Bioengineering
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KAIST Offers Hope to Musicians with Dystonia
< Photo 1. Conductor and Pianist João Carlos Martins before the Recital at the Carnegie Hall preparing with his bionic gloves >
KAIST’s neuroscientist and professor, Dr. Daesoo Kim attended the “Conference for Musicians with Dystonia” supported by the World Health Organization (WHO) and the Carnegie Hall concert of legendary pianist João Carlos Martins, who is also a dystonia patient, to announce his team’s recent advancements toward finding a cure for dystonia.
On November 19, 2022, a “miracle concert” was held in Carnegie Hall. João Carlos Martins was a renowned world-class pianist in the 70s and 80s, but he had to put an end to his musical career due to focal dystonia in his fingers. But in 2020, he began using a bionic glove developed by industrial designer Ubiratã Bizarro Costa and after years of hard work he was back in Carnegie Hall as an 82-year-old man.
During the concert, he conducted the NOVUS NY orchestra in a performance of Bach, and later even played the piano himself. In particular, between his performances, he gave shout-outs to scientists studying dystonia including KAIST Professor Daesoo Kim, asking them to continue working towards curing rare diseases for musicians.
< Photo 2. Professor Daesoo Kim with Conductor and Pianist João Carlos Martins >
Musician’s dystonia affects 1-3% of musicians around the world and musicians make up approximately 5% of the total number of dystonia patients. Musicians who are no longer able to practice music due to the disease often experience stress and depression, which may even lead to suicide in extreme cases. Musicians are known to be particularly prone to such diseases due to excessive practice regimens, perfectionism, and even genetics. Currently, botulinum toxin (Botox) is used to suppress abnormal muscles, but muscle function suppression ultimately means that the musician is no longer able to play the instrument. João Carlos Martins himself underwent several Botox procedures and three brain surgeries, but saw no therapeutic results. This is why a new treatment was necessary.
Professor Daesoo Kim’s research team at KAIST took note of the fact that abnormal muscle tension is caused by excessive stress, and developed NT-1, a treatment that blocks the development of the symptoms of dystonia from the brain, allowing patients to use their muscles as they normally would. The research team published their findings in Science Advances in 2021, and João Carlos Martins invited Professor Daesoo Kim to the UN conference and his concert after reading this paper.
< Photo 3. Professor Daesoo Kim (3rd from the left) photographed with other guests at the recital including Dr. Dévora Kestel, the Director of the Mental Health and Substance Use at WHO, sharing the center with Conductor and Pianist João Carlos Martins >
During the UN conference held the day prior to the Carnegie Hall concert, Dr. Dévora Kestel, Director of the Mental Health and Substance Use at WHO, said, “Although dystonia is not as well-known, it is a common disease around the world, and needs our society’s attention and the devotion of many researchers.” Professor Daesoo Kim said, “NT-1 is a drug that blocks the cause of dystonia in the brain, and will allow musicians to continue practicing music. We aim to attain clinical approval in Korea by 2024.”
NT-1 is currently under development by NeuroTobe, a faculty-led start-up company at KAIST, headed by Professor Daesoo Kim as the CEO. The synthesis of the drug for clinical testing has been successfully completed, and it has shown excellent efficacy and safety through various rounds of animal testing. Unlike Botox, which takes a few days to show its therapeutic effects after receiving the procedure from a hospital, NT-1 shows its therapeutic effects within an hour after taking it. As a so-called “edible Botox”, it is expected to help treat various muscular diseases and ailments.
2022.12.27 View 10649 -
KAIST develops biocompatible adhesive applicable to hair transplants
Aside from being used as a new medical adhesive, the new material can be applied to developing a new method of hair transplants, which cannot be repeated multiple times using current method of implanting the wholly intact follicles into the skin.
Medical adhesives are materials that can be applied to various uses such as wound healing, hemostasis, vascular anastomosis, and tissue engineering, and is expected to contribute greatly to the development of minimally invasive surgery and organ transplants. However, adhesives with high adhesion, low toxicity, and capable of decomposing in the body are rare. Adhesives based on natural proteins, such as fibrin and collagen, have high biocompatibility but insufficient adhesive strength. Synthetic polymer adhesives based on urethane or acrylic have greater adhesion but do not decompose well and may cause an inflammatory reaction in the body.
A joint research team led by Professor Myungeun Seo and Professor Haeshin Lee from the KAIST Department of Chemistry developed a bio-friendly adhesive from biocompatible polymers using tannic acid, the source of astringency in wine.
The research team focused on tannic acid, a natural polyphenolic product. Tannic acid is a polyphenol present in large amounts in fruit peels, nuts, and cacao. It has a high affinity and coating ability on other substances, and we sense the astringent taste in wine when tannic acid sticks to the surface of our tongue. When tannic acid is mixed with hydrophilic polymers, they form coacervates, or small droplets of jelly-like fluids that sink. If the polymers used are biocompatible, the mixture can be applied as a medical adhesive with low toxicity. However, coacervates are fundamentally fluid-like and cannot withstand large forces, which limits their adhesive capabilities. Thus, while research to utilize it as an adhesive has been actively discussed, a biodegradable material exhibiting strong adhesion due to its high shear strength has not yet been developed.
The research team figured out a way to enhance adhesion by mixing two biocompatible FDA-approved polymers, polyethylene glycol (PEG) and polylactic acid (PLA). While PEG, which is used widely in eyedrops and cream, is hydrophilic, PLA, a well-known bioplastic derived from lactic acid, is insoluble in water. The team combined the two into a block copolymer, which forms hydrophilic PLA aggregates in water with PEG blocks surrounding them. A coacervate created by mixing the micelles and tannic acid would behave like a solid due to the hard PLA components, and show an elastic modulus improved by a thousand times compared to PEG, enabling it to withstand much greater force as an adhesive.
Figure 1. (Above) Principle of biodegradable adhesive made by mixing poly(ethylene glycol)-poly(lactic acid) diblock copolymer and tannic acid in water. Yellow coacervate is precipitated through hydrogen bonding between the block copolymer micelles and tannic acid, and exhibits adhesion. After heat treatment, hydrogen bonds are rearranged to further improve adhesion. (Bottom) Adhesion comparison. Compared to using poly(ethylene glycol) polymer (d), it can support 10 times more weight when using block copolymer (e) and 60 times more weight after heat treatment (f). The indicated G' values represent the elastic modulus of the material.
Furthermore, the research team observed that the material’s mechanical properties can be improved by over a hundred times through a heating and cooling process that is used to heat-treat metals. They also discovered that this is due to the enforced interactions between micelle and tannic acid arrays.
The research team used the fact that the material shows minimal irritation to the skin and decomposes well in the body to demonstrate its possible application as an adhesive for hair transplantation through an animal experiment. Professor Haeshin Lee, who has pioneered various application fields including medical adhesives, hemostatic agents, and browning shampoo, focused on the adhesive capacities and low toxicity of polyphenols like tannic acid, and now looks forward to it improving the limitations of current hair transplant methods, which still involve follicle transfer and are difficult to be repeated multiple times.
Figure 2. (a) Overview of a hair transplantation method using a biodegradable adhesive (right) compared to a conventional hair transplantation method (left) that transplants hair containing hair follicles. After applying an adhesive to the tip of the hair, it is fixed to the skin by implanting it through a subcutaneous injection, and repeated treatment is possible. (b) Initial animal test results. One day after 15 hair transplantation, 12 strands of hair remain. If you pull the 3 strands of hair, you can see that the whole body is pulled up, indicating that it is firmly implanted into the skin. All strands of hair applied without the new adhesive material fell off, and in the case of adhesive without heat treatment, the efficiency was 1/7.
This research was conducted by first co-authors Dr. Jongmin Park (currently a senior researcher at the Korea Research Institute of Chemical Technology) from Professor Myeongeun Seo’s team and Dr. Eunsook Park from Professor Haeshin Lee’s team in the KAIST Department of Chemistry, and through joint research with the teams led by Professor Hyungjun Kim from the KAIST Department of Chemistry and Professor Siyoung Choi from the Department of Chemical and Biomolecular Engineering. The research was published online on August 22 in the international journal Au (JACS Au) under the title Biodegradable Block Copolymer-Tannic Acid Glue.
This study was funded by the Support Research Under Protection Project of the National Research Foundation (NRF), Leading Research Center Support Project (Research Center for Multiscale Chiral Structure), Biodegradable Plastics Commercialization and Demonstration Project by the Ministry of Trade and Industry, and institutional funding from the Korea Research Institute of Chemical Technology.
2022.10.07 View 10487 -
Establishing a novel strategy to tackle Huntington’s disease
A platform to take on the Huntington’s disease via an innovative approach established by KAIST’s researchers through international collaboration with scientists in the Netherlands, France, and Sweden.
Through an international joint research effort involving ProQR Therapeutics of the Netherlands, Université Grenoble Alpes of France, and KTH Royal Institute of Technology of Sweden, Professor Ji-Soon Song's research team in the Department of Biological Sciences and KAIST Institute for BioCentury of KAIST, established a noble strategy to treat Huntington's disease. The new works showed that the protein converted from disease form to its disease-free form maintains its original function, providing new roadblocks to approach Huntington’s disease.
This research, titled, “A pathogenic-proteolysis resistant huntingtin isoform induced by an antisense oligonucleotide maintains huntingtin function”, co-authored by Hyeongju Kim, was published in the online edition of 'Journal of Clinical Investigation Insight' on August 9, 2022.
Huntington's disease is a dominantly inherited neurodegenerative disease and is caused by a mutation in a protein called ‘huntingtin’, which adds a distinctive feature of an expanded stretch of glutamine amino acids called polyglutamine to the protein. It is estimated that one in every 10,000 have Huntington's disease in United States. The patients would suffer a decade of regression before death, and, thus far, there is no known cure for the disease.
The cleavage near the stretched polyglutamine in mutated huntingtin is known to be the cause of the Huntington’s disease. However, as huntingtin protein is required for the development and normal function of the brain, it is critical to specifically eliminate the disease-causing protein while maintaining the ones that are still normally functioning.
The research team showed that huntingtin delta 12, the converted form of huntingtin that is resistant to developing cleavages at the ends of the protein, the known cause of the Huntington’s disease (HD), alleviated the disease’s symptoms while maintaining the functions of normal huntingtin.
Figure. Huntington's disease resistance huntingtin protein induced by antisense oligonucleotide (AON) is resistant to Caspase-6 cleavage, therefore, does not cause Huntington’s disease while maintaining normal functions of huntingtin.
The research was welcomed as it is sure to fuel innovate strategies to tackle Huntington’s disease without altering the essential function of huntingtin.
This work was supported by a Global Research Lab grant from the National Research Foundation of Korea (NRF) and by a EUREKA Eurostars 2 grant from European Union Horizon 2020.
2022.09.02 View 7059 -
Interactive Map of Metabolical Synthesis of Chemicals
An interactive map that compiled the chemicals produced by biological, chemical and combined reactions has been distributed on the web
- A team led by Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering, organized and distributed an all-inclusive listing of chemical substances that can be synthesized using microorganisms
- It is expected to be used by researchers around the world as it enables easy assessment of the synthetic pathway through the web.
A research team comprised of Woo Dae Jang, Gi Bae Kim, and Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering at KAIST reported an interactive metabolic map of bio-based chemicals. Their research paper “An interactive metabolic map of bio-based chemicals” was published online in Trends in Biotechnology on August 10, 2022.
As a response to rapid climate change and environmental pollution, research on the production of petrochemical products using microorganisms is receiving attention as a sustainable alternative to existing methods of productions. In order to synthesize various chemical substances, materials, and fuel using microorganisms, it is necessary to first construct the biosynthetic pathway toward desired product by exploration and discovery and introduce them into microorganisms. In addition, in order to efficiently synthesize various chemical substances, it is sometimes necessary to employ chemical methods along with bioengineering methods using microorganisms at the same time. For the production of non-native chemicals, novel pathways are designed by recruiting enzymes from heterologous sources or employing enzymes designed though rational engineering, directed evolution, or ab initio design.
The research team had completed a map of chemicals which compiled all available pathways of biological and/or chemical reactions that lead to the production of various bio-based chemicals back in 2019 and published the map in Nature Catalysis. The map was distributed in the form of a poster to industries and academia so that the synthesis paths of bio-based chemicals could be checked at a glance.
The research team has expanded the bio-based chemicals map this time in the form of an interactive map on the web so that anyone with internet access can quickly explore efficient paths to synthesize desired products. The web-based map provides interactive visual tools to allow interactive visualization, exploration, and analysis of complex networks of biological and/or chemical reactions toward the desired products. In addition, the reported paper also discusses the production of natural compounds that are used for diverse purposes such as food and medicine, which will help designing novel pathways through similar approaches or by exploiting the promiscuity of enzymes described in the map. The published bio-based chemicals map is also available at http://systemsbiotech.co.kr.
The co-first authors, Dr. Woo Dae Jang and Ph.D. student Gi Bae Kim, said, “We conducted this study to address the demand for updating the previously distributed chemicals map and enhancing its versatility.” “The map is expected to be utilized in a variety of research and in efforts to set strategies and prospects for chemical production incorporating bio and chemical methods that are detailed in the map.”
Distinguished Professor Sang Yup Lee said, “The interactive bio-based chemicals map is expected to help design and optimization of the metabolic pathways for the biosynthesis of target chemicals together with the strategies of chemical conversions, serving as a blueprint for developing further ideas on the production of desired chemicals through biological and/or chemical reactions.”
The interactive metabolic map of bio-based chemicals.
2022.08.11 View 13530 -
A New Therapeutic Drug for Alzheimer’s Disease without Inflammatory Side Effects
Although Aduhelm, a monoclonal antibody targeting amyloid beta (Aβ), recently became the first US FDA approved drug for Alzheimer’s disease (AD) based on its ability to decrease Aβ plaque burden in AD patients, its effect on cognitive improvement is still controversial. Moreover, about 40% of the patients treated with this antibody experienced serious side effects including cerebral edemas (ARIA-E) and hemorrhages (ARIA-H) that are likely related to inflammatory responses in the brain when the Aβ antibody binds Fc receptors (FCR) of immune cells such as microglia and macrophages.
These inflammatory side effects can cause neuronal cell death and synapse elimination by activated microglia, and even have the potential to exacerbate cognitive impairment in AD patients. Thus, current Aβ antibody-based immunotherapy holds the inherent risk of doing more harm than good due to their inflammatory side effects.
To overcome these problems, a team of researchers at KAIST in South Korea has developed a novel fusion protein drug, αAβ-Gas6, which efficiently eliminates Aβ via an entirely different mechanism than Aβ antibody-based immunotherapy. In a mouse model of AD, αAβ-Gas6 not only removed Aβ with higher potency, but also circumvented the neurotoxic inflammatory side effects associated with conventional antibody treatments.
Their findings were published on August 4 in Nature Medicine.
Schematic of a chimeric Gas6 fusion protein. A single chain variable fragment (scFv) of
an Amyloid β (Aβ)-targeting monoclonal antibody is fused with a truncated receptor binding
domain of Gas6, a bridging molecule for the clearance of dead cells via TAM (TYRO3, AXL,
and MERTK) receptors, which are expressed by microglia and astrocytes.
“FcR activation by Aβ targeting antibodies induces microglia-mediated Aβ phagocytosis, but it also produces inflammatory signals, inevitably damaging brain tissues,” said paper authors Chan Hyuk Kim and Won-Suk Chung, associate professors in the Department of Biological Sciences at KAIST.
“Therefore, we utilized efferocytosis, a cellular process by which dead cells are removed by phagocytes as an alternative pathway for the clearance of Aβ in the brain,” Prof. Kim and Chung said. “Efferocytosis is accompanied by anti-inflammatory responses to maintain tissue homeostasis. To exploit this process, we engineered Gas6, a soluble adaptor protein that mediates efferocytosis via TAM phagocytic receptors in such a way that its target specificity was redirected from dead cells to Aβ plaques.”
The professors and their team demonstrated that the resulting αAβ-Gas6 induced Aβ engulfment by activating not only microglial but also astrocytic phagocytosis since TAM phagocytic receptors are highly expressed by these two major phagocytes in the brain. Importantly, αAβ-Gas6 promoted the robust uptake of Aβ without showing any signs of inflammation and neurotoxicity, which contrasts sharply with the treatment using an Aβ monoclonal antibody. Moreover, they showed that αAβ-Gas6 substantially reduced excessive synapse elimination by microglia, consequently leading to better behavioral rescues in AD model mice.
“By using a mouse model of cerebral amyloid angiopathy (CAA), a cerebrovascular disorder caused by the deposition of Aβ within the walls of the brain’s blood vessels, we also showed that the intrathecal administration of Gas6 fusion protein significantly eliminated cerebrovascular amyloids, along with a reduction of microhemorrhages. These data demonstrate that aAb-Gas6 is a potent therapeutic agent in eliminating Aβ without exacerbating CAA-related microhemorrhages.”
The resulting αAβ-Gas6 clears Aβ oligomers and fibrils without causing neurotoxicity (a-b, neurons: red, and fragmented axons: yellow) and proinflammatory responses (c, TNF release), which are conversely exacerbated by the treatment of an Aβ-targeting monoclonal antibody (Aducanumab).
Professors Kim and Chung noted, “We believe our approach can be a breakthrough in treating AD without causing inflammatory side effects and synapse loss. Our approach holds promise as a novel therapeutic platform that is applicable to more than AD. By modifying the target-specificity of the fusion protein, the Gas6-fusion protein can be applied to various neurological disorders as well as autoimmune diseases affected by toxic molecules that should be removed without causing inflammatory responses.”
The number and total area of Aβ plaques (Thioflavin-T, green) were significantly reduced in αAβ-Gas6-treated AD mouse brains compared to Aducanumab-treated ones (a, b). The cognitive functions of AD model mice were significantly rescued by αAβ-Gas6 treatment, whereas Aducanumab-treated AD mice showed partial rescue in these cognitive tests (c-e).
Professors Kim and Chung founded “Illimis Therapeutics” based on this strategy of designing chimeric Gas6 fusion proteins that would remove toxic aggregates from the nervous system. Through this company, they are planning to further develop various Gas6-fusion proteins not only for Ab but also for Tau to treat AD symptoms.
This work was supported by KAIST and the Korea Health Technology R&D Project that was administered by the Korea Health Industry Development Institute (KHIDI) and the Korea Dementia Research Center (KDRC) funded by the Ministry of Health & Welfare (MOHW) and the Ministry of Science and ICT (MSIT), and KAIST.
Other contributors include Hyuncheol Jung and Se Young Lee, Sungjoon Lim, Hyeong Ryeol Choi, Yeseong Choi, Minjin Kim, Segi Kim, the Department of Biological Sciences, and the Korea Advanced Institute of Science and Technology (KAIST).
To receive more up-to-date information on this new development, follow “Illimis Therapeutics” on twitter @Illimistx.
2022.08.05 View 11587 -
President-Elect Suk-Yeol Yoon Meets and Talks with KAIST Students
President-Elect Yoon stresses science and technology-powered economic growth during his visit to KAIST
Korean President-elect Suk-Yeol Yoon stressed that semiconductors are the key strategical industry that will take the lead during the fourth industrial revolution powered by AI and data during a meeting with KAIST graduate students on April 29. President-elect Yoon promised systemic policy support for making science and technology breakthroughs possible and better rewarding young researchers who are devoted to advances in R&D during his meeting at KAIST.
Before he met with the students, he toured the National Nanofab Center, which is affiliated with KAIST, and was briefed on the center’s role and responsibilities.
President-elect Yoon, who will take office on May 10, said that the best way to ensure prompt growth in Korea’s aging society hinges on advances in science and technology. “All-out investments in science and technology will help us move forward to improve people’s quality of life and lessen the social divide,” he explained.
Eight Master’s and PhD candidates majoring in nuclear engineering, AI robotics, semiconductors, electrical engineering, aerospace, and bioengineering attended the meeting with President-elect Yoon. The students asked for help dealing with the challenges they are experiencing while researching and called for deregulation in the process of forming startups.
PhD candidate Jae Wan Cho from the Department Nuclear and Quantum Engineering stressed the importance of energy security. He asked for the prompt development of new types of nuclear reactors such as small modular reactors, adding, “Korea has very excellent technologies in nuclear plant construction and parts manufacturing, but lags behind in the new types of nuclear reactors. This sector will develop new energy markets and create synergy along with the shipbuilding industry, which will emerge as new pillars of our export.”
Student entrepreneurs such as PhD candidate Kwang Min Kim from the Department of Bio and Brain Engineering and PhD candidate Dong Yoon Shin from the Department of Mechanical and Aerospace Engineering asked for more deregulation in the process of creating startups. PhD candidate Dong Hon Lee from the School of Electrical Engineering pointed out the insecure future caused by the ‘special research fellow system,’ where the number of fellows who have been designated alternative military service has drastically decreased.
2022.05.02 View 5979 -
Label-Free Multiplexed Microtomography of Endogenous Subcellular Dynamics Using Deep Learning
AI-based holographic microscopy allows molecular imaging without introducing exogenous labeling agents
A research team upgraded the 3D microtomography observing dynamics of label-free live cells in multiplexed fluorescence imaging. The AI-powered 3D holotomographic microscopy extracts various molecular information from live unlabeled biological cells in real time without exogenous labeling or staining agents.
Professor YongKeum Park’s team and the startup Tomocube encoded 3D refractive index tomograms using the refractive index as a means of measurement. Then they decoded the information with a deep learning-based model that infers multiple 3D fluorescence tomograms from the refractive index measurements of the corresponding subcellular targets, thereby achieving multiplexed micro tomography. This study was reported in Nature Cell Biology online on December 7, 2021.
Fluorescence microscopy is the most widely used optical microscopy technique due to its high biochemical specificity. However, it needs to genetically manipulate or to stain cells with fluorescent labels in order to express fluorescent proteins. These labeling processes inevitably affect the intrinsic physiology of cells. It also has challenges in long-term measuring due to photobleaching and phototoxicity. The overlapped spectra of multiplexed fluorescence signals also hinder the viewing of various structures at the same time. More critically, it took several hours to observe the cells after preparing them.
3D holographic microscopy, also known as holotomography, is providing new ways to quantitatively image live cells without pretreatments such as staining. Holotomography can accurately and quickly measure the morphological and structural information of cells, but only provides limited biochemical and molecular information.
The 'AI microscope' created in this process takes advantage of the features of both holographic microscopy and fluorescence microscopy. That is, a specific image from a fluorescence microscope can be obtained without a fluorescent label. Therefore, the microscope can observe many types of cellular structures in their natural state in 3D and at the same time as fast as one millisecond, and long-term measurements over several days are also possible.
The Tomocube-KAIST team showed that fluorescence images can be directly and precisely predicted from holotomographic images in various cells and conditions. Using the quantitative relationship between the spatial distribution of the refractive index found by AI and the major structures in cells, it was possible to decipher the spatial distribution of the refractive index. And surprisingly, it confirmed that this relationship is constant regardless of cell type.
Professor Park said, “We were able to develop a new concept microscope that combines the advantages of several microscopes with the multidisciplinary research of AI, optics, and biology. It will be immediately applicable for new types of cells not included in the existing data and is expected to be widely applicable for various biological and medical research.”
When comparing the molecular image information extracted by AI with the molecular image information physically obtained by fluorescence staining in 3D space, it showed a 97% or more conformity, which is a level that is difficult to distinguish with the naked eye.
“Compared to the sub-60% accuracy of the fluorescence information extracted from the model developed by the Google AI team, it showed significantly higher performance,” Professor Park added.
This work was supported by the KAIST Up program, the BK21+ program, Tomocube, the National Research Foundation of Korea, and the Ministry of Science and ICT, and the Ministry of Health & Welfare.
-Publication
Hyun-seok Min, Won-Do Heo, YongKeun Park, et al. “Label-free multiplexed microtomography of endogenous subcellular dynamics using generalizable deep learning,” Nature Cell Biology (doi.org/10.1038/s41556-021-00802-x) published online December 07 2021.
-Profile
Professor YongKeun Park
Biomedical Optics Laboratory
Department of Physics
KAIST
2022.02.09 View 10552 -
A Genetic Change for Achieving a Long and Healthy Life
Researchers identified a single amino acid change in the tumor suppressor protein in PTEN that extends healthy periods while maintaining longevity
Living a long, healthy life is everyone’s wish, but it is not an easy one to achieve. Many aging studies are developing strategies to increase health spans, the period of life spent with good health, without chronic diseases and disabilities. Researchers at KAIST presented new insights for improving the health span by just regulating the activity of a protein.
A research group under Professor Seung-Jae V. Lee from the Department of Biological Sciences identified a single amino acid change in the tumor suppressor protein phosphatase and tensin homolog (PTEN) that dramatically extends healthy periods while maintaining longevity. This study highlights the importance of the well-conserved tumor suppressor protein PTEN in health span regulation, which can be targeted to develop therapies for promoting healthy longevity in humans. The research was published in Nature Communications on September 24, 2021.
Insulin and insulin-like growth factor-1 (IGF-1) signaling (IIS) is one of the evolutionarily conserved aging-modulatory pathways present in life forms ranging from tiny roundworms to humans. The proper reduction of IIS leads to longevity in animals but often causes defects in multiple health parameters including impaired motility, reproduction, and growth.
The research team found that a specific amino acid change in the PTEN protein improves health status while retaining the longevity conferred by reduced IIS. They used the roundworm C. elegans, an excellent model animal that has been widely used for aging research, mainly because of its very short normal lifespan of about two to three weeks. The PTEN protein is a phosphatase that removes phosphate from lipids as well as proteins. Interestingly, the newly identified amino acid change delicately recalibrated the IIS by partially maintaining protein phosphatase activity while reducing lipid phosphatase activity.
As a result, the amino acid change in the PTEN protein maintained the activity of the longevity-promoting transcription factor Forkhead Box O (FOXO) protein while restricting the detrimental upregulation of another transcription factor, NRF2, leading to long and healthy life in animals with reduced IIS.
Professor Lee said, “Our study raises the exciting possibility of simultaneously promoting longevity and health in humans by slightly tweaking the activity of one protein, PTEN.”
This work was supported by the MInistry of Science and ICT through the National Research Foundation of Korea.
-Publication:Hae-Eun H. Park, Wooseon Hwang, Seokjin Ham, Eunah Kim, Ozlem Altintas, Sangsoon Park, Heehwa G. Son, Yujin Lee, Dongyeop Lee, Won Do Heo, and Seung-Jae V. Lee. 2021. “A PTEN variant uncouples longevity from impaired fitness in Caenorhabditis elegans with reduced insulin/IGF-1 signaling,” Nature Communications, 12(1), 5631. (https://doi.org/10.1038/s41467-021-25920-w)
-ProfileProfessor Seung-Jae V. LeeMolecular Genetics of Aging LaboratoryDepartment of Biological Sciences KAIST
2021.11.19 View 8497 -
The Dynamic Tracking of Tissue-Specific Secretory Proteins
Researchers develop a versatile and powerful tool for studying the spatiotemporal dynamics of secretory proteins, a valuable class of biomarkers and therapeutic targets
Researchers have presented a method for profiling tissue-specific secretory proteins in live mice. This method is expected to be applicable to various tissues or disease models for investigating biomarkers or therapeutic targets involved in disease progression. This research was reported in Nature Communications on September 1.
Secretory proteins released into the blood play essential roles in physiological systems. They are core mediators of interorgan communication, while serving as biomarkers and therapeutic targets.
Previous studies have analyzed conditioned media from culture models to identify cell type-specific secretory proteins, but these models often fail to fully recapitulate the intricacies of multi-organ systems and thus do not sufficiently reflect biological realities.
These limitations provided compelling motivation for the research team led by Jae Myoung Suh and his collaborators to develop techniques that could identify and resolve characteristics of tissue-specific secretory proteins along time and space dimensions.
For addressing this gap in the current methodology, the research team utilized proximity-labeling enzymes such as TurboID to label secretory proteins in endoplasmic reticulum lumen using biotin. Thereafter, the biotin-labeled secretory proteins were readily enriched through streptavidin affinity purification and could be identified through mass spectrometry.
To demonstrate its functionality in live mice, research team delivered TurboID to mouse livers via an adenovirus. After administering the biotin, only liver-derived secretory proteins were successfully detected in the plasma of the mice. Interestingly, the pattern of biotin-labeled proteins secreted from the liver was clearly distinctive from those of hepatocyte cell lines.
First author Kwang-eun Kim from the Graduate School of Medical Science and Engineering explained, “The proteins secreted by the liver were significantly different from the results of cell culture models. This data shows the limitations of cell culture models for secretory protein study, and this technique can overcome those limitations. It can be further used to discover biomarkers and therapeutic targets that can more fully reflect the physiological state.”
This work research was supported by the National Research Foundation of Korea, the KAIST Key Research Institutes Project (Interdisciplinary Research Group), and the Institute for Basic Science in Korea.
-PublicationKwang-eun Kim, Isaac Park et al., “Dynamic tracking and identification of tissue-specific secretory proteins in the circulation of live mice,” Nature Communications on Sept.1,
2021(https://doi.org/10.1038/s41467-021-25546-y)
-ProfileProfessor Jae Myoung Suh Integrated Lab of Metabolism, Obesity and Diabetes Researchhttps://imodkaist.wixsite.com/home
Graduate School of Medical Science and Engineering College of Life Science and BioengineeringKAIST
2021.09.14 View 9227 -
A Study Reveals What Triggers Lung Damage during COVID-19
A longitudinal study of macrophages from SARS-CoV-2 infected lungs offers new insights into dynamic immunological changes
A KAIST immunology research team found that a specific subtype of macrophages that originated from blood monocytes plays a key role in the hyper-inflammatory response in SARS-CoV-2 infected lungs, by performing single-cell RNA sequencing of bronchoalveolar lavage fluid cells. This study provides new insights for understanding dynamic changes in immune responses to COVID-19.
In the early phase of COVID-19, SARS-CoV-2 infected lung tissue and the immediate defense system is activated. This early and fast response is called ‘innate immunity,’ provided by immune cells residing in lungs. Macrophages are major cell types of the innate immune system of the lungs, and newly differentiated macrophages originating from the bloodstream also contribute to early defenses against viruses.
Professor Su-Hyung Park and his collaborators investigated the quantitative and qualitative evaluation of immune responses in the lungs of SARS-CoV-2 infected ferrets. To overcome the limitations of research using patient-originated specimens, the researchers used a ferret infection model to obtain SARS-CoV-2 infected lungs sequentially with a defined time interval.
The researchers analyzed the 10 subtypes of macrophages during the five-day course of SARS-CoV-2 infection, and found that infiltrating macrophages originating from activated monocytes in the blood were key players for viral clearance as well as damaged lung tissue. Moreover, they found that the differentiation process of these inflammatory macrophages resembled the immune responses in the lung tissue of severe COVID-19 patients.
Currently, the research team is conducting a follow-up study to identify the dynamic changes in immune responses during the use of immunosuppressive agents to control hyper-inflammatory response called ‘cytokine storm’ in patients with COVID-19.
Dr. Jeong Seok Lee, the chief medical officer at Genome Insight Inc., explained, “Our analysis will enhance the understanding of the early features of COVID-19 immunity and provide a scientific background for the more precise use of immunosuppressive agents targeting specific macrophage subtypes.”
“This study is the first longitudinal study using sequentially obtained immune cells originating from SARS-CoV-2 infected lungs. The research describes the innate immune response to COVID-19 using single cell transcriptome data and enhances our understanding of the two phases of inflammatory responses,” Professor Park said.
This work was supported by the Ministry of Health and Welfare and KAIST, and was published in Nature Communications on July 28.
-PublicationSu-Hyung Park, Jeong Seok Lee, Su-Hyung Park et al. “Single-cell transcriptome of bronchoalverolar lavage fluid reveals sequential change of macrophages during SARS-CoV-2 infection in ferrets” Nature Communications (https://doi.org/10.1038/s41467-021-24807-0)
-ProfileProfessor Su-Hyung ParkLaboratory of Translational Immunology and Vaccinologyhttps://ltiv.kaist.ac.kr/
Graduate School of Medical Science and EngineeringKAIST
2021.08.04 View 12591 -
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 7793 -
Astrocytes Eat Connections to Maintain Plasticity in Adult Brains
Developing brains constantly sprout new neuronal connections called synapses as they learn and remember. Important connections — the ones that are repeatedly introduced, such as how to avoid danger — are nurtured and reinforced, while connections deemed unnecessary are pruned away. Adult brains undergo similar pruning, but it was unclear how or why synapses in the adult brain get eliminated.
Now, a team of KAIST researchers has found the mechanism underlying plasticity and, potentially, neurological disorders in adult brains. They published their findings on December 23 in Nature.
“Our findings have profound implications for our understanding of how neural circuits change during learning and memory, as well as in diseases,” said paper author Won-Suk Chung, an assistant professor in the Department of Biological Sciences at KAIST. “Changes in synapse number have strong association with the prevalence of various neurological disorders, such as autism spectrum disorder, schizophrenia, frontotemporal dementia, and several forms of seizures.”
Gray matter in the brain contains microglia and astrocytes, two complementary cells that, among other things, support neurons and synapses. Microglial are a frontline immunity defense, responsible for eating pathogens and dead cells, and astrocytes are star-shaped cells that help structure the brain and maintain homeostasis by helping to control signaling between neurons. According to Professor Chung, it is generally thought that microglial eat synapses as part of its clean-up effort in a process known as phagocytosis.
“Using novel tools, we show that, for the first time, it is astrocytes and not microglia that constantly eliminate excessive and unnecessary adult excitatory synaptic connections in response to neuronal activity,” Professor Chung said. “Our paper challenges the general consensus in this field that microglia are the primary synapse phagocytes that control synapse numbers in the brain.”
Professor Chung and his team developed a molecular sensor to detect synapse elimination by glial cells and quantified how often and by which type of cell synapses were eliminated. They also deployed it in a mouse model without MEGF10, the gene that allows astrocytes to eliminate synapses. Adult animals with this defective astrocytic phagocytosis had unusually increased excitatory synapse numbers in the hippocampus. Through a collaboration with Dr. Hyungju Park at KBRI, they showed that these increased excitatory synapses are functionally impaired, which cause defective learning and memory formation in MEGF10 deleted animals.
“Through this process, we show that, at least in the adult hippocampal CA1 region, astrocytes are the major player in eliminating synapses, and this astrocytic function is essential for controlling synapse number and plasticity,” Chung said.
Professor Chung noted that researchers are only beginning to understand how synapse elimination affects maturation and homeostasis in the brain. In his group’s preliminary data in other brain regions, it appears that each region has different rates of synaptic elimination by astrocytes. They suspect a variety of internal and external factors are influencing how astrocytes modulate each regional circuit, and plan to elucidate these variables.
“Our long-term goal is understanding how astrocyte-mediated synapse turnover affects the initiation and progression of various neurological disorders,” Professor Chung said. “It is intriguing to postulate that modulating astrocytic phagocytosis to restore synaptic connectivity may be a novel strategy in treating various brain disorders.”
This work was supported by the Samsung Science & Technology Foundation, the National Research Foundation of Korea, and the Korea Brain Research Institute basic research program.
Other contributors include Joon-Hyuk Lee and Se Young Lee, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST); Ji-young Kim, Hyoeun Lee and Hyungju Park; Research Group for Neurovascular Unit, Korea Brain Research Institute (KBRI); Seulgi Noh, and Ji Young Mun, Research Group for Neural Circuit, KBRI. Kim, Noh and Park are also affiliated with the Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST).
-Profile
Professor Won-Suk Chung
Department of Biological Sciences
Gliabiology Lab (https://www.kaistglia.org/)
KAIST
-Publication
"Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis"
https://doi.org/10.1038/s41586-020-03060-3
2020.12.24 View 11795