medical+science
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Scientist Discover How Circadian Rhythm Can Be Both Strong and Flexible
Study reveals that master and slave oscillators function via different molecular mechanisms
From tiny fruit flies to human beings, all animals on Earth maintain their daily rhythms based on their internal circadian clock. The circadian clock enables organisms to undergo rhythmic changes in behavior and physiology based on a 24-hour circadian cycle. For example, our own biological clock tells our brain to release melatonin, a sleep-inducing hormone, at night time.
The discovery of the molecular mechanism of the circadian clock was bestowed the Nobel Prize in Physiology or Medicine 2017. From what we know, no one centralized clock is responsible for our circadian cycles. Instead, it operates in a hierarchical network where there are “master pacemaker” and “slave oscillator”.
The master pacemaker receives various input signals from the environment such as light. The master then drives the slave oscillator that regulates various outputs such as sleep, feeding, and metabolism. Despite the different roles of the pacemaker neurons, they are known to share common molecular mechanisms that are well conserved in all lifeforms. For example, interlocked systems of multiple transcriptional-translational feedback loops (TTFLs) composed of core clock proteins have been deeply studied in fruit flies.
However, there is still much that we need to learn about our own biological clock. The hierarchically-organized nature of master and slave clock neurons leads to a prevailing belief that they share an identical molecular clockwork. At the same time, the different roles they serve in regulating bodily rhythms also raise the question of whether they might function under different molecular clockworks.
Research team led by Professor Kim Jae Kyoung from the Department of Mathematical Sciences, a chief investigator at the Biomedical Mathematics Group at the Institute for Basic Science, used a combination of mathematical and experimental approaches using fruit flies to answer this question. The team found that the master clock and the slave clock operate via different molecular mechanisms.
In both master and slave neurons of fruit flies, a circadian rhythm-related protein called PER is produced and degraded at different rates depending on the time of the day. Previously, the team found that the master clock neuron (sLNvs) and the slave clock neuron (DN1ps) have different profiles of PER in wild-type and Clk-Δ mutant Drosophila. This hinted that there might be a potential difference in molecular clockworks between the master and slave clock neurons.
However, due to the complexity of the molecular clockwork, it was challenging to identify the source of such differences. Thus, the team developed a mathematical model describing the molecular clockworks of the master and slave clocks. Then, all possible molecular differences between the master and slave clock neurons were systematically investigated by using computer simulations. The model predicted that PER is more efficiently produced and then rapidly degraded in the master clock compared to the slave clock neurons. This prediction was then confirmed by the follow-up experiments using animal.
Then, why do the master clock neurons have such different molecular properties from the slave clock neurons? To answer this question, the research team again used the combination of mathematical model simulation and experiments. It was found that the faster rate of synthesis of PER in the master clock neurons allows them to generate synchronized rhythms with a high level of amplitude. Generation of such a strong rhythm with high amplitude is critical to delivering clear signals to slave clock neurons.
However, such strong rhythms would typically be unfavorable when it comes to adapting to environmental changes. These include natural causes such as different daylight hours across summer and winter seasons, up to more extreme artificial cases such as jet lag that occurs after international travel. Thanks to the distinct property of the master clock neurons, it is able to undergo phase dispersion when the standard light-dark cycle is disrupted, drastically reducing the level of PER. The master clock neurons can then easily adapt to the new diurnal cycle. Our master pacemaker’s plasticity explains how we can quickly adjust to the new time zones after international flights after just a brief period of jet lag.
It is hoped that the findings of this study can have future clinical implications when it comes to treating various disorders that affect our circadian rhythm. Professor Kim notes, “When the circadian clock loses its robustness and flexibility, the circadian rhythms sleep disorders can occur. As this study identifies the molecular mechanism that generates robustness and flexibility of the circadian clock, it can facilitate the identification of the cause of and treatment strategy for the circadian rhythm sleep disorders.” This work was supported by the Human Frontier Science Program.
-PublicationEui Min Jeong, Miri Kwon, Eunjoo Cho, Sang Hyuk Lee, Hyun Kim, Eun Young Kim, and Jae Kyoung Kim, “Systematic modeling-driven experiments identify distinct molecularclockworks underlying hierarchically organized pacemaker neurons,” February 22, 2022, Proceedings of the National Academy of Sciences of the United States of America
-ProfileProfessor Jae Kyoung KimDepartment of Mathematical SciencesKAIST
2022.02.23 View 7148 -
President Lee Presents Plans to Nurture Next-Generation Talents
President Lee stressed that nurturing medical scientists, semiconductor R&D personnel, startup entrepreneurs, and global innovators are key missions he will continue to pursue during a news conference
KAIST President Kwang Hyung Lee said that nurturing medical scientists, semiconductor R&D personnel, startup entrepreneurs, and global innovators are key missions he will continue to pursue during an online news conference marking the 1st anniversary of him becoming the president on February 15.
He said that nurturing physician-scientists is the most critical mission for KAIST to help the nation create a new growth engine. He said KAIST will help the nation drive the bio-industry and provide medical science resources for the nation’s health sector. To this end, he said that KAIST will open its Medical Science and Technology School by 2026.
“We plan to expand the current Graduate School of Medical Science and Engineering into a new Medical Science and Technology School that will focus entirely on a condensed MD-PhD course converging the fields of AI, bio, and physics,” he said.
The school aims to foster medical scientists whose research results will eventually be commercialized. He said that the university is now discussing revisions to related laws and regulations with the government and other universities.
To supply human resources to the semiconductor industry, President Lee said the university will add a campus in Pyongtaek City that will serve as an advanced convergence research hub in the field of next generation semiconductors in collaboration with Samsung Electronics and the city of Pyongtaek. The three-stage opening plan projected the final opening of the campus by 2036. During the first stage, which will be completed by 2026, it will construct the campus infrastructure in Pyongtaek city where Samsung Semiconductors runs two massive semiconductor complexes. By 2031, it plans to launch the open research platform including a future cities research center and future vehicles research center. The campus will open the global industrial collaboration cluster hub by 2036.
In the global arena, President Lee said he is working to open the New York campus with stakeholders in the United States. He announced the plan last December that was endorsed by New York-based entrepreneur Hee-Nam Bae, the chairman of Big Continent Inc. President Lee and Chairman Lee signed an MOU for the funding to open the campus in New York.
“We are discussing how to facilitate the plan and best accommodate the interests and potential of our students. Many ideas and plans are on the table and we think it will take longer than expected to finalize the plan,” explained President Lee.
However, he added that the basic idea is to offer art tech and health technology programs as well as an AI-based finance MBA at the New York campus, in addition to it serving as the startup accelerator of KAIST.
President Lee stressed the importance of technology commercialization when successfully launching KAIST Holdings last month to help spinoffs of KAIST labs accelerate their end results. He said that KAIST Holdings will build a virtuous supporting system to commercialize the technology startups coming from KAIST.
“We plan to list at least 10 KAIST startups on the KOSDAQ and two on the NASDAQ by 2031. KAIST Holdings also aims to nurture companies valued at a total of one billion KRW and earn 100 billion KRW in technology fees by 2031.
2022.02.17 View 8131 -
'Mini-Lungs' Reveal Early Stages of SARS-CoV-2 Infection
Researchers in Korea and the UK have successfully grown miniature models of critical lung structures called alveoli, and used them to study how the coronavirus that causes COVID-19 infects the lungs.
To date, there have been more than 40 million cases of COVID-19 and almost 1.13 million deaths worldwide. The main target tissues of SARS-CoV-2, the virus that causes COVID-19, especially in patients that develop pneumonia, appear to be alveoli – tiny air sacs in the lungs that take up the oxygen we breathe and exchange it with carbon dioxide to exhale.
To better understand how SARS-CoV-2 infects the lungs and causes disease, a team of Professor Young Seok Ju from the Graduate School of Medical Science and Engineering at KAIST in collaboration with the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge turned to organoids – ‘mini-organs’ grown in three dimensions to mimic the behaviour of tissue and organs.
The team used tissue donated to tissue banks at the Royal Papworth Hospital NHS Foundation Trust and Addenbrooke’s Hospital, Cambridge University NHS Foundations Trust, UK, and Seoul National University Hospital to extract a type of lung cell known as human lung alveolar type 2 cells. By reprogramming these cells back to their earlier ‘stem cell’ stage, they were able to grow self-organizing alveolar-like 3D structures that mimic the behaviour of key lung tissue.
“The research community now has a powerful new platform to study precisely how the virus infects the lungs, as well as explore possible treatments,” said Professor Ju, co-senior author of the research.
Dr. Joo-Hyeon Lee, another co-senior author at the Wellcome-MRC Cambridge Stem Cell Institute, said: “We still know surprisingly little about how SARS-CoV-2 infects the lungs and causes disease. Our approach has allowed us to grow 3D models of key lung tissue – in a sense, ‘mini-lungs’ – in the lab and study what happens when they become infected.”
The team infected the organoids with a strain of SARS-CoV-2 taken from a patient in Korea who was diagnosed with COVID-19 on January 26 after traveling to Wuhan, China. Using a combination of fluorescence imaging and single cell genetic analysis, they were able to study how the cells responded to the virus.
When the 3D models were exposed to SARS-CoV-2, the virus began to replicate rapidly, reaching full cellular infection just six hours after infection. Replication enables the virus to spread throughout the body, infecting other cells and tissue.
Around the same time, the cells began to produce interferons – proteins that act as warning signals to neighbouring cells, telling them to activate their antiviral defences. After 48 hours, the interferons triggered the innate immune response – its first line of defence – and the cells started fighting back against infection.
Sixty hours after infection, a subset of alveolar cells began to disintegrate, leading to cell death and damage to the lung tissue.
Although the researchers observed changes to the lung cells within three days of infection, clinical symptoms of COVID-19 rarely occur so quickly and can sometimes take more than ten days after exposure to appear. The team say there are several possible reasons for this. It may take several days from the virus first infiltrating the upper respiratory tract to it reaching the alveoli. It may also require a substantial proportion of alveolar cells to be infected or for further interactions with immune cells resulting in inflammation before a patient displays symptoms.
“Based on our model we can tackle many unanswered key questions, such as understanding genetic susceptibility to SARS-CoV-2, assessing relative infectivity of viral mutants, and revealing the damage processes of the virus in human alveolar cells,” said Professor Ju. “Most importantly, it provides the opportunity to develop and screen potential therapeutic agents against SARS-CoV-2 infection.”
“We hope to use our technique to grow these 3D models from cells of patients who are particularly vulnerable to infection, such as the elderly or people with diseased lungs, and find out what happens to their tissue,” added Dr. Lee.
The research was a collaboration involving scientists from KAIST, the University of Cambridge, Korea National Institute of Health, Institute for Basic Science (IBS), Seoul National University Hospital and Genome Insight in Korea.
- ProfileProfessor Young Seok JuLaboratory of Cancer Genomics https://julab.kaist.ac.kr the Graduate School of Medical Science and EngineeringKAIST
2020.10.26 View 9892 -
Professor Won-Ki Cho Selected as the 2020 SUHF Young Investigator
Professor Won-Ki Cho from the Department of Biological Sciences was named one of three recipients of the 2020 Suh Kyung-Bae Science Foundation (SUHF) Young Investigator Award.
The SUHF is a non-profit organization established in 2016 and funded by a personal donation of 300 billion KRW in shares from Chairman and CEO Kyung-Bae Suh of the Amorepacific Group. The primary purpose of the foundation is to serve as a platform to nurture and provide comprehensive long-term support for creative and passionate young Korean scientists committed to pursuing research in the field of life sciences. The SUHF selects three to five scientists through an open recruiting process every year and grants each scientist a maximum of 2.5 billion KRW over a period of up to five years.
Since January this year, the foundation received 67 research proposals from scientists across the nation, especially from those who had less than five years of experience as professors, and selected the three recipients.
Professor Cho proposed research on how to observe the interactions between nuclear structures and constantly-changing chromatin monomers in four dimensions through ultra-high-resolution imaging of single living cells. This proposal was recognized as one that could help us better understand the process of transcription regulation, which remains a long-standing question in biology.
The other awards were given to Professor Soung-hun Roh of Seoul National University and Professor Joo-Hyeon Lee of the University of Cambridge.
With these three new awardees, a total of 17 scientists have been named SUHF Young Investigators to date, and the funding to support these scientists now totals 42.5 billion KRW.
Professor Inkyung Jung and Professor Ki-Jun Yoon from the Department of Biological Sciences, and Professor Young Seok Ju and Professor Jeong Ho Lee from the Graduate School of Medical Science and Engineering are the four previous winners from KAIST in the years 2017 through 2019.
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2020.10.15 View 10986 -
Two Professors Recognized for the National R&D Excellence 100
< Professor Haeng-Ki Lee (left) and Professor Jeong-Ho Lee (right) >
Two KAIST professors were listed among the 2019 National R&D Excellence 100 announced by the Ministry of Science and ICT and the Korea Institute of S&T Evaluation and Planning.
Professor Haeng-Ki Lee from the Department of Civil and Environmental Engineering was recognized in the field of mechanics and materials for his research on developing new construction materials through the convergence of nano- and biotechnologies.
In the field of life and marine science, Professor Jeong-Ho Lee from the Graduate School of Medical Science and Engineering was lauded for his research of diagnostic tools and therapies for glioblastoma and pediatric brain tumors.
A certificate from the Minister of Ministry of Science and ICT will be conferred to these two professors, and their names will be inscribed on a special 2019 National R&D Excellence 100 plaque to celebrate their achievements. The professors will also be given privileges during the process of new R&D project selection.
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2019.10.15 View 9474 -
KAIST Professors Selected as Y-KAST Members
Professor YongKeun Park, Professor Bumjoon Kim, Professor Keon Jae Lee, and Professor Young Seok Ju were selected as the newest members of the Young Korean Academy of Science and Technology (Y-KAST).
The Korean Academy of Science and Technology, an academic institution of professional experts, selected 26 promising scientists under the age of 43 to join Y-KAST. and four KAIST professors were included in the list.
The newest members were conferred on February 26.
Research Field
Name
Natural Sciences
YongKeun Park (Dept. of Physics)
Engineering
Bumjoon Kim (Dept. of Chemical and Biomolecular Engineering)
Agricultural & Fishery Sciences
Keon Jae Lee (Dept. of Materials Science and Engineering)
Medical Sciences
Young Seok Ju (Graduate School of Medical Science and Engineering)
2018.03.05 View 7947 -
13 KAIST Faculty Named as Inaugural Members of Y-KAST
The Korean Academy of Science and Technology (KAST) launched the Young Korean Academy of Science and Technology (Y-KAST) and selected 73 scientists as its inaugural members on February 24. Among them, 13 KAIST faculty were recognized as the inaugural members of Y-KAST.
Y-KAIST, made up of distinguished mid-career scientists under the age of 45, will take the leading role in international collaboration as well as innovative agenda-making in science and technology.
The inaugural members include Professor Hyotcherl Ihee of the Department of Chemistry and Dr. Sung-Jin Oh of the Center for Mathematical Challenges at the Korea Institute for Advanced Study (KIAS), affiliated with KAIST. Professor Ihee is gaining wide acclaim in the fields of physics and chemistry, and in 2016, Dr. Oh was the youngest ever awardee of the Presidential Award of Young Scientist.
The other Y-KAIST members are as follows: Professors Haeshin Lee of the Department of Chemistry; Mi Young Kim, Byung-Kwan Cho, and Ji-Joon Song of the Department of Biological Sciences; Song-Yong Kim of the Department of Mechanical Engineering; Sang-il Oum of the Department of Mathematical Sciences; Jung Kyoon Choi of the Department of Bio and Brain Engineering; Seokwoo Jeon, Sang Ouk Kim, and Il-Doo Kim of the Department of Materials Science and Engineering; Jang Wook Choi of the Graduate School of EEWS (Energy, Environment, Water and Sustainability); and Jeong Ho Lee of the Graduate School of Medical Science and Engineering.
The leading countries of the Academy of Science, which include Germany, Sweden, Belgium, Canada, and Japan, have established the Young Academy of Science since 2010 in order to encourage the research activities of their young scientists and to establish a global platform for collaborative research projects through their active networking at home and abroad.
President Myung-Chul Lee of KAST said, “We will spare no effort to connect these outstanding mid-career researchers for their future collaboration. Their networking will make significant impacts toward their own research activities as well as the global stature of Korea’s science and technology R&D.
(Photo caption: Members of Y-KAST pose at the inaugural ceremony of Y-KAST on February 24.)
2017.03.02 View 15401 -
KAIST and Sejong City Goverment Agree to Establish a Graduate School of Medical Science and Engineering
KAIST and the government of Sejong City will cooperate to establish a graduate school of medical science and engineering. On June 11, 2015, President Steve Kang of KAIST and Mayor Choon-Hee Lee of Sejong City signed a memorandum of understanding at the city hall of Sejong to establish the school.
Under the agreement, the two organizations will work out details to establish the graduate school in Sejong on such issues as administrative assistance, financial support, curriculum development, and the creation of an environment conducive to the growth of medical science.
President Kang said, “Once this graduate school is established, KAIST will be able to offer Korea and the world top-notch researchers in the field of medical science. I have high hopes that the school will produce high-impact research breakthroughs and lead in the advancement of interdisciplinary studies in biotechnology.”
In the picture below, President Steve Kang of KAIST (third from the left) holds the signed memorandum of understanding with Mayor Choon-Hee Lee of Sejong (fourth from the left).
2015.06.16 View 6085 -
Liver Damage Mechanism of Hepatitis C Proven
KAIST researchers found mechanics behind a Hepatitis C virus, thereby taking a step closer to the development of a cure for Hepatitis C.
Professor Choi Chul Hui (Department of Biological and Brain Engineering) and Professor Shin Eui Chul (Graduate School of Medical Sciences) proved, for the first time in the world, the mechanism behind liver damage of a patient with Hepatitis C.
It is anticipated that this discovery will allow for the development of a Hepatitis C cure that has no side effects and little Liver damage.
Hepatitis C is an immune response of the body to the Hepatitis C virus and causes liver irritation.
Around 170million people are infected with Hepatitis C worldwide including 1% of the Korean population. Once infected, most cases turn into chronic cases and may lead to liver cancer.
However it was impossible to infect Hepatitis C within a test tube cell environment until 2005 and up till then Chimpanzees were used to study the virus which proved to be a huge barrier to research.
The research team used cells infected with Hepatitis C virus and found out that the virus works by increasing the destruction of cells by the TNF-a protein responsible for the cell’s immune response.
In addition the protein structure of the virus that causes this reaction was successfully found.
Conventionally the Hepatitis C medication focused on the suppressing the growth of the virus and therefore had many side effects.
The experimental results allow new medication aimed at suppressing the actual mechanism of liver damage to be discovered.
The result was selected as the cover dissertation of the September Edition of the Hepatolog magazine.
2012.09.11 View 11494 -
Graduate School of Medical Sciences sign Exchange Agreement with Yonsei Graduate School of Medicine
KAIST’s Graduate School of Medical Sciences signed on the 22nd of February an Exchange Agreement with the Yonsei Graduate School of Medicine.
The Agreement was signed with hopes of cooperation in research in the field of medical science and will establish a Cooperation Committee. The committee will put in motion cooperative research, training programs, exchange students, exchange of technology, and hold symposiums and seminars.
The representatives stated that the agreement is more than just a symbolic, ceremonial agreement. The agreement was made so that both graduate schools will develop into a world-class research institute in medical sciences.
2011.03.02 View 9203