduate of the School of Computing in 2011 completed his master’s and PhD at Alto University in Finland in 2014. He has been teaching at NYU since 2015 and received the Samsung Ho-Am Prize for Engineering this year in recognition of his outstanding researches in the fields of machine learning and AI.
“I hope this will encourage young female students to continue their studies in computer science and encourage others to join the discipline in the future, thereby contributing to building a more diverse community of computer scientists,” he said in his written message. His parents and President Kwang Hyung Lee attended the donation ceremony held at the Daejeon campus on June 24.
Professor Cho has developed neural network machine learning translation algorithm that is widely being used in translation engines. His contributions to AI-powered translations and innovation in the industry led him to win one of the most prestigious prizes in Korea.
He decided to donate his 300 million KRW prize money to fund two 100 million KRW scholarships named after each of his parents: the Lim Mi-Sook Scholarship is for female computer scientists and the Bae-Gyu Scholarly Award for Classics is in honor of his father, who is a Korean literature professor at Soongsil University in Korea. He will also fund a scholarship at Alto University.
“I recall there were less than five female students out of 70 students in my cohort during my undergraduate studies at KAIST even in later 2000s. Back then, it just felt natural that boys majored computer science and girls in biology.”
He said he wanted to acknowledge his mother, who had to give up her teaching career in the 1980s to take care of her children. “It made all of us think more about the burden of raising children that is placed often disproportionately on mothers and how it should be better distributed among parents, relatives, and society in order to ensure and maximize equity in education as well as career development and advances.”
He added, “As a small step to help build a more diverse environment, I have decided to donate to this fund to provide a small supplement to the small group of female students majoring in computer science.
2021.07.01 View 7327 -
Prof. Sang Wan Lee Selected for 2021 IBM Academic Award
Professor Sang Wan Lee from the Department of Bio and Brain Engineering was selected as the recipient of the 2021 IBM Global University Program Academic Award. The award recognizes individual faculty members whose emerging science and technology contains significant interest for universities and IBM.
Professor Lee, whose research focuses on artificial intelligence and computational neuroscience, won the award for his research proposal titled A Neuroscience-Inspired Approach for Metacognitive Reinforcement Learning. IBM provides a gift of $40,000 to the recipient’s institution in recognition of the selection of the project but not as a contract for services.
Professor Lee’s project aims to exploit the unique characteristics of human reinforcement learning. Specifically, he plans to examines the hypothesis that metacognition, a human’s ability to estimate their uncertainty level, serves to guide sample-efficient and near-optimal exploration, making it possible to achieve an optimal balance between model-based and model-free reinforcement learning.
He was also selected as the winner of the Google Research Award in 2016 and has been working with DeepMind and University College London to conduct basic research on decision-making brain science to establish a theory on frontal lobe meta-enhance learning.
"We plan to conduct joint research for utilizing brain-based artificial intelligence technology and frontal lobe meta-enhanced learning technology modeling in collaboration with an international research team including IBM, DeepMind, MIT, and Oxford,” Professor Lee said.
2021.06.25 View 8995 -
Wearable Device to Monitor Sweat in Real Time
An on-skin platform for the wireless monitoring of flow rate, cumulative loss, and temperature of sweat in real time
An electronic patch can monitor your sweating and check your health status. Even more, the soft microfluidic device that adheres to the surface of the skin, captures, stores, and performs biomarker analysis of sweat as it is released through the eccrine glands.
This wearable and wireless electronic device developed by Professor Kyeongha Kwon and her collaborators is a digital and wireless platform that could help track the so-called ‘filling process’ of sweat without having to visually examine the device. The platform was integrated with microfluidic systems to analyze the sweat’s components.
To monitor the sweat release rate in real time, the researchers created a ‘thermal flow sensing module.’ They designed a sophisticated microfluidic channel to allow the collected sweat to flow through a narrow passage and a heat source was placed on the outer surface of the channel to induce a heat exchange between the sweat and the heated channel.
As a result, the researchers could develop a wireless electronic patch that can measure the temperature difference in a specific location upstream and downstream of the heat source with an electronic circuit and convert it into a digital signal to measure the sweat release rate in real time. The patch accurately measured the perspiration rate in the range of 0-5 microliters/minute (μl/min), which was considered physiologically significant. The sensor can measure the flow of sweat directly and then use the information it collected to quantify total sweat loss. Moreover, the device features advanced microfluidic systems and colorimetric chemical reagents to gather pH measurements and determine the concentration of chloride, creatinine, and glucose in a user's sweat.
Professor Kwon said that these indicators could be used to diagnose various diseases related with sweating such as cystic fibrosis, diabetes, kidney dysfunction, and metabolic alkalosis. “As the sweat flowing in the microfluidic channel is completely separated from the electronic circuit, the new patch overcame the shortcomings of existing flow rate measuring devices, which were vulnerable to corrosion and aging,” she explained.
The patch can be easily attached to the skin with flexible circuit board printing technology and silicone sealing technology. It has an additional sensor that detects changes in skin temperature. Using a smartphone app, a user can check the data measured by the wearable patch in real time.
Professor Kwon added, “This patch can be widely used for personal hydration strategies, the detection of dehydration symptoms, and other health management purposes. It can also be used in a systematic drug delivery system, such as for measuring the blood flow rate in blood vessels near the skin’s surface or measuring a drug’s release rate in real time to calculate the exact dosage.”
-PublicationKyeongha Kwon, Jong Uk Kim, John A. Rogers, et al. “An on-skin platform for wireless monitoring of flow rate, cumulative loss and temperature of sweat in real time.” Nature Electronics (doi.org/10.1038/s41928-021-00556-2)
-ProfileProfessor Kyeongha KwonSchool of Electrical EngineeringKAIST
2021.06.25 View 7845 -
Biomimetic Resonant Acoustic Sensor Detecting Far-Distant Voices Accurately to Hit the Market
A KAIST research team led by Professor Keon Jae Lee from the Department of Materials Science and Engineering has developed a bioinspired flexible piezoelectric acoustic sensor with multi-resonant ultrathin piezoelectric membrane mimicking the basilar membrane of the human cochlea. The flexible acoustic sensor has been miniaturized for embedding into smartphones and the first commercial prototype is ready for accurate and far-distant voice detection.
In 2018, Professor Lee presented the first concept of a flexible piezoelectric acoustic sensor, inspired by the fact that humans can accurately detect far-distant voices using a multi-resonant trapezoidal membrane with 20,000 hair cells. However, previous acoustic sensors could not be integrated into commercial products like smartphones and AI speakers due to their large device size.
In this work, the research team fabricated a mobile-sized acoustic sensor by adopting ultrathin piezoelectric membranes with high sensitivity. Simulation studies proved that the ultrathin polymer underneath inorganic piezoelectric thin film can broaden the resonant bandwidth to cover the entire voice frequency range using seven channels. Based on this theory, the research team successfully demonstrated the miniaturized acoustic sensor mounted in commercial smartphones and AI speakers for machine learning-based biometric authentication and voice processing. (Please refer to the explanatory movie KAIST Flexible Piezoelectric Mobile Acoustic Sensor).
The resonant mobile acoustic sensor has superior sensitivity and multi-channel signals compared to conventional condenser microphones with a single channel, and it has shown highly accurate and far-distant speaker identification with a small amount of voice training data. The error rate of speaker identification was significantly reduced by 56% (with 150 training datasets) and 75% (with 2,800 training datasets) compared to that of a MEMS condenser device.
Professor Lee said, “Recently, Google has been targeting the ‘Wolverine Project’ on far-distant voice separation from multi-users for next-generation AI user interfaces. I expect that our multi-channel resonant acoustic sensor with abundant voice information is the best fit for this application. Currently, the mass production process is on the verge of completion, so we hope that this will be used in our daily lives very soon.”
Professor Lee also established a startup company called Fronics Inc., located both in Korea and U.S. (branch office) to commercialize this flexible acoustic sensor and is seeking collaborations with global AI companies.
These research results entitled “Biomimetic and Flexible Piezoelectric Mobile Acoustic Sensors with Multi-Resonant Ultrathin Structures for Machine Learning Biometrics” were published in Science Advances in 2021 (7, eabe5683).
-Publication
“Biomimetic and flexible piezoelectric mobile acoustic sensors with multiresonant ultrathin structures for machine learning biometrics,” Science Advances (DOI: 10.1126/sciadv.abe5683)
-Profile
Professor Keon Jae Lee
Department of Materials Science and Engineering
Flexible and Nanobio Device Lab
http://fand.kaist.ac.kr/
KAIST
2021.06.14 View 8131 -
Krafton Matches Alumni Donations to Raise 11 Billion KRW for SW Developers
Alumni donations from the School of Computing, including Baemin and Devsisters, continue to grow
Alumni from the KAIST School of Computing who are current and former developers at the leading game company Krafton, established by KAIST alumna Byung-Gyu Chang, made an agreement to help raise 11 billion KRW during a ceremony on June 4. The funds raised in the matching grant will be used to nurture software developers.
Krafton Chairman Chang donated 10 billion won last January. His donation inspired other alumni working at Krafton as well as its former developers. Eleven KAIST alumni raised 5.5 billion KRW in two months and discussed the matching grant idea with Chairman Chang.
The Krafton matching grant ceremony was attended by President Kwang Hyung Lee, Provost and Executive Vice President Seung Seob Lee, Vice President for Research Sang Yup Lee, Head of the School of Computing Sukyoung Ryu, Krafton Chairman Byung-gyu Chang, and KAIST alumnus from Krafton Seung-woo Shin. Other alumni donors including Krafton CEO Changhan Kim joined the ceremony online.
Krafton CEO Changhan Kim said, “Just as our alma mater played an important role in growing our company, we hope that our donation could help support good developers. This will not only help our company, but advance our industry.”
KAIST and Krafton also signed a business agreement to foster competitive developers. Krafton said it plans to continue giving back to society through the matching grant program.
Head of the School of Computing Sukyoung Ryu thanked Chairman Chang and alumni who took part in the fund raising, saying, “To take the lead in rapidly changing computer technology, we desperately need more top students, faculty members, and facilities. We need more resources and infrastructure for interdisciplinary research.”
The School of Computing has seen significant growth recently. Its number of undergraduate students has increased from 450 in 2016 to more than 900 in 2021. With this donation, the school will expand its current buildings to provide diverse educational and mentoring programs in more spacious facilities.
Seung-woo Shin (Class of ’92), who joined Krafton’s matching grant, said, “I have always been thankful for the people I met and what I learned at KAIST. I was moved by the idea of giving back to the school.”
Seong-jung Ryu (Class of ’97) said, “This donation reminded me of the good times I had back then. I thought it was crucial that the department’s facilities be extended, so I naturally wanted to take part.”
Alumni donations, especially from the School of Computing, have also continued to grow more recently. Woowa Brothers Corp. CEO Beom-Jun Kim, the developer of the meal delivery app ‘Baemin’ donated 100 million KRW in April. Baemin became the most used app in the country during the COVID-19 pandemic.
He explained, “I have been thinking about ways to give something to the next generation, rather than ‘paying back’ those who helped me in the past.”
Encouraged by Baemin’s donation, alumni couple Ha-Yeon Seo and Dong-Hun Hahn from the School of Computing and eleven alumni engineers working at Devsisters Corp. also followed suit.
2021.06.09 View 8076 -
Natural Rainbow Colorants Microbially Produced
Integrated strategies of systems metabolic engineering and membrane engineering led to the production of natural rainbow colorants comprising seven natural colorants from bacteria for the first time
A research group at KAIST has engineered bacterial strains capable of producing three carotenoids and four violacein derivatives, completing the seven colors in the rainbow spectrum. The research team integrated systems metabolic engineering and membrane engineering strategies for the production of seven natural rainbow colorants in engineered Escherichia coli strains. The strategies will be also useful for the efficient production of other industrially important natural products used in the food, pharmaceutical, and cosmetic industries.
Colorants are widely used in our lives and are directly related to human health when we eat food additives and wear cosmetics. However, most of these colorants are made from petroleum, causing unexpected side effects and health problems. Furthermore, they raise environmental concerns such as water pollution from dyeing fabric in the textiles industry. For these reasons, the demand for the production of natural colorants using microorganisms has increased, but could not be readily realized due to the high cost and low yield of the bioprocesses.
These challenges inspired the metabolic engineers at KAIST including researchers Dr. Dongsoo Yang and Dr. Seon Young Park, and Distinguished Professor Sang Yup Lee from the Department of Chemical and Biomolecular Engineering. The team reported the study entitled “Production of rainbow colorants by metabolically engineered Escherichia coli” in Advanced Science online on May 5. It was selected as the journal cover of the July 7 issue.
This research reports for the first time the production of rainbow colorants comprising three carotenoids and four violacein derivatives from glucose or glycerol via systems metabolic engineering and membrane engineering. The research group focused on the production of hydrophobic natural colorants useful for lipophilic food and dyeing garments. First, using systems metabolic engineering, which is an integrated technology to engineer the metabolism of a microorganism, three carotenoids comprising astaxanthin (red), -carotene (orange), and zeaxanthin (yellow), and four violacein derivatives comprising proviolacein (green), prodeoxyviolacein (blue), violacein (navy), and deoxyviolacein (purple) could be produced. Thus, the production of natural colorants covering the complete rainbow spectrum was achieved.
When hydrophobic colorants are produced from microorganisms, the colorants are accumulated inside the cell. As the accumulation capacity is limited, the hydrophobic colorants could not be produced with concentrations higher than the limit. In this regard, the researchers engineered the cell morphology and generated inner-membrane vesicles (spherical membranous structures) to increase the intracellular capacity for accumulating the natural colorants. To further promote production, the researchers generated outer-membrane vesicles to secrete the natural colorants, thus succeeding in efficiently producing all of seven rainbow colorants. It was even more impressive that the production of natural green and navy colorants was achieved for the first time.
“The production of the seven natural rainbow colorants that can replace the current petroleum-based synthetic colorants was achieved for the first time,” said Dr. Dongsoo Yang. He explained that another important point of the research is that integrated metabolic engineering strategies developed from this study can be generally applicable for the efficient production of other natural products useful as pharmaceuticals or nutraceuticals. “As maintaining good health in an aging society is becoming increasingly important, we expect that the technology and strategies developed here will play pivotal roles in producing other valuable natural products of medical or nutritional importance,” explained Distinguished Professor Lee.
This work was supported by the "Cooperative Research Program for Agriculture Science & Technology Development (Project No. PJ01550602)" Rural Development Administration, Republic of Korea.
-Publication:Dongsoo Yang, Seon Young Park, and Sang Yup Lee. Production of rainbow colorants by metabolically engineered Escherichia coli. Advanced Science, 2100743.
-Profile Distinguished Professor Sang Yup LeeMetabolic &Biomolecular Engineering National Research Laboratoryhttp://mbel.kaist.ac.kr
Department of Chemical and Biomolecular EngineeringKAIST
2021.06.09 View 8574 -
Ultrafast, on-Chip PCR Could Speed Up Diagnoses during Pandemics
A rapid point-of-care diagnostic plasmofluidic chip can deliver result in only 8 minutes
Reverse transcription-polymerase chain reaction (RT-PCR) has been the gold standard for diagnosis during the COVID-19 pandemic. However, the PCR portion of the test requires bulky, expensive machines and takes about an hour to complete, making it difficult to quickly diagnose someone at a testing site. Now, researchers at KAIST have developed a plasmofluidic chip that can perform PCR in only about 8 minutes, which could speed up diagnoses during current and future pandemics.
The rapid diagnosis of COVID-19 and other highly contagious viral diseases is important for timely medical care, quarantining and contact tracing. Currently, RT-PCR uses enzymes to reverse transcribe tiny amounts of viral RNA to DNA, and then amplifies the DNA so that it can be detected by a fluorescent probe. It is the most sensitive and reliable diagnostic method.
But because the PCR portion of the test requires 30-40 cycles of heating and cooling in special machines, it takes about an hour to perform, and samples must typically be sent away to a lab, meaning that a patient usually has to wait a day or two to receive their diagnosis.
Professor Ki-Hun Jeong at the Department of Bio and Brain Engineering and his colleagues wanted to develop a plasmofluidic PCR chip that could quickly heat and cool miniscule volumes of liquids, allowing accurate point-of-care diagnoses in a fraction of the time. The research was reported in ACS Nano on May 19.
The researchers devised a postage stamp-sized polydimethylsiloxane chip with a microchamber array for the PCR reactions. When a drop of a sample is added to the chip, a vacuum pulls the liquid into the microchambers, which are positioned above glass nanopillars with gold nanoislands. Any microbubbles, which could interfere with the PCR reaction, diffuse out through an air-permeable wall. When a white LED is turned on beneath the chip, the gold nanoislands on the nanopillars quickly convert light to heat, and then rapidly cool when the light is switched off.
The researchers tested the device on a piece of DNA containing a SARS-CoV-2 gene, accomplishing 40 heating and cooling cycles and fluorescence detection in only 5 minutes, with an additional 3 minutes for sample loading. The amplification efficiency was 91%, whereas a comparable conventional PCR process has an efficiency of 98%. With the reverse transcriptase step added prior to sample loading, the entire testing time with the new method could take 10-13 minutes, as opposed to about an hour for typical RT-PCR testing. The new device could provide many opportunities for rapid point-of-care diagnostics during a pandemic, the researchers say.
-Publication
Ultrafast and Real-Time Nanoplasmonic On-Chip Polymerase Chain Reaction for Rapid and Quantitative Molecular Diagnostics
ACS Nano (https://doi.org/10.1021/acsnano.1c02154)
-Professor
Ki-Hun Jeong
Biophotonics Laboratory
https://biophotonics.kaist.ac.kr/
Department of Bio and Brain Engineeinrg
KAIST
2021.06.08 View 8158 -
KAIST to join Deep Space Exploration Project
KAIST agreed to launch the Deep Space Exploration Research Consortium with two key leading aerospace research institutes, the Korea Aerospace Research Institute (KARI) and the Korea Astronomy and Space Science Institute (KASI) during a recent meeting at the KAIST campus. President Kwang Hyung Lee, KARI President Sang-Yool Lee, KASI President Young-Deuk Park, and Vice Minister of Science and ICT Hong-taek Yong attended the meeting to discuss medium- and long-term deep space exploration plans and collaborations.
The three entities have cooperated in scientific research for the last 30 years during which Korea has been developing its space exploration expertise. They signed the MoU for Cooperation for R&D and Industrialization on Deep Space Exploration’ last December. The research consortium will share and discuss research plans for space science research and exploration technology, and contribute to planning the nation’s deep space exploration.
At the meeting, KAIST reported its plans to return KITSAT-1 to Earth, Korea’s first satellite using local technology, and to explore the radiation belt (the Van Allen belt) around Earth. KAIST launched Korea’s first satellite KITSAT-1 in 1992. Meanwhile, KARI shared their plans to launch a lunar landing module using a Korean Space Launch Vehicle by 2030 and explained the current technologies and research related to a lunar landing and space exploration. Based on the payload technology it has been building on for the last 20 years, KASI emphasized the importance of research for deep space exploration in relation to the formation of the universe and the origin of mankind.
Vice Minister of Science and Technology Yong also stressed that “to enhance Korea’s capabilities for space research after launching our space launch vehicle, Nuri, in October, there must be continued efforts and preparation for higher level space research, including space exploration planning. The various experts’ opinions discussed in today’s meeting will be taken into consideration for governmental policies related to the ‘National Space Exploration Roadmap’ to be established in the latter half of this year.”
2021.06.07 View 6388 -
What Guides Habitual Seeking Behavior Explained
A new role of the ventral striatum explains habitual seeking behavior
Researchers have been investigating how the brain controls habitual seeking behaviors such as addiction. A recent study by Professor Sue-Hyun Lee from the Department of Bio and Brain Engineering revealed that a long-term value memory maintained in the ventral striatum in the brain is a neural basis of our habitual seeking behavior. This research was conducted in collaboration with the research team lead by Professor Hyoung F. Kim from Seoul National University. Given that addictive behavior is deemed a habitual one, this research provides new insights for developing therapeutic interventions for addiction.
Habitual seeking behavior involves strong stimulus responses, mostly rapid and automatic ones. The ventral striatum in the brain has been thought to be important for value learning and addictive behaviors. However, it was unclear if the ventral striatum processes and retains long-term memories that guide habitual seeking.
Professor Lee’s team reported a new role of the human ventral striatum where long-term memory of high-valued objects are retained as a single representation and may be used to evaluate visual stimuli automatically to guide habitual behavior.
“Our findings propose a role of the ventral striatum as a director that guides habitual behavior with the script of value information written in the past,” said Professor Lee.
The research team investigated whether learned values were retained in the ventral striatum while the subjects passively viewed previously learned objects in the absence of any immediate outcome. Neural responses in the ventral striatum during the incidental perception of learned objects were examined using fMRI and single-unit recording.
The study found significant value discrimination responses in the ventral striatum after learning and a retention period of several days. Moreover, the similarity of neural representations for good objects increased after learning, an outcome positively correlated with the habitual seeking response for good objects.
“These findings suggest that the ventral striatum plays a role in automatic evaluations of objects based on the neural representation of positive values retained since learning, to guide habitual seeking behaviors,” explained Professor Lee.
“We will fully investigate the function of different parts of the entire basal ganglia including the ventral striatum. We also expect that this understanding may lead to the development of better treatment for mental illnesses related to habitual behaviors or addiction problems.”
This study, supported by the National Research Foundation of Korea, was reported at Nature Communications (https://doi.org/10.1038/s41467-021-22335-5.)
-ProfileProfessor Sue-Hyun LeeDepartment of Bio and Brain EngineeringMemory and Cognition Laboratoryhttp://memory.kaist.ac.kr/lecture
KAIST
2021.06.03 View 7910 -
Identification of How Chemotherapy Drug Works Could Deliver Personalized Cancer Treatment
The chemotherapy drug decitabine is commonly used to treat patients with blood cancers, but its response rate is somewhat low. Researchers have now identified why this is the case, opening the door to more personalized cancer therapies for those with these types of cancers, and perhaps further afield.
Researchers have identified the genetic and molecular mechanisms within cells that make the chemotherapy drug decitabine—used to treat patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) —work for some patients but not others. The findings should assist clinicians in developing more patient-specific treatment strategies.
The findings were published in the Proceedings of the National Academies of Science on March 30.
The chemotherapy drug decitabine, also known by its brand name Dacogen, works by modifying our DNA that in turn switches on genes that stop the cancer cells from growing and replicating. However, decitabine’s response rate is somewhat low (showing improvement in just 30-35% of patients), which leaves something of a mystery as to why it works well for some patients but not for others. To find out why this happens, researchers from the KAIST investigated the molecular mediators that are involved with regulating the effects of the drug.
Decitabine works to activate the production of endogenous retroviruses (ERVs), which in turn induces an immune response. ERVs are viruses that long ago inserted dormant copies of themselves into the human genome. Decitabine in essence, ‘reactivates’ these viral elements and produces double-stranded RNAs (dsRNAs) that the immune system views as a foreign body.
“However, the mechanisms involved in this process, in particular how production and transport of these ERV dsRNAs were regulated within the cell were understudied,” said corresponding author Yoosik Kim, professor in the Department of Chemical and Biomolecular Engineering at KAIST.
“So to explain why decitabine works in some patients but not others, we investigated what these molecular mechanisms were,” added Kim.
To do so, the researchers used image-based RNA interference (RNAi) screening. This is a relatively new technique in which specific sequences within a genome are knocked out of action or “downregulated.” Large-scale screening, which can be performed in cultured cells or within live organisms, works to investigate the function of different genes. The KAIST researchers collaborated with the Institut Pasteur Korea to analyze the effect of downregulating genes that recognize ERV dsRNAs and could be involved in the cellular response to decitabine.
From these initial screening results, they performed an even more detailed downregulation screening analysis. Through the screening, they were able to identify two particular gene sequences involved in the production of an RNA-binding protein called Staufen1 and the production of a strand of RNA that does not in turn produce any proteins called TINCR that play a key regulatory role in response to the drug. Staufen1 binds directly to dsRNAs and stabilizes them in concert with the TINCR.
If a patient is not producing sufficient Staufen1 and TINCR, then the dsRNA viral mimics quickly degrade before the immune system can spot them. And, crucially for cancer therapy, this means that patients with lower expression (activation) of these sequences will show inferior response to decitabine. Indeed, the researchers confirmed that MDS/AML patients with low Staufen1 and TINCR expression did not benefit from decitabine therapy.
“We can now isolate patients who will not benefit from the therapy and direct them to a different type of therapy,” said first author Yongsuk Ku. “This serves as an important step toward developing a patient-specific treatment cancer strategy.”
As the researchers used patient samples taken from bone marrow, the next step will be to try to develop a testing method that can identify the problem from just blood samples, which are much easier to acquire from patients.
The team plans to investigate if the analysis can be extended to patients with solid tumors in addition to those with blood cancers.
-Profile
Professor Yoosik Kim
https://qcbio.kaist.ac.kr/
Department of Chemical and Biomolecular Engineering
KAIST
-Publication
Noncanonical immune response to the inhibition of DNA methylation by Staufen1 via stabilization of endogenous retrovirus RNAs, PNAS
2021.05.24 View 8138 -
Dr. Won-Joon Lee from the ADD Wins the Jeong Hun Cho Award
Dr. Won-Joon Lee from the Agency for Defense Development (ADD) became the 17th Jeong Hun Cho Award recipient. KAIST PhD candidate Sok-Min Choi from the Department of Aerospace Engineering, Master’s-PhD combined course student Hyong-Won Choi from Korea University, and Chong-Ho Park from Kongju National University High School were also selected.
The award recognizes promising young scientists who makes significant achievements in the field of aerospace engineering in honor of Jeong Hun Cho, the former PhD candidate in the Department of Aerospace Engineering who died in a lab accident in May in 2003. Cho’s family endowed the award and scholarship to honor him. Three scholarship recipients from Cho’s alma mater, KAIST, Korea University, and Kongju National High School are selected every year.
Dr. Lee from the ADD has conducted research on shape design methods and radar absorbing structures for unmanned aerial vehicles, publishing more than 24 articles in SCI-level journals and 17 at academic conferences.
Dr. Lee was awarded 25 million KRW in prize money. The two students from KAIST and Korea University each received a 4 million KRW scholarship and Park received 3 million KRW.
2021.05.17 View 4117