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History as a researcher, Professor Minamino
Tohru Minamino, Professor, Department of Cardiovascular Biology and Medicine Niigata University Graduate School of Medical and Dental Sciences

Introduction

I decided to research telomere and telomerase, and vascular aging when I found a review paper in a day. I do not know that was a coincidence or fate. My motto is “There is no coincidence. Carve out a career for myself not accepting my fate.” I will show you my last ten and several years of experience.

Entrance to basic Research-Internal medicine department No.3, Medical school, Tokyo
university

I received advanced clinical training as an internal cardiologist for 5 years after graduation. I was also attracted to the dynamism of clinical situation of cardiology as other people. However, I had more interests in the pathophysiology of individual diseases as I gradually got accustomed to the routine flow of clinical procedures. I was most impressed with familial dilated cardiomyopathy. In those days, it was not even certain there was a causative gene. I supposed that we could treat dilated myocardiopathy by identifying the gene. I contacted the laboratory of Professor Yoshio Yazaki, which was the center of molecular biology for cardiovascular disease and was welcomed as a research student. At first, I was to belong to the heart failure group led by Dr. Issei Komuro (current Professor at University of Tokyo) , however, was assigned to the vascular biology group of which Dr. Hiroki Kurihara (current Professor at University of Tokyo) was a chief with a recommendation of Professor Yazaki. There, I started researching on endothelin and arteriosclerosis that were widely researched all over the world.

I remember Dr. Kurihara said “Which drawer do you want?” on the first day. In those days, the laboratory of Professor Yazaki was not so wide, where about 10 persons were researching hard from morning to night in a laboratory room with area of about 11 through 16 square meters. I was given a drawer (I could own 4 drawers 3 years after). I started researching. I vividly remember I run a test on the lid of the centrifuge when I lost fighting over the laboratory tables. I possibly could complete the dissertation in the third year. I tried to find a theme for which I could spend my life trying to deal with. On one day, I came across an interesting review paper on telomerase in the library. It was an article describing that a technique was developed to allow telomerase activity to be easily measured with human cancer cells. At that time, telomerase was not identified as a molecule, however, it could be detected as an enzymatic activity. I was very interested in the review paper and decided to research telomere and telomerase, and vascular aging since then.

Start of research on aging of vessels-Harvard medical school

Telomeres exist at both ends of chromosome contributing to the stability. Regrettably, our DNA replication is not perfect and telomeres get shorter by division. When telomeres get short to some extent, the cell recognizes the shortened telomere as DNA damage inducing p53-dependent cellular senescence. Telomerase is an enzyme that adds telomeres. However, telomeres get shortened due to division for normal cells because the cells except cancer cells and stem cells have lower telomerase activity. I formed a hypothesis that aging at the cell level might cause the aging of blood vessels.

I planned to look for a laboratory abroad to start a new research. However, almost all researches on telomere at that time were performed on cancer cells and even researches on vascular aging were not performed in laboratories specializing on vascular biology. I debated whether to study vascular aging while supported in a laboratory that was famous for telomere biology or to study telomere in a laboratory of vascular biology without support. Finally, I decided to choose the latter to prove myself. Therefore, I asked Dr. Stella Kourembanas, who hosted a laboratory specializing vascular biology at Harvard Medical University, to have an interview and allow me to research telomere as a sub-theme. She was researching low oxygen, vascularization and vascular remodeling and readily agreed to receive my request. In this way, I could start the researches on “low oxygen and vascularization” and “telomere, telomerase and vascular aging.”

We were poor, however, very excited in Boston. A postdoctoral fellow receives so low wages that I was subsidized with coupons of egg and milk by the state government. A questionnaire for the subsidiary asked me whether I ate other things than foods such as paper or earth. I could conduct experiments from morning to midnight because I did not need to practice clinical service. I performed my experiments by sacrificing my days off and my family members blamed me of that. I achieved many outcomes in the second year. So, I contributed research papers, however, which were subjected to harsh criticism. A reviewer said, “Why do you need to research telomere or telomerase on vessels?” putting it too bluntly. Post bubble recession trailed on in Japan toward the end of the third year in the US. My father ran a company, which was suffering from the recession. So, I decide to return to Japan.

(Photo taken near Boston where I lived)

Research on aging and regeneration of vessels after returning to Japan - Respiratory and Cardiovascular Medicine, Graduate School of Medicine, Chiba university

In the earlier days after returning to Japan, I worked for an affiliated hospital of Chiba University that is my alma mater. I got kind of nervous about catheter intervention that I performed after several years of interval, however, it was very joyful. I almost gave up the research on vascular aging because I could not have been able to get very far with it during three years of the research in the US. I performed angioplasty on patients who was rushed to hospital every day, however, they are always re-hospitalized due to angina or myocardial infarction caused by other vascular lesions. In those situation, I recognized I should develop an innovative therapy. Around that time, my research papers on telomere, telomerase and vascular aging1) that have been hardly accepted were received at last. So, I decided to fortify my resolve to restart the research on vascular aging. I kept on researching half a day per week in one of those gaps-between-catheter examinations. Afterward, I kept on contributing research articles on works in the US with patience. I could obtain two publications for “Low oxygen and vascularization” and “Telomere, telomerase and vascular aging”2,3) .

After returning to Chiba University, I continued the research on vascular aging and vascularization with permission by Professor Komuro who had just moved from University of Tokyo. At that time, researches on telomere in vessels and cellular senescence are being recognized in the world and I published that telomere-dependent senescence is important for vascular aging4,5) and telomere-independent aging signals (angiotensin II and insulin signals) are also important for vascular aging6,7) after returning to the university. When I think that the research paper on heart failure that was accepted by Nature for the first time had contents that combine two themes (low oxygen and p53) that I had in the US, I am overcome by deep emotion8) . After that, I am delighted that I could contribute the data that telomere is related with diabetes to Nat Med9) . Taking the fact that I could continue the research owing to many people into heart, I want to work hard aiming at further meaningful researches.

Conclusion

There are unlimited number of fields of medical research for basic and clinic basis. However, I think it is important to well improve ourselves in a filed, i.e., the path to take. It is also important that we should meet the hardship recognizing we cannot change the fate. It will be a real pleasure for me to send such a message through this essay.

references

1)
Minamino T, Mitsialis SA, Kourembanas S: Hypoxia extends the life span of vascular smooth muscle cells through telomerase activation. Mol Cell Biol. 21: 3336-3342, 2001.
2)
Minamino T, Christou H, Hsieh CM et al: Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Natl Acad Sci U S A. 98: 8798-8803, 2001.
3)
Minamino T, Kourembanas S: Mechanisms of telomerase induction during vascular smooth muscle cell proliferation. Circ Res. 89: 237-243, 2001.
4)
Minamino T, Miyauchi H, Yoshida T et al: Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation. 105: 1541-1544, 2002.
5)
Minamino T, Komuro I: Vascular aging: insights from studies on cellular senescence, stem cell aging, and progeroid syndromes. Nat Clin Pract Cardiovasc Med. 5: 637-648, 2008.
6)
Kunieda T, Minamino T, Nishi J et al: Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway. Circulation. 114: 953-960, 2006.
7)
Miyauchi H, Minamino T, Tateno K et al: Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway. Embo J. 23: 212-220, 2004.
8)
Sano M, Minamino T, Toko H et al: p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature. 446: 444-448, 2007.
9)
Minamino T, Orimo M, Shimizu I et al: A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med. 15: 1082-1087, 2009.