Contact: Moonsuk Seon Institution: DGIST(Daegu Gyeongbuk Institute of Science and Technology)
This is Part 1 of an article written by Sang Chul Park, chair professor at Daegu Gyeongbuk Institute of Science & Technology (DGIST) and the Well Aging Research Center in South Korea. Sang Chul Park discusses about aging revolution, pursuit for human longevity and well aging.
The first written epic of human kind, the Gilgamesh story in Mesopotamian myths tells us the recklessness and futility of pursuing immortality. Nevertheless, my lifelong ambition has been never changed but to reveal and manipulate the mystery of definiteness, limitation and mortality of life. When I read the famous Homer’s Odyssey in high school days, the agony of Odysseus to sail between Scylla and Charybdis was not appealing to me. Only after grown up, the presence of perils and hazards in either side of life aroused me to ponder on its significance. And I come to realize what I could do at such a situation is nothing but to choose the some better. My journey of scientific research was not far from such a sailing. I have been enforced to sail between cumbrous questions of life and death, immortality and mortality, irreversibility and reversibility. Despite uncertainty ahead, I have marched pompously forward with the words of Ernest Hemingway in his famous book of Old Man and Sea, which has been always ringing a bell to my ears, “A man can be destroyed, but never defeated”. In this essay, why, what and how of my voyage on aging research have been proceeded will be introduced in sequence of my life.
Dreams and Pains for Growing
My first and serious conflict was to determine what to do for my lifelong mission after graduation from Seoul National University Medical School (SNUMC) in 1973. In those days, frankly speaking, my country Korea was yet suffering from scars and aftermath of the Korean War, and the University was barely equipped with facilities and experts. Nonetheless, I had a belief that the basic fundamental approach for life should be essential and utmost requiring, for which Biochemistry would be the right direction, to which I must devote myself. Thereafter, my graduate days of Sturm und Drang began with dream and ambition. But the reality was not so simple. In the Department of Biochemistry of SNUMC, there were three professors of different expertise, while I was the only one assistant in the whole Department, who joined the Department for the first time after 15 years of vacancy as MD graduate. Thereby, my duty was to support all three professors together. Consequently from morning till night every day, I had to hurry and rush for this and that, assisting not only for teaching but for experiments. Professor Ki Young Lee, the founder of Korean Society of Biochemistry, worked for comparison of base ratio of nucleic acids from varying animals and plants; Professor Seung Won Kim majored in enzymology and metabolic regulation; Professor Bum Suck Tchai carried out the nutritional survey for children. My ineludible participation into all of those works allowed me to glimpse and taste the varying technologies and ideas of versatile fields. Though those days were terribly busy, hard and complicated, yet to my memory it was a fortune to be able to learn and acquire the philosophy of comparison, change and care. Ever after, these principle influenced me strongly to have more integrative thinking and interactive concepts on science and human beings: compare of cancer and aging, young and old, city and country; change from normal to cancer, from young to old; care for sick, old and poor, which have been always lingering around in my mind and aroused me to be keen.
After graduate days, I had to admit to Korean Navy as a military medical officer for three years to do my military duty. During military period, my jobs were to optimize and modernize many protocols of training and living of military members, used to simply follow the hackneyed US military system, and to establish the marine research institute for healthcare and training system for crews of ships and submarines and to monitor the water pollution of sea and vessels. These totally unacquainted experiences led me to open eyes to diversity of strange and exotic worlds.
Then I crossed the Pacific to work as the postdoctorate fellow at Laboratory of Biochemistry, in NHLBI, NIH (National Heart Lung Blood Institute, National Institutes of Health), led by Dr. Earl Stadtman. In this laboratory, my eyes were clearly washed and the delights of research penetrated into my heart. My mission was to complete the unique and elaborate glutamine synthetase (GS) system for its nitrogen sensing and control mechanism in E.coli under Dr. Sue Goo Rhee’s guidance. The GS system is consisted with glutamine synthetase(glnA ), adenylyl transferase(glnE ), PII protein(glnB ), and uridylyl transferase(glnD ). I could successfully clone and characterize the uridylyl transferase, the ultimate regulator of GS system. Through characterization of this enzyme, GS system could be completed and the mystery of genetic and metabolic regulation of nitrogen sensing and utilization could be figured out as the TriCyclic Cascade system. These works led me to understand the harmony of genetic and metabolic control, the biological beauty of sensing and integrity, and the significance of relativity and ratio of biomolecules. This well balanced integration of signals of metabolism and genetics for amplification and efficiency to maintain and flourish the life enlightens me the holiness and grandeur of life.
Moreover, the days at NIH let me open my eyes to aging research, because Dr. Earl Stadtman was the right person who discovered the protein oxidation by oxidative stress and initiated the protein works in aging research. At that time, my mission was not directly related with protein oxidation, but I could join all the discussion with those members working at the front on aging related protein oxidation, protein stability and other aging-related projects. Therefore, I am deeply indebted to Dr. Earl Stadtman for my basic concept on aging and later aging research.
No Way but Cancer: Challenge to Multistep Carcinogenesis
Returning back to SNU in 1984, I was obliged to establish my own laboratory, since my professors were twenty and more years senior to me, preparing for retirement. With very limited resources, I was in terrible situation what to do and how to do, which forced me to decide the simple and clear target rather than elaborate but expensive works of beautiful biochemistry. Since I had done the survey and screening of the mutagens in Korean favorite foods for my PhD thesis works, cancer related projects were more convenient to me at that time. Moreover, the highest morbidity and mortality of the digestive organ cancers such as stomach cancer and hepatoma in Korean population provided me a good excuse for cancer research. I adopted Ames test for mutagen screening and carried out broad survey of raw and cooked food materials altogether. With this approach, I could discriminate the good and bad food materials and cooking process of Korean traditional diets. Thereby, it was natural for me to participate in nutrition and food societies as well as to be involved in the public health education. But my desire was not for screening but for mechanism.
As a Biochemist, the essential molecular mechanism is the goal to achieve. My works on cancer were extended to elucidate the mechanism of cancer generation, why cancer cells are immortal and how the normal cells can be transformed to gain the immortality. At that time, there were no idea at all on telomere and stem cell, and only primitive concept of oncogenes. I preferred the stepwise transformation, consisted with multi steps, rather than to the abrupt certain single step effect, because my hunch on life process was based on gradual stepwise changes as in metabolic pathway. I presumed that cancer must be similar not exceptional. I started the animal experiments with chemical-induced mammary cancer models, in which cancers could be readily induced by single IV or per os treatment of NMU (N-methylnitrosourea) or DMBA (7,12 dimethyl benzanthracene)(8). With this model system, I tried to reveal the mechanism for multistep carcinogenesis of initiation, promotion and progression.
During the time, I was happy and fortunate to be acquainted with my dear lifelong Japanese master, Dr. Hirota Fujiki of National Cancer Center, who discovered so many tumor promoters, such as Okadaic acid, Teleocidin and Nodularin, etc. Later, he moved to Saitama Cancer Institute and then to Tokushima Bunri University. He kindly introduced me to the global cancer society and provided me with so many precious information and supports, which shall not be forgotten in my life. Together with him and Professor In Kyoung Lim, we organized Korea-Japan Cancer Research Group and later Korea-Japan Cancer and Aging Scientists Meeting until now for more than 30 years consecutively with 12 more biannual international conferences and Journal of Cancer Research and Clinical Oncology meeting reports.
It was the success of friendship between Korea and Japan and also between him and me along with all of our colleagues. Since from Dr. Fujiki’s works, the importance of tumor promotion step was realized, I did follow the assumption that inhibition or blockage of this promotion step would be the best way for cancer prevention.
Thereby, I paid a special attention on the preneoplastic stage of carcinogenesis, because this step is prior to cancerous status, which might be in reversible state. It might be significant and of use to develop the tools and methods to adjust the carcinogenesis step back to normal status by intervening this stage. I tried to develop the markers and methods for identifying and to screen and test the blocking or inhibiting substances against preneoplastic changes or looking for any possibility of restoring or reversing the preneoplastic lesion. If cancer is one way program for immortality, at what stage of carcinogenesis, the immortality is gained? And for such changes, what could be the biochemical markers? I presumed that this kind of one way phenomenon must be based on certain biochemical irreversible mechanism, which was very intriguing to me.
During this period, thanks to my frontier experience of cloning and overproduction of genes with genetic engineering tools at NIH, I was invited to SNU Institute of Molecular Biology and Genetics as the founding member and also participated as one of the core organizers for the Korean Society of Molecular Biology (which later become Korean Society of Molecular and Cellular Biology), which is now the biggest and most active biological society in Korea.
Crosslinking as a Bridge of Cancer to Aging: From Immortality to Mortality
Dealing with preneoplastic lesion, I was preoccupied by the concept of biochemical switch on and off for biological reversibility. For the on/off mechanism, I supposed the requirement of some structural fixation of molecules for one way process, which must not be reversible. I picked up enzymatic crosslinking by transglutaminases (TGase) as the candidate mechanism for biochemical irreversibility, since it was known that the isopeptide linkage formed by TGase could not be degraded by any known proteolytic enzymes. At that time, proteasome and autophagy system were far beyond our knowledge. There have been already many reports of the increased non-enzymatic crosslinking of the biomolecules in aging, implicating their responsibility for degenerate change. However, I preferred the enzymatic crosslinking to non-enzymatic crosslinking, because enzymatic control needs not only the genetic but also metabolic regulation, while nonenzymatic mechanism would be totally dependent on random event. It was not conceivable at that time to me that the nature allows randomness to control the life process. With this enzyme as the target, a spectrum of works such as discovery and purification of new isozyme TGase 3 from human skin, and its relation with apoptosis, dystrophy, and exercise had been performed. For the research, I visited and met Dr. Ron Sooil Chung and Dr. Peter Steinert of NIH to get the information and for collaboration.
Meanwhile, my group has obtained an interesting result that TGase activity is highly increased in aging tissues, while cancer and growing tissues have low activities of TGases. Increased activity of TGase with aging attracted me to concern about aging. Why and how enzymatic crosslinking activity is increased in aging? Is there any possibility to block aging by inhibiting this crosslinking activity? I was thrilled and decided to devote all my efforts to aging research. And at the same time, since I was in trouble with my personal abhorrence to develop transgenic or knockout mice for confirming oncogene effect, I was seriously looking for shifting the theme of my research, which would not require heavy genetic manipulation. In that aspect, aging research was much better and more agreeable to me than cancer research, and fortunately crosslinking TGase formed a bridge for me to cross cancer research to join aging research.
Thereafter, I started to participate in international aging research meetings and learned the Strehler’s 4 principle of irreversibility, inevitability, degeneracy and universality for aging. The concept that lifespan can be defined by aging process attracted me strongly. If aging is the one-way program for mortality, what are the biochemical fixatives for aging process? And what would be the essential biochemical parameters to discriminate mortality and immortality, in other words, cancer and aging? For the question, I assumed the enzymatic crosslinking hypothesis of aging. The evidence that the TGase activity increases with aging would not suffice the theory. Thereby, TGase knock out or deletion experiment was expected to clarify the role of TGase in aging process. But it was not. Phenotypic defect was limited, indicating that TGase would not be sufficiently functional for aging. The results were very disappointing and pushed me back into labyrinth of aging. If not crosslinking, what would be the most significant pathognomonic change of cancer, normal and aging status?