Successful cardiac cell implantation into a living heart

“Back in the 1980s, my professor said that by conducting research in basic medical sciences, we could identify the fundamental causes of diseases and develop new therapeutic strategies, and that this would eventually help us treat patients with intractable diseases. He was a huge inspiration to me, and that is primarily the reason why I decided to pursue a career in this field,” said Director Koh. He received the 17th Wunsch Medical Award from the Korean Academy of Medical Sciences and Boehringer Ingelheim Korea in 2007, almost a decade after Kyung Woo Cho, his professor at Chonbuk National University Medical School, received the same award.
When Director Koh was an undergraduate medical student, he would conduct various experiments in a laboratory using white mice, microscopes and pipettes. During his graduate course work, he did research on how urine is produced by kidneys. He expressed his passion for and difficulties in the experiments by saying, “In those days, I used to conduct the mouth-pipetting of capillaries to analyze the composition of urine. I did the pipetting so many times that my eardrum once split.” After finishing his military duty as a flight surgeon at the Republic of Korea Air Force Academy, Director Koh began his post-doctoral course in the U.S. He said, “At first, I worked as a research fellow at Cornell University, where I attended seminars rather than conducting experiments. After that, I became a research associate at Indiana University and conducted a lot of experiments on cell implantation.” At Indiana University’s Krannert Institute of Cardiology, Director Koh’s first research topic was to demonstrate that the cells implanted into the heart of a living mouse are alive after the implantation. He said, “After countless trials and errors for nine months, we succeeded in cardiac cell implantation for cardiac regeneration.” Since finding success in that experiment, which was very challenging at that time and essential for the regeneration of heart tissue, Director Koh has succeeded in subsequent experiments on implanting stem cells and muscle cells for three years, during which he has achieved considerable outcomes as a researcher, according to him. The outcomes resulted in a patent, which has earned him an annual royalty of about 5,000 U.S. dollars for over 20 years.
In 1995, Director Koh became a professor at Chonbuk National University Medical School, his alma mater, and in three years, his research project was recognized as a form of Creative Research and acquired funding from the National Research Foundation of Korea (NRF). His project has taken many twists and turns since its inception: the zebrafish that were supposed to be used in cardiac muscle regeneration experiments all died because of poor breeding farm conditions. Moreover, it was difficult to recruit other researchers: no medical graduate students applied, and a clinical pathologist, an archeology major and so forth participated in the research. The research group discovered angiogensis promoting factors by culturing vascular endothelial cells in the umbilical cord and focused their research on the factors’ mechanisms. Director Koh said, “Thanks to our use of more than 7,000 umbilical cords and the Creative Research fund, we could publish a quality paper and create a good reputation for ourselves.”

“COMP-Ang1” distributed to researchers in other countries

(Director Koh talks with one of his researchers who is looking into
blood vessels of white mice.)

Director Koh is a highly established scientist in the field of vascular biology. The generation, differentiation, and regeneration of the blood vessels are fundamental to maintaining life. He has been thrust into the global spotlight for identifying angiogenesis-promoting proteins and their mechanisms.
Director Koh said, “I still vividly remember when we succeeded in developing COMP-Ang1, an angiogenesis-promoting protein, and shared the results and substances with researchers in other countries. As a result, my research has become widely known, and our research group has been recognized globally for pioneering research in the field of angiogenesis.” Director Koh focused on Ang1, a type of angiopoietin (Ang) that is a key regulator of angiogenesis. The problem with using Ang1 proteins was that they were viscous and insoluble in water, resulting in clumping. Director Koh newly designed the protein structure and succeeded in producing COMPAng1. The new proteins were water-soluble and did not clump together, as well as providing stable effects. An animal study showed that COMP-Ang1 healed vascular wounds more rapidly by promoting angiogenesis and induced the mitigation of inflammation by reducing the production of inflammatory substances.
Director Koh said, “Following the development of COMP-Ang1 after many twists and turns, I presented the outcomes of the research by publishing two consecutive papers in the U.S. Proceedings of the National Academy of Sciences (PNAS), and I was flooded with emails from researchers in the field, asking me to send them the COPAng1 protein.”
He also said, “Although some researchers published better papers using COMP-Ang1, we came to be a global leading group in this field by having contributed to unveiling the important mechanisms of angiogenesis through the use of COMP-Ang1 for five to ten years.” COMP-Ang1, which plays an important role in angiogenesis, has become a key substance in the field of vascular biology.
Director Koh is frequently invited as a keynote lecturer to academic societies in the field of angiogenesis. Also, he edits journals in related fields: he has been serving as a member of the editorial board of Blood, one of the world’s most prestigious hematology journals published by the American Society of Hematology; and he has recently joined the editorial board of Cancer Research, one of the major cancer journals published by the American Association for Cancer Research.

“DAPP,” a new solution for inhibiting tumor angiogenesis

Director Koh has conducted intensive research on tumor angiogenesis. To accelerate its growth, a tumor stimulates blood vessel generation to obtain sufficient oxygen and nutrients. These new vessels are used to feed tumor cells with nutrients and also to spread them around the body. Recently, a vascular targeting therapy has emerged as a popular anticancer therapeutic option. Unlike traditional therapies, which directly attack tumor cells, this new therapy targets tumor vessels. It cuts off pathways that deliver nutrients and spread tumor cells, thus starving the cells to death or inhibiting metastasis.
Director Koh and his research group developed a new molecular substance, which can simultaneously bind vascular endothelial growth factor A (VEGF-A) and angiopoietin-2 (Ang2), effectively blocking their actions. They named the substance “double anti-angiogenic protein (DAPP)” and the acronym is pronounced /dap/, which evokes a Korean word that means a “solution” to a problem. In fact, the tumor sizes of DAAP-administered laboratory animals have been conspicuously reduced and DAPP has shown better anticancer effects than traditional anti-angiogenic proteins. Based on the research results about this new candidate drug substance, Korean and overseas pharmaceutical companies have begun producing DAAP-containing drugs for clinical trials.
Last year, Director Koh’s research group identified that a RhoJ protein is highly expressed in tumor vessels and plays a critical role in tumor angiogenesis and vessel integrity. It was confirmed that blocking the RhoJ expression of the mice with cancer resulted in the disruption of intratumoral vessels and the inhibition of the growth of peritumoral vessels. If a therapeutic agent for the RhoJ blockade is developed, it will provide a “double assault” on tumor vessels, both against intratumoral vessels that maintain tumor cells and peritumoral vessels that are involved in tumor growth.
Director Koh has unveiled the roles of essential proteins in tumor angiogenesis and vessel integrity, thereby paving the way for the development of new therapeutic options. In recognition of his achievement in this field, Director Koh received the 2012 Asan Medical Award from the Asan Foundation.

1. The formation of the blood vessels (red) during the early stages of pregnancy in the uterus, with the embryo colored in green. In order to produce efficient amount of bloody supply, a variety of blood vessels including thin and large vessels are concurrently formed.
2. The appearance of blood vessel network (green) in the postnatal retina. Arteries, veins, and capillaries are well aligned along the retina. Newly formed tip cells (yellow) in the peripheral end of the blood vessels could be observed.

Research on the blood vessels of different organs as well as lymphatic vessels

Three to four years ago, Director Koh started basic research on the generation, differentiation, aging, integrity, and regeneration of the blood vessels in different organs such as the eye, thyroid glands, lungs, intestines, uterus and adipose tissues. 80~90% of the graduate students under his direction and supervision were house staff from various hospital departments and were participating in Director Koh’s research as part of their mandatory military service. Based on this diversity, they could conduct in-depth research on the blood vessels of individual organs on the molecular and cellular levels after completing a short-term training program. In doing such pioneering research, the Center for Vascular Research is able to fiercely compete with some of the American and European institutes including Germany’s Max Planck Institute for Molecular Biomedicine. Director Koh explained in more detail why blood vessels are important in the therapeutic treatment. “Each organ undergoes different processes in terms of the generation, differentiation, and reconstruction of blood vessels, and each blood vessel contains different conditions as they are involved in different types of homeostasis or diseases such as tumors and infections. We can gain insight regarding efficient vascular regeneration, as well as therapeutic strategies for vascular diseases by conducting research on the generation, differentiation, integrity, and modulation of different blood vessels depending on each organ’s type of homeostasis or disease.” In addition, Director Koh is interested in exploring the roles of lymphatic vessels and pericytes. Blood vessels and lymphatic vessels are considered the water and sewer pipes of the human body. He said, “There are approximately 600 lymph nodes in the human body. Pathogenic viruses and bacteria, immune cells, and tumor cells travel through lymphatic vessels scattered throughout the body and arrive at lymph nodes, leading to immune responses.” He added, “I am planning to conduct research focused on the roles of lymphatic vessels when immune cells interact with antigens in lymph nodes.” The role of pericytes is another topic to be explored. Pericytes wrap around endothelial cells in capillaries where the exchange of gases, nutrients, and waste takes place. Recent findings indicate that they contribute to the differentiation and integrity of blood vessels by secreting special kinds of molecular substances. Moreover, the Center for Vascular Research plans to embark on the demanding task of bioimaging secreted molecular substances. Director Koh said, “Using the images, we are planning to observe how secreted substances, such as capillary hormones and growth hormones, enter blood vessels and modulate them. To do that, we will collaborate with bioimaging researchers to develop effective methods such as the fluorescent staining of the substances.” The Center plans to conduct cardiovascular research as well. Emphasizing that the heart is a part of the blood vessels, Director Koh explained, “The pathogenic role of blood vessels is critical in cardiovascular diseases. Even when implanting myocardial stem cells, angiogenesis must take place simultaneously.” When he was a research associate at the Krannert Institute of Cardiology, Indiana University, Director Koh carried out a successful trial of cardiac cell implantation for cardiac regeneration, which was the first time it had been done in the world. These series of successful implantations of cardiac stem cells and muscle cells has laid the foundation for myocardial regeneration research using stem cells for the past 20 years. Myocardial regeneration research using stem cells is a highly competitive global field. Director Koh said, “For the next ten years, I will conduct basic research to generate cardiac stem cells appropriate for myocardial regeneration and identify their characteristics, and at the same time I will undertake applied research to develop efficient implantation methods.”

Director Koh with his researchers. With his ambition to make the Center for Vascular Research a world-class research center, Director Koh suggested the establishment of a joint lab with the Max Planck Institute for Molecular Biomedicine in Münster, Germany.

Suggestion: a joint lab with the Max Planck Institute for Molecular Biomedicine

Having a desire to develop new drugs, Director Koh has long stressed the importance of the bioindustry. Some experts call the industry “the Fourth Wave” and estimate that by 2030, the global antibody drug market will reach about 500 trillion Korean won (approximately 423 billion U.S. dollars). Director Koh said, “The development of protein therapeutics is the biggest field. Because basic research in this field is highly likely to find its application, we are participating, directly and indirectly, mortality rate of sepsis is expected to drastically decrease. Recently, we have developed an antibody for protecting vascular endothelial cells from pathogen-induced damages through collaborative research.”
Finally, Director Koh expressed his ambitious plan to make the Center for Vascular Research a world-class research center. He said, “We will conduct research that will not only enhance national prestige but also add to the Center’s reputation through outstanding discoveries that have the potential to transform the research paradigm.” He also said, “I hope that researchers from all over the world come to work with us. I would like to bring together excellent researchers and make a new breakthrough in the field.” Specifically, he suggested the establishment of a joint lab with the Max Planck Institute for Molecular Biomedicine in Münster, Germany. There are about 85 different Max Planck Institutes, approximately one-third of which conduct research in the biomedical field. Currently, Director Koh is conducting collaborative research and information exchanges with three to four senior-level researchers of the Institute.