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KAIST team develops smart immune system that can pin down on malignant tumors
A joint research team led by Professor Jung Kyoon Choi of the KAIST Department of Bio and Brain Engineering and Professor Jong-Eun Park of the KAIST Graduate School of Medical Science and Engineering (GSMSE) announced the development of the key technologies to treat cancers using smart immune cells designed based on AI and big data analysis. This technology is expected to be a next-generation immunotherapy that allows precision targeting of tumor cells by having the chimeric antigen receptors (CARs) operate through a logical circuit. Professor Hee Jung An of CHA Bundang Medical Center and Professor Hae-Ock Lee of the Catholic University of Korea also participated in this research to contribute joint effort. Professor Jung Kyoon Choi’s team built a gene expression database from millions of cells, and used this to successfully develop and verify a deep-learning algorithm that could detect the differences in gene expression patterns between tumor cells and normal cells through a logical circuit. CAR immune cells that were fitted with the logic circuits discovered through this methodology could distinguish between tumorous and normal cells as a computer would, and therefore showed potentials to strike only on tumor cells accurately without causing unwanted side effects. This research, conducted by co-first authors Dr. Joonha Kwon of the KAIST Department of Bio and Brain Engineering and Ph.D. candidate Junho Kang of KAIST GSMSE, was published by Nature Biotechnology on February 16, under the title Single-cell mapping of combinatorial target antigens for CAR switches using logic gates. An area in cancer research where the most attempts and advances have been made in recent years is immunotherapy. This field of treatment, which utilizes the patient’s own immune system in order to overcome cancer, has several methods including immune checkpoint inhibitors, cancer vaccines and cellular treatments. Immune cells like CAR-T or CAR-NK equipped with chimera antigen receptors, in particular, can recognize cancer antigens and directly destroy cancer cells. Starting with its success in blood cancer treatment, scientists have been trying to expand the application of CAR cell therapy to treat solid cancer. But there have been difficulties to develop CAR cells with effective killing abilities against solid cancer cells with minimized side effects. Accordingly, in recent years, the development of smarter CAR engineering technologies, i.e., computational logic gates such as AND, OR, and NOT, to effectively target cancer cells has been underway. At this point in time, the research team built a large-scale database for cancer and normal cells to discover the exact genes that are expressed only from cancer cells at a single-cell level. The team followed this up by developing an AI algorithm that could search for a combination of genes that best distinguishes cancer cells from normal cells. This algorithm, in particular, has been used to find a logic circuit that can specifically target cancer cells through cell-level simulations of all gene combinations. CAR-T cells equipped with logic circuits discovered through this methodology are expected to distinguish cancerous cells from normal cells like computers, thereby minimizing side effects and maximizing the effects of chemotherapy. Dr. Joonha Kwon, who is the first author of this paper, said, “this research suggests a new method that hasn’t been tried before. What’s particularly noteworthy is the process in which we found the optimal CAR cell circuit through simulations of millions of individual tumors and normal cells.” He added, “This is an innovative technology that can apply AI and computer logic circuits to immune cell engineering. It would contribute greatly to expanding CAR therapy, which is being successfully used for blood cancer, to solid cancers as well.” This research was funded by the Original Technology Development Project and Research Program for Next Generation Applied Omic of the Korea Research Foundation. Figure 1. A schematic diagram of manufacturing and administration process of CAR therapy and of cancer cell-specific dual targeting using CAR. Figure 2. Deep learning (convolutional neural networks, CNNs) algorithm for selection of dual targets based on gene combination (left) and algorithm for calculating expressing cell fractions by gene combination according to logical circuit (right).
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
Distinguished Professor Koh Donates His Ho-Am Prize Money
(From left: Distinguished Professor Gou Young Koh and KAIST President Sung-Chul Shin) Distinguished Professor Gou Young Koh from the Graduate School of Medical Science and Engineering donated one hundred million KRW to KAIST that he received for winning the Ho-Am Prize. Professor Koh, who is widely renowned for angiogenesis, was appointed as the 2018 laureate of the 28th Ho-Am Prize for demonstrating the effective reduction of tumor progression and metastasis via tumor vessel normalization. He made the donation to the Graduate School of Medical Science and Engineering, where he conducted his research. “As a basic medical scientist, it is my great honor to receive this prize for the recognition of my research outcome. I will give impetus to research for continuous development,” Professor Koh said. Professor Koh also received the 5th Asan Award in Medicine in 2012 and the 7th Kyung-Ahm Award in 2011. He was also the awardee of the 17th Wunsch Medical Award. He has donated cash prizes to the school every time he is awarded. KAIST President Sung-Chul Shin said, “I would like to express my gratitude to the professor for his generous donation to the school. It will be a great help fostering outstanding medical scientists. Professor Koh received his MD-PhD from the Medical School of Chonbuk National University. After finishing his post-doctoral program at Cornell University and Indiana State University, he was appointed as a professor at Chonbuk National University and POSTECH. Currently, he holds the position of distinguished professor at KAIST and director of the IBS Center for Vascular Research.
Professor Gou Young Koh, 2018 Laureate of Ho-Am Prize
Distinguished Professor Gou Young Koh from the Graduate School of Medical Science and Engineering was appointed a 2018 laureate in medicine of the Ho-Am Prize by the Ho-Am Foundation. Professor Koh is a renowned expert in the field of tumor angiogenesis by exploring the hidden nature of capillary and lymphatic vessels in human organs. He was recognized for demonstrating the effective reduction of tumor progression and metastasis via tumor vessel normalization. This counterintuitive study result is regarded as a stepping stone for a drug discovery to prevent microvascular diseases. Besides Professor Koh, Professor Hee Oh from Yale University (Science), Professor Nam-Gyu Park from Sungkyunkwan University (Engineering), Opera Singer Kwangchul Youn (The Arts) and Sister Carla Kang (Community Service) received awards. The Ho-Am Prize is presented to individuals who have contributed to academics, the arts, and social development, or furthered the welfare of humanity, and commemorates the noble spirit of public service espoused by the late Chairman Byung-chull Lee, who used the pen name Ho-Am. It was established in 1990 by Kun-Hee Lee, the chairman of Samsung. Awards have been presented to 143 individuals worth a total of 24.4 billion KRW.
Cooperative Tumor Cell Membrane-Targeted Phototherapy
A KAIST research team led by Professor Ji-Ho Park in the Bio and Brain Engineering Department at KAIST developed a technology for the effective treatment of cancer by delivering synthetic receptors throughout tumor tissue. The study, led by Ph.D. candidate Heegon Kim, was published online in Nature Communications on June 19. Cancer targeted therapy generally refers to therapy targeting specific molecules that are involved in the growth and generation of cancer. The targeted delivery of therapeutics using targeting agents such as antibodies or nanomaterials has improved the precision and safety of cancer therapy. However, the paucity and heterogeneity of identified molecular targets within tumors have resulted in poor and uneven distribution of targeted agents, thus compromising treatment outcomes. To solve this problem, the team constructed a cooperative targeting system in which synthetic and biological nanocomponents participate together in the tumor cell membrane-selective localization of synthetic receptors to amplify the subsequent targeting of therapeutics. Here, synthetic and biological nanocomponents refer to liposomes and extracellular vesicles, respectively. The synthetic receptors are first delivered selectively to tumor cell membranes in the perivascular region using liposomes. By hitchhiking with extracellular vesicles secreted by the cells, the synthetic receptors are transferred to neighboring cells and further spread throughout the tumor tissues where the molecular targets are limited. Hitchhiking extracellular vesicles for delivery of synthetic receptors was possible since extracellular vesicles, such as exosomes, mediate intercellular communications by transferring various biological components such as lipids, cytosolic proteins, and RNA through a membrane fusion process. They also play a supportive role in promoting tumor progression in that tumor-derived extracellular vesicles deliver oncogenic signals to normal host cells. The team showed that this tumor cell membrane-targeted delivery of synthetic receptors led to a uniform distribution of synthetic receptors throughout a tumor and subsequently led to enhanced phototherapeutic efficacy of the targeted photosensitizer. Professor Park said, “The cooperative tumor targeting system is expected to be applied in treating various diseases that are hard to target.” The research was funded by the Basic Science Research Program through the National Research Foundation funded by the Ministry of Science, ICT & Future Planning, and the National R&D Program for Cancer Control funded by the Ministry for Health and Welfare. (Ph.D. candidates Hee Gon Kim (left) and Chanhee Oh) Figure 1. A schematic of a cooperative tumor targeting system via delivery of synthetic receptors. Figure 2. A confocal microscopic image of a tumor section after cooperative targeting by synthetic receptor delivery. Green and magenta represent vessels and therapeutic agents inside a tumor respectively.
Anti-Cancer Therapy Delivering Drug to an Entire Tumor Developed
KAIST’s Department of Bio and Brain Engineering Professor Ji-Ho Park and his team successfully developed a new highly efficacious anti-cancer nanotechnology by delivering anti-cancer drugs uniformly to an entire tumor. Their research results were published in Nano Letters online on March 31, 2015. To treat inoperable tumors, anti-cancer medicine is commonly used. However, efficient drug delivery to tumor cells is often difficult, treating an entire tumor with drugs even more so. Using the existing drug delivery systems, including nanotechnology, a drug can be delivered only to tumor cells near blood vessels, leaving cells at the heart of a tumor intact. Since most drugs are injected into the bloodstream, tumor recurrence post medication is frequent. Therefore, the team used liposomes that can fuse to the cell membrane and enter the cell. Once inside liposomes the drug can travel into the bloodstream, enter tumor cells near blood vessels, where they are loaded to exosomes, which are naturally occurring nanoparticles in the body. Since exosomes can travel between cells, the drug can be delivered efficiently into inner cells of the tumor. Exosomes, which are secreted by cells that exist in the tumor microenvironment, is known to have an important role in tumor progression and metastasis since they transfer biological materials between cells. The research team started the investigation recognizing the possibility of delivering the anti-cancer drug to the entire tumor using exosomes. The team injected the light-sensitive anti-cancer drug using their new delivery technique into experimental mice. The researchers applied light to the tumor site to activate the anti-cancer treatment and analyzed a tissue sample. They observed the effects of the anti-cancer drug in the entire tumor tissue. The team’s results establish a ground-breaking foothold in drug delivery technology development that can be tailored to specific diseases by understanding its microenvironment. The work paves the way to more effective drug delivery systems for many chronic diseases, including cancer tumors that were difficult to treat due to the inability to penetrate deep into the tissue. The team is currently conducting experiments with other anti-cancer drugs, which are being developed by pharmaceutical companies, using their tumor-penetrating drug delivery nanotechnology, to identify its effects on malignant tumors. Professor Park said, “This research is the first to apply biological nanoparticles, exosomes that are continuously secreted and can transfer materials to neighboring cells, to deliver drugs directly to the heart of tumor.” Picture: Incorporation of hydrophilic and hydrophobic compounds into membrane vesicles by engineering the parental cells via synthetic liposomes.
Professor Kwang-Hyun Cho Recognzied by "Scientist of the Month" Award
Professor Kwang-Hyun Cho of KAIST’s Department of Bio and Brain Engineering received the “Scientist of the Month” award in February 2015 from the Ministry of Science, ICT, and Future Planning of the Republic of Korea and the National Research Foundation of Korea. The award was in recognition of Professor Cho’s contribution to the advanced technique of controlling the death of cancer cells based on systems biology, a convergence research in information technology (IT) and biotechnology. Professor Cho has published around 140 articles in international journals, including 34 papers in renowned science journals such as Nature, Science, and Cell in the past three years. His work also includes systems biology textbooks and many entries in international academic encyclopaedia. His field, systems biology, is a new biological research paradigm that identifies and controls the fundamental principles of organisms on a systems level. A well-known tumour suppressor protein, p53, is known to suppress abnormal cell growth and promote apoptosis of can cells, and thus was a focus of research by many scientists, but its effect has been insignificant and brought many side effects. This was due to the complex function of p53 that controls various positive and negative feedbacks. Therefore, there was a limit to understanding the protein with the existing biological approach. However, Professor Cho found the kinetic change and function of p53 via a systems biology approach. By applying IT technology to complex biological networks, he also identified the response to stress and the survival and death signal transduction pathways of cardiomyocytes and developed new control methods for cancer cells. Professor Cho said, “This award served as a momentum to turn over a new leaf.” He added, “I hope convergence research such as my field will bring more innovative ideas on the boundaries of academia.”
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.
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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