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Systems biology demystifies the resistance mechanism of targeted cancer medication
Korean researchers have found the fundamental resistance mechanism of the MEK inhibitor, a recently highlighted chemotherapy method, laying the foundation for future research on overcoming cancer drug resistance and improving cancer survival rates. This research is meaningful because it was conducted through systems biology, a fusion of IT and biotechnology. The research was conducted by Professor Gwang hyun Cho’s team from the Department of Biology at KAIST and was supported by the Ministry of Education, Science and Technology and the National Research Foundation of Korea. The research was published as the cover paper for the June edition of the Journal of Molecular Cell Biology (Title: The cross regulation between ERK and PI3K signaling pathways determines the tumoricidal efficacy of MEK inhibitor). Targeted anticancer medication targets certain molecules in the signaling pathway of the tumor cell and not only has fewer side effects than pre-existing anticancer medication, but also has high clinical efficacy. The technology also allows the creation of personalized medication and has been widely praised by scientists worldwide. However, resistances to the targeted medication have often been found before or during the clinical stage, eventually causing the medications to fail to reach the drug development stage. Moreover, even if the drug is effective, the survival rate is low and the redevelopment rate is high. An active pathway in most tumor cells is the ERK (Extracellular signal-regulated kinases) signaling pathway. This pathway is especially important in the development of skin cancer or thyroid cancer, which are developed by the mutation of the BRAF gene inside the path. In these cases, the MEK (Extracellular signal-regulated kinases) inhibitor is an effective treatment because it targets the pathway itself. However, the built-up resistance to the inhibitor commonly leads to the redevelopment of cancer. Professor Cho’s research team used large scale computer simulations to analyze the fundamental resistance mechanism of the MEK inhibitor and used molecular cell biological experiments as well as bio-imaging* techniques to verify the results. * Bio-imaging: Checking biological phenomena at the cellular and molecular levels using imagery The research team used different mutational variables, which revealed that the use of the MEK inhibitor reduced the transmission of the ERK signal but led to the activation of another signaling pathway (the PI3K signaling pathway), reducing the effectiveness of the medication. Professor Cho’s team also found that this response originated from the complex interaction between the signaling matter as well as the feedback network structure, suggesting that the mix of the MEK inhibitor with other drugs could improve the effects of the targeted anticancer medication. Professor Cho stated that this research was the first of its kind to examine the drug resistivity against the MEK inhibitor at the systematic dimension and showed how the effects of drugs on the signaling pathways of cells could be predicted using computer simulation. It also showed how basic research on signaling networks can be applied to clinical drug use, successfully suggesting a new research platform on overcoming resistance to targeting medication using its fundamental mechanism.
Successful Development of Excavation System of Biomarkers containing Protein Decomposition Control Enzyme Information
A Korean team of researchers successfully developed a biomarker excavation system named E3Net that excavates biomarkers containing information of the enzymes that control the decomposition of proteins. The development of the system paved the possibility of development of new high quality biomarkers. *Biomarker: Molecular information of unique patterns derived from genes and proteins that allow the monitoring of physical changes from genetic or environmental causes. Professor Lee Kwan Soo’s team (Department of Biological Sciences) composed of Doctorate candidate Han Young Woong, Lee Ho Dong Ph.D. and Professor Park Jong Chul published a dissertation in the April edition of Molecular and Cellular Proteomics. (Dissertation Title: A system for exploring E3-mediated regulatory networks of cellular functions). Professor Lee’s team compiled all available information of the enzyme that controls protein decomposition (E3 enzyme) and successfully compiled the inter-substrate network by extracting information from 20,000 biology related data base dissertations. The result was the development of the E3Net system that analyzes the related cell function and disease. Cells have a system that produces, destroys, and recycles proteins in response to the ever changing environmental conditions. Error in these processes leads to disease. Therefore finding the relationship between E3 enzymes that control the decomposition of proteins and the substrates will allow disease curing and prevention to become much easier. E3 enzyme is responsible for 80% of the protein decomposition and is therefore predicted to be related to various diseases. However the information on E3 enzyme and inter-substrate behavior are spread out among numerous dissertations and data bases which prevented methodological analysis of the role of the related cells and characteristics of the disease itself. Professor Lee’s team was successful in creating the E3Net that compiled 2,201 pieces of E3 substrate information, 4,896 pieces of substrate information, and 1,671 pieces of inter-substrate relationship information. This compilation allows for the systematic analysis of cells and diseases. The newly created network is 10 times larger than the existing network and is the first case where it is possible to accurately find the cell function and related diseases. It is anticipated that the use of the E3Net will allow the excavation of new biomarkers for the development of personalized drug systems. The research team applied the E3Net to find tens of new candidate biomarkers related to the major modern diseases like diabetes and cancer.
High-resolution Atomic Imaging of Specimens in Liquid Observed by Transmission Electron Microscopes Using Graphene Liquid Cells
Looking into specimens in liquid at the atomic level to understand nanoscale processes so far regarded as impossible to witnessThe Korea Advanced Institute of Science and Technology (KAIST) announced that a research team from the Department of Materials Science and Engineering has developed a technology that enables scientists and engineers to observe processes occurring in liquid media on the smallest possible scale which is less than a nanometer. Professor Jeong Yong Lee and Researcher Jong Min Yuk, in collaboration with Professors Paul Alivisatos’s and Alex Zettl’s groups at the University of California, Berkeley, succeeded in making a graphene liquid cell or capsule, confining an ultra-thin liquid film between layers of graphene, for real-time and in situ imagining of nanoscale processes in fluids with atomic-level resolution by a transmission electron microscope (TEM). Their research was published in the April 6, 2012 issue of Science. (http://www.sciencemag.org/content/336/6077/61.abstract) The graphene liquid cell (GLC) is composed of two sheets of graphene sandwiched to create a sealed chamber where a platinum growth solution is encapsulated in the form of a thin slice. Each graphene layer has a thickness of one carbon atom, the thinnest membrane that has ever been used to fabricate a liquid cell required for TEM. The research team peered inside the GLC to observe the growth and dynamics of platinum nanocrystals in solution as they coalesced into a larger size, during which the graphene membrane with the encapsulated liquid remained intact. The researchers from KAIST and the UC Berkeley identified important features in the ongoing process of the nanocrystals’ coalescence and their expansion through coalescence to form certain shapes by imaging the phenomena with atomic-level resolution. Professor Lee said, “It has now become possible for scientists to observe what is happening in liquids on an atomic level under transmission electron microscopes.” Researcher Yuk, one of the first authors of the paper, explained his research work. “This research will promote other fields of study related to materials in a fluid stage including physical, chemical, and biological phenomena at the atomic level and promises numerous applications in the future. Pending further studies on liquid microscopy, the full application of a graphene-liquid-cell (GLC) TEM to biological samples is yet to be confirmed. Nonetheless, the GLC is the most effective technique developed today to sustain the natural state of fluid samples or species suspended in the liquid for a TEM imaging.” The transmission electron microscope (TEM), first introduced in the 1930s, produces images at a significantly higher resolution than light microscopes, allowing users to examine the smallest level of physical, chemical, and biological phenomena. Observations by TEM with atomic resolution, however, have been limited to solid and/or frozen samples, and thus it has previously been impossible to study the real time fluid dynamics of liquid phases. TEM imaging is performed in a high vacuum chamber in which a thin slice of the imaged sample is situated, and an electron beam passes through the slice to create an image. In this process, a liquid medium, unlike solid or frozen samples, evaporates, making it difficult to observe under TEM. Attempts to produce a liquid capsule have thus far been made with electron-transparent membranes of such materials as silicon nitride or silicon oxide; such liquid capsules are relatively thick (tens to one hundred nanometers), however, resulting in poor electron transmittance with a reduced resolution of only a few nanometers. Silicon nitride is 25 nanometers thick, whereas graphene is only 0.34 nanometers. Graphene, most commonly found in bulk graphite, is the thinnest material made out of carbon atoms. It has unique properties such as mechanical tensile strength, high flexibility, impermeability to small molecules, and high electrical conductivity. Graphene is an excellent material to hold micro- and nanoscopic objects for observation in a transmission electron microscope by minimizing scattering of the electron beam that irradiates a liquid sample while reducing charging and heating effects. ### Figure 1. Schematic illustration of graphene liquid cells. Sandwiched two sheets of graphene encapsulate a platinum growth solution. Figure 2. In-situ TEM observation of nanocrystal growth and shape evolution. TEM images of platinum nanocrystal coalescence and their faceting in the growth solution.
A Step Closer to Ultra Slim Mobile Phone
Professor Baek Kyung Wook (department of Material Science and Engineering) succeeded in developing an ultra-thin conjugation technique that can perfectly replace the modular contact in electronic devices. The research team developed a compound material using ultra-fine solder-adhesive film and developed the vertical ultrasonic conjugation process thereby making a reliable utra-thin conjugation. The developed technique allowed for very thin and reliable conjugation and will be able to replace the socket type connector and is expected to revolutionize the electronic device industry. In mobile electronic devices like the smartphone, the trend is to incorporate various functional modules like camera, display, touchscreens, etc. in addition to striving for miniaturization of the device. Recently the problem was the fact that the number of modules within the device was increasing due to the incorporation of various functions, and consequently the volume that these modules took up increased as well, which made miniaturization almost impossible. Professor Baek‘s team succeeded in improving upon this problem by creating a compound material that has ultra-fine solder particles that can melt to form alloy fusion with the electrode and thermosetting adhesive film that can wrap around the electrode and provide mechanical protection. The use of this material made it possible to reduce the thickness of the connector by hundredth fold which improved electrical, mechanical properties and highly reliable. From a processing standpoint the conventional conjugation process involved heating the mechanical block and was therefore hard to manage its production and also consumed 1000W and took up to 15 seconds. By contrast, Professor Baek’s team’s new process uses only ultrasound to locally heat and melt the conjugation point itself thereby reducing power consumption to 100W and conjugation time to 1~5 seconds. The technique developed by Professor Baek and Lee Ki Won Doctorate student was awarded Excellent Dissertation Award by world famous journals like the Electronic Components and Technology Conference and is being recognized worldwide.
Bio Pharmaceutical Business Center: Now Open
The Signboard Hanging Ceremony for the Bio Pharmaceutical Business Center for the Integrated Research for the field of Bio Pharmaceutics. 150 representatives from various bio pharmaceutics related businesses and institutes were present for this ceremony. The Ministry of Education, Science and Technology placed the Molecular Process research team, Personalized Drug Delivery Medium research team, and the newly formed Cancer Cell Detection using Blood research team at the Bio Pharmaceutical Business Center at KAIST.
New York Times, "First, Catch Your Faculty-A Recipe for Excellence"
The World Bank has recently published a new book entitled “The Road to Academic Excellence: The Making of World Class Research Universities.” The report (book) examined the recent experience of 11 universities in 9 countries (for Korea, it sampled Pohang University of Science and Technology, established in 1986) that have undergone transformations in order to become world-class universities. The book has received a wide coverage from the media all around the world since its publication in late September, among others, the latest article by New York Times (NYT), dated October 16, 2011. The gist of the book, i.e., what elements are required should a research university to become “truly prestigious” in the global scene, is well introduced by the NYT article, and here’s the link: New York Times, “First, Catch Your Faculty-A Recipe for Excellence” http://www.nytimes.com/2011/10/17/world/americas/17iht-educLede17.html
Artificial Photosynthesis Technology Developed using Solar Cell Material
Humanity is facing global warming and the exhaustion of fossil fuel. In order to remedy these problems, efforts to produce fuel without the production of carbon dioxide using solar energy continues constantly. KAIST’s Professor Park Chan Beom and Professor Ryu Jeong Ki’s research teams of the department of Material Science and Engineering has developed an artificial photosynthesis system that mimics the photosynthesis in nature using solar cell technology. The development of the technology is sure to pave the way to ‘Eco-Friendly Green Biological Process’. Photosynthesis is the process by which a biological entity produces chemical products like carbohydrates using physical and chemical reactions using solar energy as its energy source. Professor Park’s team was able to develop the artificial photosynthesis technology with a biological catalyst as its basis. The result of the experiment was published in ‘Advanced Materials’ magazine on the 26th of April edition and has been patented.
The 40th Anniversary of the Establishment of KAIST Commemoration Held
KAIST, aspiring to become the best Science and Technology University, has turned 40. KAIST held the commemoration ceremony for the 40th Anniversary of the Establishment of KAIST in the auditorium. Five awards (Scholar, Creative Lecture, Excellence in Lecture, International Cooperation, Experiment) were given to Professors Kim Eun Jun and Walton Jones (department of Biology), Professor Abigail Shin (department of Humanities and Social Sciences), Professor Shin Seong Chul (department of Physics), and Professor Lee Sang Yeop (department of Biological Chemical Engineering). Each recipient received a prize of five million won. Professor Song Joon Hwa (department of Computer Sciences) received the ‘New Knowledge Award’ in recognition of his development of the Orchestrator Mobile platform. The new platform is different from Android or the IOS platform in that it allows a fluid relationship to be formed between the smartphone and the user. KAIST also showed off its new emblem. The emblem consists of a star which represents the KAIST’s goals of becoming the world leader, of training leaders, the center point, and hope. The main keywords are: ‘Leadership’, ‘Premium’, ‘Scientific’, and ‘Humanity’. KAIST plans on having various events from May 9th when there will be the Vision Declaration.
Success in differentiating Functional Vascular Progenitor Cells (VPC)
KAIST’s Professor Han Yong Man successfully differentiated vascular progenitor cells from human embryonic stem cells and reversed differentiated stem cells. The research went beyond the current method of synthesis of embryonic body or mice cell ball culture and used the careful alteration of signal transmission system of the human embryonic stem cells to differentiate the formation of vascular progenitor cells. The team controlled the MEK/ERK and BMP signal transmission system that serves an important role in the self replication of human embryonic stem cells and successfully differentiated 20% of the cells experimented on to vascular progenitor cells. The vascular progenitor cells produced with such a method successfully differentiated into cells forming the endodermis of the blood vessel, vascular smooth muscle cells and hematopoietic cells in an environment outside of the human body and also successfully differentiated into blood vessels in nude mice. In addition, the vascular progenitor cell derived from human embryonic cells successfully formed blood vessels or secreted vascular growth factors and increased the blood flow and the necrosis of blood vessels when injected into an animal with limb ischemic illness. The research was funded by the Ministry of Education, Science and Technology, 21st Century Frontier Research and Development Institution’s Cell Application Research Department and Professor Ko Kyu Young (KAIST), Professor Choi Chul Hee (KAIST), Professor Jeong Hyung Min (Cha Medical School) and Doctor Jo Lee Sook (Researcher in Korea Bio Engineering Institute) participated in it. The results of the research was published as the cover paper of the September edition of “Blood (IF:10.55)”, the American Blood Journal and has been patented domestically and has finished registration of foreign PCT. The results of the experiment opened the possibility of providing a patient specific cure using stem cells in the field of blood vessel illness.
KAIST developed a plastic film board less sensitive to heat.
The research result was made the cover of magazine, Advanced Materials and is accredited to paving the way to commercialize flexible display screens and solar power cells. Transparent plastic and glass cloths, which have a limited thermal expansion needed for the production of flexible display screens and solar power cells, were developed by Korean researchers. The research, led by KAIST’s Professor Byoung-Soo Bae, was funded by the Engineering Research Center under the initiative of the Ministry of Education, Science and Technology and the National Research Foundation. The research result was printed as the cover paper of ‘Advanced Materials’ which is the leading magazine in the field of materials science. Professor Bae’s team developed a hybrid material with the same properties as fiber glass. With the material, they created a transparent, plastic film sheet resistant to heat. Transparent plastic film sheets were used by researchers all over the world to develop devices such as flexible displays or solar power cells that can be fit into various living spaces. However, plastic films are heat sensitive and tend to expand as temperature increases, thereby making it difficult to produce displays or solar power cells. The new transparent, plastic film screen shows that heat expansion index (13ppm/oC) similar to that of glass fiber (9ppm/oC) due to the presence of glass fibers; its heat resistance allows to be used for displays and solar power cells over 250oC. Professor Bae’s team succeeded in producing a flexible thin plastic film available for use in LCD or AMOLED screens and thin solar power cells. Professor Bae commented, “Not only the newly developed plastic film has superior qualities, compared to the old models, but also it is cheap to produce, potentially bringing forward the day when flexible displays and solar panels become commonplace. With the cooperation of various industries, research institutes and universities, we will strive to improve the existing design and develop it further.”
International Workshop on EEWS 2010 was held.
On October 7 and 8th at Fusion Hall of KI Building, KAIST, the 2010 International Workshop on EEWS (Energy, Environment, Water, and Sustainability) was held. The third to be held, forty national and international academic professionals including Mark Shannon, professor at University of Illinois at Urbana-Champaign, Domen Kazunari, Tokyo University professor, Dong Sub Kim, CTO of SK Energy and Doyoung Seung, Senior Vice President of GS Caltex, participated at this year’s workshop. In twelve sessions, themes including Artificial Photosynthesis, Wireless Power Transfer, Green Aviation, Safe Nuclear Fuel Reuse, Fuel Cells in Action, LED 2.0, Foundation of Energy-Water Nexus, and Flexible Battery & Solar Cell were presented and discussed. “Through this workshop, current EEWS policy and research progress from different countries and the future of related technologies will be foreseen,” said Jae Kyu Lee, Dean of KAIST EEWS Initiative. “I hope it became an opportunity to create cooperative relationships with leading researchers.” EEWS is a research project conducted by KAIST to solve global issues that mankind faces today such as depletion of energy, environmental pollution, water shortage, and sustainability.
An internationally renowned academic journal published the research result produced by a KAST research team on its cover.
Fc DAAP VEGF-Trap Photograph showing the gross features of tumor growth along the mesentery-intestinal border. T: tumor. Scale bars represent 5 mm. Professor Gou-Young Koh of the Biological Sciences Department, KAIST, and his research team published their research result in Cancer Cell, a peer-review scientific journal, as a cover article dated August 17, 2010. It is the first time for the journal to pick up a paper written by a Korean research team and publish it as the cover. It has been known that a vascular growth factor (VEGF) is closely related to the growth of a tumor. The research team recently discovered that in addition to VEGF, another growth factor, angiopoietin-2 (Ang2), is also engaged with the increase of tumors. Professor Koh said, “VEGF and the angiopoietins play critical roles in tumor progression and metastasis, and a single inhibitor targeting both factors have not been available.” The team led by Professor Koh has developed a double anti-angiogenic protein (DAAP) that can simultaneously bind VEGF-A and the angiopoietins and block their actions. Professor Koh said in his paper, “DAAP is a highly effective molecule for regressing tumor angiogenesis and metastasis in implanted and spontaneous solid tumor; it can also effectively reduce ascites formation and vascular leakage in an ovarian carcinoma model. Thus, simultaneous blockade of VEGF-A and angiopoietins with DAAP is an effective therapeutic strategy for blocking tumor angiogenesis, metastasis, and vascular leakage.” So far, cancer patients have received Avastin, anticancer drug, to inhibit VEGF, but the drug has not successfully restrained the growth of cancer tumors and brought to some of the patients with serious side effects instead. Professor Koh said, “DAAP will be very effective to control the expansion of tumor growth factors, which will open up a new possibility for the development of more helpful cancer medicine with low side effects.”
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