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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 13187 -
Quantum Laser Turns Energy Loss into Gain
A new laser that generates quantum particles can recycle lost energy for highly efficient, low threshold laser applications
Scientists at KAIST have fabricated a laser system that generates highly interactive quantum particles at room temperature. Their findings, published in the journal Nature Photonics, could lead to a single microcavity laser system that requires lower threshold energy as its energy loss increases.
The system, developed by KAIST physicist Yong-Hoon Cho and colleagues, involves shining light through a single hexagonal-shaped microcavity treated with a loss-modulated silicon nitride substrate. The system design leads to the generation of a polariton laser at room temperature, which is exciting because this usually requires cryogenic temperatures.
The researchers found another unique and counter-intuitive feature of this design. Normally, energy is lost during laser operation. But in this system, as energy loss increased, the amount of energy needed to induce lasing decreased. Exploiting this phenomenon could lead to the development of high efficiency, low threshold lasers for future quantum optical devices.
“This system applies a concept of quantum physics known as parity-time reversal symmetry,” explains Professor Cho. “This is an important platform that allows energy loss to be used as gain. It can be used to reduce laser threshold energy for classical optical devices and sensors, as well as quantum devices and controlling the direction of light.”
The key is the design and materials. The hexagonal microcavity divides light particles into two different modes: one that passes through the upward-facing triangle of the hexagon and another that passes through its downward-facing triangle. Both modes of light particles have the same energy and path but don’t interact with each other.
However, the light particles do interact with other particles called excitons, provided by the hexagonal microcavity, which is made of semiconductors. This interaction leads to the generation of new quantum particles called polaritons that then interact with each other to generate the polariton laser. By controlling the degree of loss between the microcavity and the semiconductor substrate, an intriguing phenomenon arises, with the threshold energy becoming smaller as energy loss increases. This research was supported by the Samsung Science and Technology Foundation and Korea’s National Research Foundation.
-PublicationSong,H.G, Choi, M, Woo, K.Y. Yong-Hoon Cho Room-temperature polaritonic non-Hermitian system with single microcavityNature Photonics (https://doi.org/10.1038/s41566-021-00820-z)
-ProfileProfessor Yong-Hoon ChoQuantum & Nanobio Photonics Laboratoryhttp://qnp.kaist.ac.kr/
Department of PhysicsKAIST
2021.07.07 View 9871 -
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 11495 -
Defining the Hund Physics Landscape of Two-Orbital Systems
Researchers identify exotic metals in unexpected quantum systems
Electrons are ubiquitous among atoms, subatomic tokens of energy that can independently change how a system behaves—but they also can change each other. An international research collaboration found that collectively measuring electrons revealed unique and unanticipated findings. The researchers published their results on May 17 in Physical Review Letters.
“It is not feasible to obtain the solution just by tracing the behavior of each individual electron,” said paper author Myung Joon Han, professor of physics at KAIST. “Instead, one should describe or track all the entangled electrons at once. This requires a clever way of treating this entanglement.”
Professor Han and the researchers used a recently developed “many-particle” theory to account for the entangled nature of electrons in solids, which approximates how electrons locally interact with one another to predict their global activity.
Through this approach, the researchers examined systems with two orbitals — the space in which electrons can inhabit. They found that the electrons locked into parallel arrangements within atom sites in solids. This phenomenon, known as Hund’s coupling, results in a Hund’s metal. This metallic phase, which can give rise to such properties as superconductivity, was thought only to exist in three-orbital systems.
“Our finding overturns a conventional viewpoint that at least three orbitals are needed for Hund’s metallicity to emerge,” Professor Han said, noting that two-orbital systems have not been a focus of attention for many physicists. “In addition to this finding of a Hund’s metal, we identified various metallic regimes that can naturally occur in generic, correlated electron materials.”
The researchers found four different correlated metals. One stems from the proximity to a Mott insulator, a state of a solid material that should be conductive but actually prevents conduction due to how the electrons interact. The other three metals form as electrons align their magnetic moments — or phases of producing a magnetic field — at various distances from the Mott insulator. Beyond identifying the metal phases, the researchers also suggested classification criteria to define each metal phase in other systems.
“This research will help scientists better characterize and understand the deeper nature of so-called ‘strongly correlated materials,’ in which the standard theory of solids breaks down due to the presence of strong Coulomb interactions between electrons,” Professor Han said, referring to the force with which the electrons attract or repel each other. These interactions are not typically present in solid materials but appear in materials with metallic phases.
The revelation of metals in two-orbital systems and the ability to determine whole system electron behavior could lead to even more discoveries, according to Professor Han.
“This will ultimately enable us to manipulate and control a variety of electron correlation phenomena,” Professor Han said.
Co-authors include Siheon Ryee from KAIST and Sangkook Choi from the Condensed Matter Physics and Materials Science Department, Brookhaven National Laboratory in the United States. Korea’s National Research Foundation and the U.S. Department of Energy’s (DOE) Office of Science, Basic Energy Sciences, supported this work.
-PublicationSiheon Ryee, Myung Joon Han, and SangKook Choi, 2021.Hund Physics Landscape of Two-Orbital Systems, Physical Review Letters, DOI: 10.1103/PhysRevLett.126.206401
-ProfileProfessor Myung Joon HanDepartment of PhysicsCollege of Natural ScienceKAIST
2021.06.17 View 8839 -
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 9724 -
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 10621 -
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 10609 -
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 8061 -
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 9716 -
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 9928 -
Gut Hormone Triggers Craving for More Proteins
- Revelations from a fly study could improve our understanding of protein malnutrition in humans. -
A new study led by KAIST researchers using fruit flies reveals how protein deficiency in the diet triggers cross talk between the gut and brain to induce a desire to eat foods rich in proteins or essential amino acids. This finding reported in the May 5 issue of Nature can lead to a better understanding of malnutrition in humans.
“All organisms require a balanced intake of carbohydrates, proteins, and fats for their well being,” explained KAIST neuroscientist and professor Greg Seong-Bae Suh. “Taking in sufficient calories alone won’t do the job, as it can still lead to severe forms of malnutrition including kwashiorkor, if the diet does not include enough proteins,” he added.
Scientists already knew that inadequate protein intake in organisms causes a preferential choice of foods rich in proteins or essential amino acids but they didn’t know precisely how this happens. A group of researchers led by Professor Suh at KAIST and Professor Won-Jae Lee at Seoul National University (SNU) investigated this process in flies by examining the effects of different genes on food preference following protein deprivation.
The group found that protein deprivation triggered the release of a gut hormone called neuropeptide CNMamide (CNMa) from a specific population of enterocytes - the intestine lining cells. Until now, scientists have known that enterocytes release digestive enzymes into the intestine to help digest and absorb nutrients in the gut. “Our study showed that enterocytes have a more complex role than we previously thought,” said Professor Suh.
Enterocytes respond to protein deprivation by releasing CNMa that conveys the nutrient status in the gut to the CNMa receptors on nerve cells in the brain. This then triggers a desire to eat foods containing essential amino acids.
Interestingly, the KAIST-SNU team also found that the microbiome - Acetobacter bacteria - present in the gut produces amino acids that can compensate for mild protein deficit in the diet. This basal level of amino acids provided by the microbiome modifies CNMa release and tempers the flies’ compensatory desire to ingest more proteins.
The research team was able to further clarify two signalling pathways that respond to protein loss from the diet and ultimately produce the CNMa hormone in these specific enterocytes.
The team said that further studies are still needed to understand how CNMa communicates with its receptors in the brain, and whether this happens by directly activating nerve cells that link the gut to the brain or by indirectly activating the brain through blood circulation. Their research could provide insights into the understanding of similar process in mammals including humans.
“We chose to investigate a simple organism, the fly, which would make it easier for us to identify and characterize key nutrient sensors. Because all organisms have cravings for needed nutrients, the nutrient sensors and their pathways we identified in flies would also be relevant to those in mammals. We believe that this research will greatly advance our understanding of the causes of metabolic disease and eating-related disorders,” Professor Suh added.
This work was supported by the Samsung Science and Technology Foundation (SSTF) and the National Research Foundation (NRF) of Korea.
Publication:
Kim, B., et al. (2021) Response of the Drosophila microbiome– gut–brain axis to amino acid deficit. Nature. Available online at https://doi.org/10.1038/s41586-021-03522-2
Profile:
Greg Seong-Bae Suh, Ph.D
Associate Professor
seongbaesuh@kaist.ac.krLab of Neural Interoception
https://www.suhlab-neuralinteroception.kaist.ac.kr/Department of Biological Sciences
https://bio.kaist.ac.kr/
Korea Advanced Institute of Science and Technology (KAIST)
https:/kaist.ac.kr/en/
Daejeon 34141, Korea
(END)
2021.05.17 View 7563 -
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 5025