Department+of+Bio
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A Key Signal Transduction Pathway Switch in Cardiomyocyte Identified
A KAIST research team has identified the fundamental principle in deciding the fate of cardiomyocyte or heart muscle cells. They have determined that it depends on the degree of stimulus in β-adrenergic receptor signal transduction pathway in the cardiomyocyte to control cells' survival or death. The findings, the team hopes, can be used to treat various heart diseases including heart failure.
The research was led by KAIST Department of Bio and Brain Engineering Chair Professor Kwang-Hyun Cho and conducted by Dr. Sung-Young Shin (lead author) and Ph.D. candidates Ho-Sung Lee and Joon-Hyuk Kang. The research was conducted jointly with GIST (Gwangju Institute of Science and Technology) Department of Biological Sciences Professor Do-Han Kim’s team. The research was supported by the Ministry of Science, ICT and Future Planning, Republic of Korea, and the National Research Foundation of Korea. The paper was published in Nature Communications on December 17, 2014 with the title, “The switching role of β-adrenergic receptor signalling in cell survival or death decision of cardiomyocytes.”
The β-adrenergic receptor signal transduction pathway can promote cell survival (mediated by β2 receptors), but also can result in cell death by inducing toxin (mediated by β1 receptors) that leads to various heart diseases including heart failure. Past attempts to identify the fundamental principle in the fate determining process of cardiomyocyte based on β-adrenergic receptor signalling concluded without much success.
The β-adrenergic receptor is a type of protein on the cell membrane of cardiomyocyte (heart muscle cell) that when stimulated by neurohormones such as epinephrine or norepinephrine would transduce signals making the cardiomyocyte contract faster and stronger.
The research team used large-scale computer simulation analysis and systems biology to identify ERK* and ICER** signal transduction pathways mediated by a feed-forward circuit as a key molecular switch that decides between cell survival and death.
Weak β-adrenergic receptor stimulations activate ERK signal transduction pathway, increasing Bcl-2*** protein expression to promote cardiomyocyte survival. On the other hand, strong β-adrenergic receptor stimulations activate ICER signal transduction pathway, reducing Bcl-2 protein expression to promote cardiomyocyte death.
Researchers used a systems biology approach to identify the mechanism of B-blocker****, a common drug prescribed for heart failure. When cardiomyocyte is treated with β1 inhibitor, strong stimulation on β-adrenergic receptor increases Bcl-2 expression, improving the chance of cardiomyocyte survival, a cell protection effect.
Professor Kwang-Hyun Cho said, “This research used systems biology, an integrated, convergence research of IT (information technology) and BT (biotechnology), to successfully identify the mechanism in deciding the fate of cardiomyocytes based on the β-adrenergic receptor signal transduction pathway for the first time. I am hopeful that this research will enable the control of cardiomyocyte survival and death to treat various heart diseases including heart failure.”
Professor Cho’s team was the first to pioneer a new field of systems biology, especially concerning the complex signal transduction network involved in diseases. Their research is focused on modelling, analyzing simulations, and experimentally proving signal pathways. Professor Cho has published 140 articles in international journals including Cell, Science, and Nature.
* ERK (Extracellular signal-regulated kinases): Signal transduction molecule involved in cell survival
** ICER (Inducible cAMP early repressor): Signal transduction molecule involved in cell death
*** Bcl-2 (B-cell lymphoma 2): Key signal transduction molecule involved in promotion of cell survival
**** β-blocker: Drug that acts as β-adrenergic receptor inhibitor known to slow the progression of heart failure, hence used most commonly in medicine.
Picture: A schematic diagram for the β-AR signalling network
2015.01.05 View 12299 -
Nanoparticle Cluster Manufacturing Technique Using DNA Binding Protein Developed
Professor Hak-Sung Kim of the Department of Biological Sciences at KAIST and Yiseul Ryu, a doctoral candidate, used the Zinc Finger protein that specifically binds to target DNA sequence to develop a new manufacturing technique for size-controllable magnetic Nanoparticle Clusters (NPCs). Their research results were published in Angewandte Chemie International Edition online on 25 November 2014.
NPCs are structures consisting of magnetic nanoparticles, gold nanoparticles, and quantum dots, each of which are smaller than 100 nm (10-9m). NPCs have a distinctive property of collectivity not seen in single nanoparticles.
Specifically NPCS differ in physical and optical properties such as Plasmon coupling absorbance, energy transfers between particles, electron transfers, and conductivity. Therefore, NPCs can be employed in biological and medical research as well as the development of nanoelectric and nanoplasmon devices.
To make use of these novel properties, the size and the composition of the cluster must be exquisitely controlled. However, previous techniques relied on chemical binding which required complex steps, making it difficult to control the size and composition of NPCs.
Professor Kim’s team used Zinc Finger, a DNA binding protein, to develop a NPCs manufacturing technique to create clusters of the desired size easily. The Zinc Finger protein contains a zinc ion and specifically recognizes DNA sequence upon binding, which allows the exquisite control of the size and the cluster composition. The technique is also bio-friendly.
Professor Kim’s team created linear structure of different sizes of NPCs using Zinc Finger proteins and three DNA sequences of different lengths. The NPCs they produced confirmed their ability to control the size and structure of the cluster by using different DNA lengths.
The NPCs showed tripled T2 relaxation rates compared to the existing MRI contrast media (Feridex) and effectively transported to targeted cells. The research findings show the potential use of NPCs in biological and medical fields such as MRI contrast media, fluorescence imaging, and drug transport.
The research used the specific binding property of protein and DNA to develop a new method to create an inorganic nanoparticle’s supramolecular assembly. The technique can be used and applied extensively in other nanoparticles for future research in diagnosis, imaging, and drug and gene delivery.
Figure 1. A Mimetic Diagram of NPCs Manufacturing Technique Using DNA Binding Protein Zinc Finger
Figure 2. Transmission Electron Microscopy Images showing different sizes of NPCs depending on the length of the DNA
2014.12.04 View 11941 -
Discovery of New Therapeutic Targets for Alzheimer's Disease
A Korean research team headed by Professor Dae-Soo Kim of Biological Sciences at KAIST and Dr. Chang-Jun Lee from the Korea Institute of Science and Technology (KIST) successfully identified that reactive astrocytes, commonly observed in brains affected by Alzheimer’s disease, produce abnormal amounts of inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) in reaction to the enzyme Monoamine oxidase B (Mao-B) and release GABA through the Bestrophin-1 channel to suppress the normal signal transmission of brain nerve cells.
By suppressing the GABA production or release from reactive astrocytes, the research team was able to restore the model mice's memory and learning impairment caused by Alzheimer’s disease. This discovery will allow the development of new drugs to treat Alzheimer’s and other related diseases.
The research result was published in the June 29, 2014 edition of Nature Medicine (Title: GABA from Reactive Astrocytes Impairs Memory in Mouse Models of Alzheimer’s Disease).
For details, please read the article below:
Technology News, July 10, 2014
"Discovery of New Drug Targets for Memory Impairment in Alzheimer’s Disease"
http://technews.tmcnet.com/news/2014/07/10/7917811.htm
2014.07.16 View 8375 -
Artificial Antibody-based Therapeutic Candidate for Lung Cancer Developed
Professor Hak-Sung Kim of Biological Sciences at KAIST publishes a cover article on artificial antibody in "Molecular Therapy".
Repebody-based lung cancer therapeutic drug candidate developed Repebody-based protein demonstrates the possibility of the development of a new drug
KAIST Biological Sciences Department’s Professor Hak-Sung Kim, in collaboration with Professor Eun-Kyung Cho from the College of Medicine at Chungnam National University, has successfully developed an artificial antibody-based, or repebody, cancer therapeutic candidate. These research results were published as a cover paper of the July edition of Molecular Therapy.
The repebody developed by Professor Kim and his team strongly binds to interleukin-6, a cancer-causing factor. It has also been confirmed that the repebody can significantly inhibit the proliferation of cancer cells in non-small-cell lung cancer animal model.
Numerous multinational pharmaceutical and biotechnology companies have invested astronomical amounts of money in research for the development of protein therapeutics with low side effects and high efficacy. More than 20 kinds of such therapeutics are currently under clinical trials, and over 100 drugs are under clinical demonstration. Among these, the majority is antibody-based therapeutics, and most of the investments are heavily concentrated in this field. However, antibody production cost is very high because it has large molecular weights and complex structural properties, and this makes it difficult to engineer. Consequently, the development costs a great deal of time and money.
In order to overcome the existing limitations of antibody-based therapeutics, Professor Kim and his team have developed a new artificial antibody, or repebody, which was published in Proceedings of the National Academy of Sciences (PNAS) in 2012. Based on this research, they have succeeded in developing a therapeutic candidate for treating non-small-cell lung cancer with a specifically strong cohesion to the cancer-causing factor, interleukin-6.
Interleukin-6 is a crucial substance within the body that is involved in immune and inflammatory-related signals. When abnormally expressed, it activates various carcinogenic pathways and promotes tumor growth and metastasis. Because of its importance, multinational pharmaceutical companies are heavily investing in developing therapeutics that can inhibit the signaling of interleukin-6.
In this study, Professor Kim and his team observed that a repebody consists of repeated modules, and they conceived a module-based affinity amplification technology that can effectively increase the binding affinity with the disease target. The developed therapeutic candidate has been confirmed in cell and animal experiments to show low immunogenicity, as well as to strongly inhibit the proliferation of non-small-cell lung cancer.
Furthermore, by investigating the complex structure of the repebody with interleukin-6, Professor Kim has identified its mechanism, which demonstrated the potential for therapeutic development. The researchers are currently carrying out pre-clinical trials for acquiring permission to perform clinical trials on animals with non-small-cell lung cancer. The repebody can be developed into a new protein drug after demonstrating its safety and efficacy.
Professor Hak-Sung Kim and his team have confirmed that the repebody can be utilized as a new protein drug, and this will be a significant contribution to Korea’s protein drugs and biotechnology industry development.
The research was supported by the Future Pioneer Industry project and sponsored by the Ministry of Science, ICT and Future Planning.
Figure 1. Professor Kim’s article published as the cover article of July edition of Molecular Therapy
Figure 2. Clinical proof of the repebody’s inhibition of cancer growth using animal models
2014.07.14 View 12113 -
KAIST Researchers Develops Sensor That Reads Emotional States of Users
A piloerection monitoring sensor attached on the skin
The American Institute of Physics distributed a press release dated June 24, 2014 on a research paper written by a KAIST research team, which was published in its journal entitled Applied Physics Letters (APL). APL features concise, up-to-date reports in significant new findings in applied physics.
According to the release, “KAIST researchers have developed a flexible, wearable 20 mm x 20 mm polymer sensor that can directly measure the degree and occurrence on the skin of goose bumps, which is caused by sudden changes in body temperature or emotional states.”
The lead researcher was Professor Young-Ho Cho from the Department of Bio and Brain Engineering at KAIST.
If you would like to read the press release, please go to the link below:
American Institute of Physics, June 24, 2014
“New technology: The goose bump sensor”
http://www.eurekalert.org/pub_releases/2014-06/aiop-ntt062314.php
2014.06.26 View 8228 -
Professor Won Do Heo on LED Light Technology for Controlling Proteins in Living Cells
With the newly developed LED technology, Professor Won Do Heo at the College of Life Science and Bioengineering, KAIST, was able to suppress cell migration and division when cells are exposed to LED light. This suggests a breakthrough to apply in future cancer cell research.
Professor Heo talked about the impact of his research in the following excerpt from a news article:
“We are already conducting research on the spread of cancer, as well as brain science in animal models with the Light-Activated Reversible Inhibition by Assembled Trap. I believe this technology will be a breakthrough in investigating cancer treatments and the function of neurons in a complex neural network, which existing technologies have not been able to do.”
From EE Times Europe, June 19, 2014
“LED Light Technology Controls Proteins in Living Cells”
http://www.ledlighting-eetimes.com/en/led-light-technology-controls-proteins-in-living-cells.html?cmp_id=7&news_id=222909336
2014.06.22 View 7554 -
A mechanism for how reactive oxygen species cause cell responses studied
A research team led by Professor Kwang-Hyun Cho of the Department of Biology and Brain Engineering, KAIST, and Dr. Gi-Sun Kwon of the Korea Research Institute of Bioscience and Biotechnology succeeded in proving the mechanism behind the determination of cell life in relation to reactive oxygen species.
The results of the venture were published in the June 3rd edition of Science Signaling. The title of the research paper is “MLK3 is part of a feedback mechanism that regulates different cellular responses to reactive oxygen species.”
The research team discovered that the molecular switch that determines the division of apoptosis of a cell was based on MLK3 feedback mechanism. MLK stands for mixed-lineage kinase.
Under sufficient stress, the mechanism instructs the cell to undergo the division but in an overly stressful environment, the mechanism stops the cell division and instead, induces apoptosis. This discovery is expected to be a breakthrough in illnesses related to the concentration of the reactive oxygen species (ROS).
At low concentration of ROS, the protein associated with cell division, ERK (extracellular-signal-regulated kinase), is activated while as the ROS concentration increases, JNK (c-Jun N-terminal protein kinases), responsible for apoptosis, becomes activated. Furthermore, through computer simulation analysis and mathematical modeling, in tandem with molecular cell biology experiments, the MLK3 based feedback mechanism was the fundamental molecular switch that determines the balance between ERK and JNK, and ultimately the cell’s responses.
Professor Cho commented that “the contradicting cell responses to ROS had remained a mystery, but with the system biology, an approach in which information technology and biotechnology converge, such riddles can be resolved. We expect that the proven mechanism will be used to overcome aging or cancer growth as a result of ROS in the near future.”
Picture shows the process of identifying cell responses caused by reactive oxygen species.
2014.06.13 View 8792 -
Binding Regulatory Mechanism of Protein Biomolecules Revealed
Professor Hak-Sung Kim
A research team led by Professor Hak-Sung Kim of Biological Sciences, KAIST, and Dr. Mun-Hyeong Seo, KAIST, has revealed a regulatory mechanism that controls the binding affinity of protein’s biomolecules, which is crucial for the protein to recognize molecules and carry out functions within the body.
The research results were published in the April 24th online edition of Nature Communications.
The protein, represented by enzyme, antibody, or hormones, specifically recognizes a variety of biomolecules in all organisms and implements signaling or immune response to precisely adjust and maintain important biological processes. The protein binding affinity of biomolecules plays a crucial role in determining the duration of the bond between two molecules, and hence to determine and control the in-vivo function of proteins.
The researchers have noted that, during the process of proteins’ recognizing biomolecules, the protein binding affinity of biomolecules is closely linked not only to the size of non-covalent interaction between two molecules, but also to the unique kinetic properties of proteins.
To identify the basic mechanism that determines the protein binding affinity of biomolecules, Professor Kim and his research team have made mutation in the allosteric site of protein to create a variety of mutant proteins with the same chemical binding surface, but with the binding affinity vastly differing from 10 to 100 times. The allosteric site of the protein refers to a region which does not directly bind with biomolecules, but crucially influences the biomolecule recognition site.
Using real-time analysis at the single-molecule level of unique kinetic properties of the produced mutant proteins, the researchers were able to identify that the protein binding affinity of biomolecules is directly associated with the protein’s specific kinetic characteristics, its structure opening rate.
Also, by proving that unique characteristics of the protein can be changed at the allosteric site, instead of protein’s direct binding site with biomolecules, the researchers have demonstrated a new methodology of regulating the in-vivo function of proteins.
The researchers expect that these results will contribute greatly to a deeper understanding of protein’s nature that governs various life phenomena and help evaluate the proof of interpreting protein binding affinity of biomolecules from the perspective of protein kinetics.
Professor Kim said, “Until now, the protein binding affinity of biomolecules was determined by a direct interaction between two molecules. Our research has identified an important fact that the structure opening rate of proteins also plays a crucial role in determining their binding affinity.”
[Picture]
A correlation graph of opening rate (kopening) and binding affinity (kd) between protein’s stable, open state and its unstable, partially closed state.
2014.05.02 View 9342 -
A Molecular Switch Controlling Self-Assembly of Protein Nanotubes Discovered
International collaborative research among South Korea, United States, and Israel research institutionsThe key to the treatment of cancer and brain disease mechanism The molecular switch that controls the self-assembly structure of the protein nanotubes, which plays crucial role in cell division and intracellular transport of materials, has been discovered. KAIST Bio and Brain Engineering Department’s Professor Myeong-Cheol Choi and Professor Chae-Yeon Song conducted the research, in collaboration with the University of California in Santa Barbara, U.S., and Hebrew University in Israel. The findings of the research were published in Nature Materials on the 19th. Microtubules are tube shaped and composed of protein that plays a key role in cell division, cytoskeleton, and intercellular material transport and is only 25nm in diameter (1/100,000 thickness of a human hair). Conventionally, cancer treatment focused on disrupting the formation of microtubules to suppress the division of cancer cells. In addition Alzheimer’s is known to be caused by the diminishing of structural integrity of microtubules responsible for intercellular material transport which leads to failure in signal transfer. The research team utilized synchrotron x-ray scattering and transmission electron microscope to analyze the self assemble structure of protein nanotubes to subnanometer accuracy. As a result, the microtubules were found to assemble into 25nm thickness tubules by stacking protein blocks 4 x 5 x 8nm in dimension. In the process, the research team discovered the molecular switch that controls the shape of these protein blocks. In addition the research team was successful in creating a new protein tube structure. Professor Choi commented that they were successful in introducing a new paradigm that suggests the possibility of controlling the complex biological functions of human’s biological system with the simple use of physical principles. He commented further that it is anticipated that the findings will allow for the application of bio nanotubes in engineering and that this is a small step in finding the mechanism behind cancer treatment and neural diseases.
2014.02.03 View 9802 -
Mechanism in regulation of cancer-related key enzyme, ATM, for DNA damage and repair revealed
Professor Kwang-Wook Choi
A research team led by Professor Kwang-Wook Choi and Dr. Seong-Tae Hong from the Department of Biological Sciences at KAIST has successfully investigated the operational mechanism of the protein Ataxia Telangiectasia Mutated (ATM), an essential protein to the function of a crucial key enzyme that repairs the damaged DNA which stores biometric information. The results were published on December 19th Nature Communications online edition.
All organisms, including humans, constantly strive to protect the information within their DNA from damages posed by a number of factors, such as carbonized materials in our daily food intake, radioactive materials such as radon emitting from the cement of buildings or ultraviolet of the sunlight, which could be a trigger for cancer.
In order to keep the DNA information safe, the organisms are always carrying out complex and sophisticated DNA repair work, which involves the crucial DNA damage repair protein ATM. Consequently, a faulty ATM leads to higher risks of cancer.
Until now, academia predicted that the Translationally Controlled Tumor Protein (TCTP) will play an important role in regulating the function of ATM. However, since most of main research regarding TCTP has only been conducted in cultured cells, it was unable to identify exactly what mechanisms TCTP employs to control ATM.
The KAIST research team identified that TCTP can combine with ATM or increase the enzymatic activity of ATM. In addition, Drosophilia, one of the most widely used model organisms for molecular genetics, has been used to identify that TCTP and ATM play a very important role in repairing the DNA damaged by radiation. This information has allowed the researchers to establish TCTP’s essential function in maintaining the DNA information in cell cultures and even in higher organisms, and to provide specific and important clues to the regulation of ATM by TCTP.
Professor Kwang-Wook Choi said, “Our research is a good example that basic research using Drosophilia can make important contributions to understanding the process of diseases, such as cancer, and to developing adequate treatment.”
The research has been funded by the Ministry of Science, ICT and Future Planning, Republic of Korea, and the National Research Foundation of Korea.
Figure 1. When the amount of TCTP protein is reduced, cells of the Drosophila's eye are abnormally deformed by radiation. Scale bars = 200mm
Figure 2. When the amount of TCTP protein is reduced, the chromosomes of Drosophilia are easily broken by radiation. Scale bars = 10 mm.
Figure 3. When gene expressions of TCTP and ATM are reduced, large defects occur in the normal development of the eye. (Left: normal Drosophilia's eye, right: development-deficient eye)
Figure 4. ATM marks the position of the broken DNA, with TCTP helping to facilitate this reaction. DNA (blue line) within the cell nucleus is coiled around the histone protein (green cylinder). When DNA is broken, ATM protein attaches a phosphate group (P). Multiple DNA repair protein recognizes the phosphate as a signal that requires repair and gathers at the site.
2014.01.07 View 11843 -
Opening Ceremony of Genetic Donguibogam held
- Medicine using traditional natural substances • Food product source technology development begins
- Over 150,000,000,000 Won for 10 years of work invested to develop source technology
- Opening ceremony held on November 26th at 3 p.m. in Bio & Brain Engineering Division Building
The research to develop medicine and food source technology using traditional natural substances hasbegun.The opening ceremony of the “Genetic Donguibogam” business group, with KAIST Department of Bio & Brain Engineering Professor Do Heon Lee as the leader, was held on November 26th at 3 p.m. in Dream Hall, Bio & Brain Engineering Division Building, KAIST, Daejeon. The attendees of the opening ceremony included Yo Eop Im, Head of the Future Technology Department of the Ministry of Science, ICT and Future Planning and around 200 experts in science and technology industry, including the National Research Foundation of Korea, KAIST, the Korea Institute of Science and Technology, Seoul National University and Yonsei University.
The business group was established to re-interpret traditional natural substances proved to be effective from experience and improve quality of life by researching its applications; and to develop integrated source technology using traditional natural substances. The group is to invest over 150,000,000,000 Won for 10 years of research to secure natural substance source technology in five stages: interpretation technology, analysis technology, verification technology, bio marker technology and human body effectiveness verification technology. Especially, the focus would be on the use of virtual body computer models and Omics* to analyse the effects of traditional natural substances mixture on human body, and to find new materials for healthcare.
This research model, it is hoped, will have a new item to pioneer in the world natural substance market as well as securing a technologically competitive edge in bio industry by developing source technology that investigates the effects of traditional natural substances using cutting edge science.
KAIST Department of Bio & Brain Engineering Professor and Head Do Heon Lee of the “Genetic Donguibogam” Business Group said, “We will push forward to develop source energy by integrating IT-BT technology with a computer virtual body to build a cooperation system with medicine and functional food industries.” He continued: “This will enable not only the creation of a new industry, but also customised medicine.”
The 12 partners of the group include KAIST, Korea Institute of Science and Technology, Seoul National University and Yonsei University and 200 experts. The research participation area will be widened to foreign research institutes and associated companies.
* Terminology
Noun) Omics is an academic discipline analysing mass information on metabolism of physiological phenomena in specific cells (transcriptome, proteome and protoplast) with an integrated approach to determine vital phenomena.
2013.12.11 View 8511 -
Two Dimensions of Value: Dopamine Neurons Represent Reward but not Aversiveness
Professor Christopher D. Fiorillo of the Bio & Brain Engineering (http://ineuron.kaist.ac.kr/web/home.html) at KAIST published a research paper in the August 2 issue of Science. The title of the paper is “Two Dimensions of Value: Dopamine Neurons Represent Reward but not Aversiveness.” The following is an introduction of his research work:
To make decisions, we need to estimate the value of sensory stimuli and motor actions, their “goodness” and “badness.” We can imagine that good and bad are two ends of a single continuum, or dimension, of value. This would be analogous to the single dimension of light intensity, which ranges from dark on one end to bright light on the other, with many shades of gray in between. Past models of behavior and learning have been based on a single continuum of value, and it has been proposed that a particular group of neurons (brain cells) that use dopamine as a neurotransmitter (chemical messenger) represent the single dimension of value, signaling both good and bad.
The experiments reported here show that dopamine neurons are sensitive to the value of reward but not punishment (like the aversiveness of a bitter taste). This demonstrates that reward and aversiveness are represented as two discrete dimensions (or categories) in the brain. “Reward” refers to the category of good things (food, water, sex, money, etc.), and “punishment” to the category of bad things (stimuli associated with harm to the body and that cause pain or other unpleasant sensations or emotions).
Rather than having one neurotransmitter (dopamine) to represent a single dimension of value, the present results imply the existence of four neurotransmitters to represent two dimensions of value. Dopamine signals evidence for reward (“gains”) and some other neurotransmitter presumably signals evidence against reward (“losses”). Likewise, there should be a neurotransmitter for evidence of danger and another for evidence of safety. It is interesting that there are three other neurotransmitters that are analogous to dopamine in many respects (serotonin, norepinephrine, and acetylcholine), and it is possible that they could represent the other three value signals.
For the research article, please visit: http://www.sciencemag.org/content/341/6145/546.abstract
For the Science 2nd issue, please visit: http://www.sciencemag.org/content/current#ResearchArticles
Illustration of Value Dimension
2013.08.08 View 7496