1 http://ees.elsevier.com/jmcc/default.asp for online submission of manuscripts Heart News and views Volume 17, Number 3, 2010 www.ishrworld.org the news Bulletin of the International Society for heart research In this issue: XX World Congress of the ISHR . . . . . . . . . . . . . . . . . . . . . . . . 1 Past Truth & Present Poetry, by Richard J. Bing . . . . . . . . . . . . . 7 President's Letter . . . . . . . . . . . . . 9 Report on Australasian Section Meeting . . . . . . . . . . . . . . . 11 Death and Senescence, by Issei Komuro . . . . . . . . . . . . . . 14 Meetings Calendar . . . . . . . . . . . . 15 T he countdown for the World Congress has started. We have only two months before the big event for our Society. I am greatly honored to inform you that over seven hundred abstracts were submitted, and we have accepted 706 presentations for moderated poster sessions. All of the abstracts report a high quality of research; there is no doubt that the meeting in Kyoto will be successful and exciting. As I noted in the previous issue of this newsletter, the Scientific Program comprises 50 symposia; including 11 Section-sponsored symposia, all of which are excellently composed to cover the wide scope of cardiovascular research interests. I would like to thank all of the members of the scientific program committees (SPCs) (the ISHR SPC, the CongressSPC, the International Advisory Committee, the Local Advisory Committee and the Section Executive Committee) for their dedicated efforts to make the program so exciting. Indeed, the programs of the symposia integrate presentations addressing topics ranging from gene to life and diseases under the main theme of “Paradigm Shift to Integrated Cardiology – Gene, function and life”. Meeting participants can also enjoy many Award lectures, a Nobel laureate lecture and an invited special lecture as highlights of the scientific program. Furthermore, the early carrier researcher (ECR) workshop and morning sessions for young researchers are set up to provide many learning opportunities. We also look forward to the active participation of early career investigators in the Richard Bing YIA Award and Poster Awards. In the evening, meeting participants will enjoy a get-together, a delicious Banquet, and satellite sessions focusing on new cardiovascular drugs. Kyoto holds a very special place in Japanese culture; it was the old capital for more than 1000 years, and thus offers a vast choice of activities for visitors involving the arts, entertainment, cuisine and fashion. You can enjoy a visit to many famous temples and shrines, and I arranged a special outing for you to enjoy the Aoi-Festival on May 15 th as a half- day excursion. Don’t miss this big event, the most solemn and graceful festival in our country. I promise a memorable and rewarding experience to all attendees. Please register now if you have not yet done so. For Congress information, visit our website at www.ishr2010.com. I look forward to seeing you in Kyoto soon. Masatsugu Hori, MD, PhD President, XX World Congress of ISHR countdown for world congress xx has started
The countdown for the World Congress has started. We have only two monthsbefore the big event for our Society. I am greatly honored to inform you thatover seven hundred abstracts were submitted, and we have accepted 706
presentations for moderated poster sessions. All of the abstracts report a high qualityof research; there is no doubt that the meeting in Kyoto will be successful and exciting.As I noted in the previous issue of this newsletter, the Scientific Program comprises50 symposia; including 11 Section-sponsored symposia, all of which are excellentlycomposed to cover the wide scope of cardiovascular research interests. I would liketo thank all of the members of the scientific program committees (SPCs) (the ISHR SPC,the CongressSPC, the International Advisory Committee, the Local Advisory Committeeand the Section Executive Committee) for their dedicated efforts to make the programso exciting. Indeed, the programs of the symposia integrate presentations addressingtopics ranging from gene to life and diseases under the main theme of “Paradigm Shiftto Integrated Cardiology – Gene, function and life”.
Meeting participants can also enjoy many Award lectures, a Nobel laureatelecture and an invited special lecture as highlights of the scientific program. Furthermore,the early carrier researcher (ECR) workshop and morning sessions for young researchersare set up to provide many learning opportunities. We also look forward to the activeparticipation of early career investigators in the Richard Bing YIA Award and PosterAwards. In the evening, meeting participants will enjoy a get-together, a deliciousBanquet, and satellite sessions focusing on new cardiovascular drugs.
Kyoto holds a very special place in Japanese culture; it was the old capital formore than 1000 years, and thus offers a vast choice of activities for visitors involvingthe arts, entertainment, cuisine and fashion. You can enjoy a visit to many famoustemples and shrines, and I arranged a special outingfor you to enjoy the Aoi-Festival on May 15th as a half-day excursion. Don’t miss this big event, the mostsolemn and graceful festival in our country. I promisea memorable and rewarding experience to all attendees.Please register now if you have not yet done so. ForCongress information, visit our website atwww.ishr2010.com. I look forward to seeing you inKyoto soon.
Masatsugu Hori, MD, PhDPresident, XX World Congress of ISHR
Nobel Laureate LectureNLL. Oliver Smithies (University of North Carolina at Chapel Hill, USA)
“Turning pages: from gels to genes”
Special LectureSL. Shinya Yamanaka (Kyoto University, Japan)
“Induction of pluripotency by defined factors”
Award LecturesDistinguished Lecture Awards:
Keith Reimer Distinguished Lecture Award (KRDLA)“Phenotypic responses due to induced genetic ablation of cMyBP-C in adult mice”
Richard L. Moss (University of Wisconsin, USA)Janice Pfeffer Distinguished Lecture Award (JPDLA)“Regulation of myocardial growth and death by oxidative stress”
Junichi Sadoshima (University of Medicine and Dentistry of New Jersey, USA)President’s Distinguished Lecture Award (PDLA)“A novel molecular mechanism and regeneration therapy for heart failure”
Issei Komuro (Chiba University/Osaka University, Japan)Outstanding Investigator Award (OIA)“Thrombospondin4 is a novel regulator of ER stress adaptation and cardioprotection”
Jeffery D. Molkentin (Cincinnati Children’s Hospital Medical Center, USA)Research Achievement Award (RAA)“20 years of changing the heart: to the sarcomere and beyond”
Jeffrey Robbins (Cincinnati Children’s Hospital Medical Center, USA)Peter Harris Distinguished Scientist Award (PHDSA)“Protecting the ischemic heart”
James M. Downey (University of South Alabama, USA)
SymposiaS1. Thrombus and anti-platelet treatment for ischemic heart diseaseS2. Cardio-renal interaction in heart failureS3. Genetic background of lethal arrhythmiaS4. Mitochondria in cell life and deathS5. Calcium signaling in cardiac dysfunction, cell death and remodellingS6. MicroRNAs in cardiovascular development and disease
Invitation to XX World Congress ISHR May 13–16, 2010 in Kyoto, Japan
You are cordially invited to join us in Kyoto. We promise a memorableand rewarding experience to all attendees.
200 outstanding speakers are invited for 50 symposia oncardiovascular science under the theme “Paradigm Shift to IntegratedCardiology-Gene, Function and Life”Over 700 abstracts submitted for free communications!Nobel Laureate lecture, special lecture and ISHR Award lectures asthe highlights of the Congress
Register now! Early bird registration is until March 31, 2010.
Masatsugu Hori, MD, PhD, FISHRPresident, XXth World Congress of the ISHR
President, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
5
S7. Signaling survivalS8. Myocardial stress: ROS, ischemia and inotropyS9. Pathophysiology and treatment of diastolic heart failureS10. Pathophysiology of pulmonary hypertension and right heart failureS11. Lipid metabolism and atherosclerosisS12. Mitochondria in myocardial ischemia and reperfusionS13. Sodium homeostasis and cardiac functionS14. Genetic mechanisms of myocardial diseaseS15. Mechanisms of cardiac electrical and mechanical dysfunction and repairS16. Calcium handling and signaling proteins: regulation and dysregulationS17. Vulnerable plaque and aborted rupture (including; RAS)S18. Genetic background in agingS19. The race for the implantable cardiomyocyte: who is winning?S20. Cardioprotective interventions in acute ischemiaS21. Toll-like receptors, heat shock, inflammation and the heartS22. Sarcomeric signals in health and cardiac diseaseS23. Influence of major cardiovascular risk factors on cardioprotective mechanismsS24. New strategies for stem cell therapy and vascular generationS25. RAAS activation and remodeling of the failing heartS26. Vascular endothelial function and cardiovascular eventsS27. Stem cell fate determination (Kaito Symposium in Memory of Yoshio Ito (ISHR President 1989-92))S28. Emerging therapeutic approaches in ischemic heart diseaseS29. Novel protein signaling mechanisms in the heartS30. Modulation of myocardial contraction by modification of sarcomeric proteinsS31. Animal models of hypertrophy and failure: what have we learned?S32. Diabetes and atherosclerosisS33. Mechanistic insight for better management of hypertensionS34. Use of stem cells to repair infarcted myocardiumS35. Novel effectors and modulators in cardiac hypertrophy and failure (Bayer Yakuhin Symposium in Memory of Howard E. Morgan (ISHR President 1983-86))S36. Nitric oxide signaling in the cardiovascular systemS38. Eicosanoids and vascular functionS39. Novel approaches for treatment of heart failureS40. Novel insights in adipocytokins and cardiovascular diseaseS41. Tissue engineering for the heartS42. Protein processing and quality controlS43. p38 MAPK inhibition in myocardial infarction and remodelling: beside the bedside?S44. Protection from cardiovascular injuryS45. Mechano-transduction and vascular biologyS46. Novel anticoagulant treatment for atrial fibrillationS47. Molecular mechanisms of myocarditis and heart failureS48. Vascular injury, repair and regeneration (Canon Symposium in Memory of Normal R. Alpert (JMCC Editor 1993-98))S49. Mechanisms of redox signalingS50. Cancer versus heart disease: can we cure both?
Tutorial SessionsTS1. How to apply imaging techniques to explore cardiovascular signalingTS2. JMCC Early Career Workshop “Publishing and its Perils”TS3. Career Development WorkshopTS4. How to apply mass spectrometry to heart research
Satellite SeminarsSS1. New drugs and diagnostic biomarkers for cardiovascular diseasesSS2. Promising future drugs for cardiovascular diseases
ISHR Section Meetings
6
■ REGISTRATION
- All participants are requested to register for the Congress.
- Advance registration at a special rate is available until Wednesday, March 31, 2010.
Registration fee (per person):
Category Until Wednesday, March 31, 2010 After Thursday, April 1 till Sunday, May 3, 2010/On-site
ISHR members ￥50,000 ￥60,000
Non-ISHR members ￥60,000 ￥70,000
Students* ￥ 5,000
Medical staffs (non-physicians)* ￥10,000
Accompanying persons ￥10,000
* Student registration: To qualify for these rates, the registrant must be (a) a member of the ISHR (member-ship applications may be submitted through Section secretaries or online - see the ISHR web pages at www.ishrworld.org), (b) enrolled in an official training program (e.g. PhD studentship) at his/her institutions at the time of the Congress. Written certification or copy of student ID confirming must be provided by the
registrant’ s Head of Department or equivalent.
Registration includes:
1) Admission to the get-together reception (May 13), banquet (May 15), all scientific programs and
the Commercial Exhibition
2) A book of abstracts and a program booklet
3) Admission to all morning tutorial seminars, luncheon seminars and satellite seminars
4) Aoi Festival half-day excursion (May 15)
How to register:
- Registration for the Congress should proceed only ONLINE. By completing the registration,
hotel & tour reservations can be made.
Deadline of advance registration: Wednesday, March 31, 2010
＊After Thursday, April 1 till Sunday, May 3, 2010, registration can be made at the on-site registration rate.
Note: Those whose abstracts are accepted are requested to register for the Congress with the remittance of the registration fee before Wednesday, March 31, 2010. Otherwise, the abstracts cannot be
included in the program.
Registration includes:
■ SOCIAL PROGRAMS
Get-together reception:
Date Thursday, May 13, 18:40Place Swan Banquet Hall, Kyoto International Conference Center
Aoi Festival half-day excursion:
Date Saturday, May 15, a.m.
Banquet:
Date Saturday, May 15, 18:20Place Swan Banquet Hall & Garden, Kyoto International Conference Center *Buffet style/Dress informal
Aoi Festival half-day excursion:
7
Past truth & present poetry
42. the national
institutes of health
and joseph j. kinyoun
Richard J. Bing
volume 17, number 3, 2010
The National Institutes of Health(NIH) in Washington, D.C. havegrown into a behemoth of science –
made up of 27 institutes and centers, andemploying over 19,000 people, 6,000 ofwhom are scientists. One of the mainfunctions of the NIH is the financial supportof research in the life sciences, particularlymedicine. How did the NIH become theirreplaceable sponsor of the life sciences?How did they develop into supposedlywise organizations which hand out strictpunishments or glorious rewards?
It all began in 1670, when American Indiansceded all claims to Staten Island to theEnglish in a deed to Governor FrancisLovelace, six years after English soldiershad conquered New Netherlands. As anirony of history, some Staten Island mensigned an oath of allegiance to the Britishcrown in 1776, on the same day that NewYork received word of the signing of theDeclaration of Independence in Phila–delphia.
In 1887, one room in the Marine Hospital onStaten Island, New York, was occupied bya laboratory belonging to the MarineHospital Service. This room was the cradleof the National Institutes of Health. TheMarine Hospital Service was establishedin 1798 to take care of the ills of merchantseamen. One of its main functions was toexamine and isolate passengers who hadarrived in New York harbor with dreadeddiseases such as yellow fever and cholera.The question was how and where to isolatethese unfortunate victims. Finally, a seriesof “pest houses” were built around NewYork Harbor to isolate these patients. The“pest houses” did not fare well amongsttheir neighbors. On September 1, 1848mobs torched the Marine Hospital quar–antine where immigrants with infectiousdisease were held. This quarantine stationwas soon replaced by others built from
landfills on artificial islands.
Staten Island was strategically located toreceive the ill, and a number of isolationfacilities were built there. It was the time ofthe ascendancy of microbiology, of Koch,Pasteur, Wassermann, Metchnikoff,Ehrlich and others. Bacteriology was thenwhat molecular biology is now: the wave ofthe future.
In 1887, the Marine Hospital Servicerecruited a young bacteriologist, Joseph J.Kinyoun to set up a laboratory in the MarineHospital. There are several photographsof the room and its equipment, whichconsisted primarily of one Zeiss Micro–scope. Kinyoun called this room “Labora–tory of Hygiene.” He became its firstdirector followed by a series of men whousually stayed 2 years in office, duringwhich time they had to placate members ofCongress, the President of the UnitedStates, and the scientific community. Notan easy balancing act!
The year 1891 was pivotal for the healthcareof the United States. In that year the
Hygienic Laboratory with Dr. Kinyoun wasmoved from Staten Island to Washington,D.C. At the beginning of the 20th century,in 1931, the “Hygienic Laboratory” wasrenamed the National Institutes of HealthThese changes sound quite seamless, butin reality they were not easily accomplished.One of the main obstacles for the Wash–ington laboratory was the acquisition ofthe ground it was to occupy. The locationof the new institute was to be in Bethesda,Maryland with its meadows, golf coursesand farmhouses. Much of the grounddesired by the new institute belonged toLuke Wilson and his wife Helen, whoattempted to leave their property to acharitable institution. They were notsuccessful, and finally wrote a letter toPresident Roosevelt offering their land asa donation to the Federal Government. In1935, the Wilsons agreed to donate theirland to NIH. From then on, the institutesgrew into the gigantic organization we knowtoday.
In 1937, looking at different job oppor–tunities, I was told of Staten Island Hospitalas an up and coming research facility. Itook the very pleasant ferry ride fromManhattan, but at that time the transfer ofthe Marine Hospital from Staten Island toWashington DC had already taken place.What happened to the sibling of the MarineHospital, left behind in Staten Island? Incontrast to the vigorous Bethesda branch,it limped along with federal help. In 1939,FDR ordered the construction and main–tenance of a public health service hospitaland the Staten Island Public Health ServiceHospital was built. It was eventually soldto the Sisters of Charity who renamed itBaley Seton after New York’s Saint ElizabethAnn Seton and her father Richard Baley, anAmerican born British army revolutionarywar surgeon. In 2000, the Sisters of Charityturned the hospital over to the St. VincentCatholic Medical Center and, in 2003, the
8
the news bulletin of the international society for heart research
hospital complex was sold to become theRichmond University Medical Center. Butthe future of the cradle of the NationalInstitutes of Health has remained uncertain.
What about Dr. Kinyoun? His life wasmore than a list of statistics. He was acourageous scientist who honestlyreported what he found, and bore theconsequences. Joseph James Kinyounwas born in 1860 in Centerview, Missouri,the son of a physician. He attended St.Louis Medical College and, like his father,graduated from Bellevue Hospital MedicalCollege in 1882. As he was interested inresearch he entered the Carnegie Labora–tory to complete a course in pathology andbacteriology. He then became an assistantsurgeon in the Marine Hospital Serviceand, as noted above, took over the directionof the one room lab on Staten Island, NewYork. In 1891 the Surgeon General movedthe lab and Kinyoun to Washington, DC.He frequently traveled to Europe to workwith leading bacteriologists.
Kinyoun’s fortunes took a bitter turn in1899 when he was assigned to SanFrancisco. There he detected BubonicPlague in Chinatown. When he made hisfindings public, the Governor of Californiaand various other authorities tried to silencehim. When he refused, he was accused offalse statements and his career wassacrificed. Dr. David Morens calls him thefirst U.S. Health Officer accused ofbioterrorism. As Kinyoun wrote then, “Iam charged…to have deliberately importedplague cultures into California, andinoculated Chinese bodies in order to getup a plague scare and ruin the state.” Hewas forced to resign from the service. Laterhe was proven to have been right.
This was a terrible blow for an honest anddedicated man. Kinyoun Houts, hisdescendent, writes, “After 16 years of whatmust be considered an exceptional andpublic career, he now once again became aprivate doctor. He worked first for private
companies but eventually accepted aprofessorship at George WashingtonUniversity.” He died in 1919. Thus the firsthead of the National Institutes of Healthhad to endure the pitfalls of politics in hispublic career.
And so as the Institutes grew, their sizebecame both a blessing and a curse.Personal contact between donor andrecipient became difficult and the minutiaeof bookkeeping became of disproportionateimportance. On the other hand, manyadvances in medicine and science wouldhave been impossible without the Insti–tutes. One can only hope that the spirit ofKinyoun will be kept alive to benefit thesick and suffering. It is for them that theInstitutes were built.
References
Adrian ED. Richard Bayley Biography (1745-1801). Retrieved from:www.faqs.org/health/bios/19/Richard-Bayley.html
Bachand R. Coming to America: Immigrants &Quarantine at the Port of New York, 1758 to1954 Part I. Retrieved from:h t t p : / / l o n g i s l a n d g e n e a l o g y . c o m /ComingtoAmerica.htm
Cantor D. 1988, Origins of the National Instituteof Health: Birth of the Hygienic Laboratory.Retrieved from:www.nlm.nih.gov/nih_origins/laboratory.html
Harden VA. Short History of the U.S. NationalInstitutes of Health (personal communication,November 12, 2009)
Houts JK. Dr Joseph James KinyounBiographical Sketch (personal communication,November 28, 2009).
Lyons M. 70 Acres of Science: The NationalInstitutes of Health Moves to Bethesda. E-book, 2006
Morens DM. 2009, Abutment: Joseph JamesKinyoun, M.D., Ph.D., presented to thecolleagues in the National Institute of Allergyand Infectious Diseases. Bethesda, Maryland
Wikipedia contributors. Bayley Seton Hospital[Internet]. Wikipedia, The Free Encyclopedia;November 26, 2009. Available from:h t t p : / / e n . w i k i p e d i a . o r g / w i k i /Bayley_Seton_Hospital
The help of Joseph Kinyoun Houts, Jr.;Barbara Harkins, Office of NIH History;Dr David Morens, NIH; and Dr VictoriaHarden, Office of NIH History is greatlyappreciated.
Richard J. Bing, M.D. �
Finale
A Note of Thanks
It is with gratitude and regret that I reportthat the article on this page is the final
installment of Dr Richard J. Bing’s “PastTruth & Present Poetry” history-of-medicine series. This article is the 42nd in theseries which began 14 years ago in responseto a fortuitous invitation from Dr TomRuigrok, Founding Editor, following a concertof chamber music composed by Dr Bing.The first 28 of these articles was publishedin 2006 as a book entitled, “Past Truth &Present Poetry – Medical discoveries andthe people behind them” (ISBN 1 903378 443). Last year, an omnibus of articles #29-40was published by the author.
As Dr Bing noted in his first article (HN&VVol 4:2), “the term ‘past truth’ refers tofactual events accompanying a scientificdiscovery while ‘present poetry ‘ stressestheir human, romantic aspects”. The Editorswould like to thank Dr Bing for the knowledgewe have gained from his ordered recountingof the historical evolution of the under–standing and treatment of cardiovasculardisease, and for sharing his personal insightsinto the human beings involved in theunfolding drama. We are grateful for thegenerous gift of his time and accumulatedwisdom.
Leslie Anderson Lobaugh,Editor, HN&V
9
president 's letter
william harvey and the discovery
of the circulation of the blood
part iii
Volume 17, Number 3, 2010
Dear Colleagues,
Herewith please find the third and final part of my account of William Harvey’s lifeand work.
In the final part of his treatise, De Motu Cordis, Harvey addressed how the blood flowsfrom the right side to the left side of the heart. He was not the first one to describe the pulmonary circulation. At least twopeople described this before him. One was a Syrian physician, Ibn al-Nafis, who lived in the 13th century and correctlydescribed the circulation of blood from the right ventricle to the lungs and then back to the left ventricle. However, sincehis writings were never translated into Western languages, these concepts were unknown to the Western world. The secondperson who described the pulmonary circulation was Michael Servetus, who did it about a century before Harvey. Hepublished these ideas in a religious book, not a scientific book, which is one of the reasons they were unknown at Harvey’stime. The second reason they were unknown was that Servetus was accused of heresy by John Calvin and burned alivein Geneva along with many of his books, and so they were not read. Harvey rediscovered what had already been discoveredby these two people. He showed clearly that there are no such things as pores in the ventricular septum (as Galen hadasserted), and that blood flows from the right ventricle to the lungs, and then back to the left ventricle.
The only thing that was missing to complete the loop (no pun intended) was the answer to this question: how does theblood go from the arteries to the veins? Harvey struggled with this “gap” but could not fill it, since he did not have the toolsto address the question. So, he postulated the existence of pores in tissues, but it was not until 1660 (three years afterHarvey’s death) that Marcello Malpighi, using the microscope – which was not available at the time of Harvey – discoveredthe existence of capillaries in tissues.
In De Motu Cordis, Harvey summarizes his new paradigm thus: “For a long time, I turned over in my mind such questionsas, ‘How much blood is transmitted and how short a time does its passage take?’ Not deeming it possible for the digestedfood mass to furnish such an abundance of blood… unless it somehow got back to the veins from the arteries and returnedto the right ventricle of the heart, I began to think whether there might not be a movement, as it were, in a circle. Now thisI afterwards found to be true; and I finally saw that the blood, forced by the action of the left ventricle into the arteries, wasdistributed to the body at large, and its several parts, in the same manner as it is sent through the lungs, impelled by theright ventricle into the pulmonary artery, and that it then passed through the veins and along the vena cava, and so roundto the left ventricle in the manner already indicated.”
Naturally, this was a revolution in medicine, for it was a direct contradiction of 1500 years of Galenism. As is the case forany paradigm change, it set off a storm in medical and philosophical circles. Harvey was attacked viciously. For example,the University of Paris opposed his concepts for at least 50 years after it was published. Apparently his medical practicealso suffered from the publication of De Motu Cordis. Harvey himself was trepid, because he wrote: “It is of a so noveland unheard-of character, that I not only fear injury to myself from the envy of a few, but I tremble lest I have mankind atlarge for my enemies, so much does want and custom, that has become as another nature, and doctrine once sown and thathas struck deep root and rested from antiquity, influence all men”. Interestingly, he did not hold the media in high regard,lamenting a problem that was a harbinger of much worse things to come. He wrote that “the crowd of foolish scribblers isscarcely less than the swarms of flies in the height of summer, and threatens with their crude and flimsy productions to stifle
10
the news bulletin of the international society for heart research
Roberto Bolli, M.D.
us as with smoke.” Things have not changed much, for today almost everything that is reported by the media is grosslydistorted, crassly inaccurate, maliciously fabricated, or blatantly false.
What is William Harvey’s legacy? I believe it is twofold. Of course, he discovered the circulation of the blood. This wasa turning point for medicine, because it enabled us to understand the human body in a manner that was impossible before.But this is not his major contribution. I think his major contribution has been the establishment of the scientific methodin biomedical research. Much has been said about Francis Bacon being the inventor of the scientific method but, actually,Bacon never used it – at least not in biological disciplines. Harvey was the first to use the scientific method in biology.He established experimentation as the principal means for biological research, an approach that we refer to as “inductivereasoning” or “experimental method”, as opposed to believing blindly what Aristotle, Galen, and others had said, orfollowing one’s personal ideas or preconceptions. Harvey must be regarded as one of the founders of modern sciencebecause he was the first to adopt the scientific method for the solution of biological problems and to study biology in aquantitative manner. This was an enormous paradigm shift, a paradigm that every scientist has followed since then andthat has become the very foundation of modern biology. Harvey was to physiology what Vesalius was to anatomy. Vesaliushad debunked Galenic anatomy with his “Fabrica”. Harvey did the same thing in physiology with “De Motu Cordis” .Thanks to these two Galen “bashers”, medicine awoke from a long sleep and shook off the shackles of ignorance andauthority. And what a long sleep it was – from the 2nd century until the 17th century A.D.
In De Generatione Animalium, Harvey writes: “Nature herself must be our advisor; the path she chalks must be our walk.For as long as we confer with our own eyes, and make our ascent from lesser things to higher, we shall be at length receivedinto her closet-secrets.” So, we must always rely on our own observations and our own reason, making small but solid stepsfrom “lesser things” to “higher”; if we do so, we will gradually begin to unravel the mysteries of nature.
I want to close this essay by citing some marvelous and eternally inspiring words written by Harvey in the preface to “DeMotu Cordis”: “True philosophers [“philosophers”, at Harvey’s time, was a term for “scientists”], who are only eager fortruth and knowledge, never regard themselves as already so thoroughly informed, but they welcome further informationfrom whomsoever and from whencesoever it may come; nor are they so narrow-minded as to imagine any of the arts orsciences transmitted to us by the ancients in such a state of forwardness or completeness that nothing is left for theingenuity and industry of others; very many, on the contrary, maintain that all we know is still infinitely less than all thatstill remains unknown; nor do philosophers pin their faith to others’ precepts in such wise that they lose their liberty andcease to give credence to the conclusions of their proper senses.” The clause I underlined and italicized is one of the mostimportant statements I have ever seen. Everybody should keep it in mind, particularly those modern scientists whoarrogantly think that they know - and can explain - everything or almost everything. This statement reminds me of Socrates,who used to say: “I am wise because I know that I do not know”.
This is Harvey’s immortal legacy, as precious and relevant now as it was 400 years ago. He advises us to be critical, to beskeptical, to challenge what we are taught, to rely on our observations, and to follow our reason. Above all, he tells us thata true scientist knows how limited our understanding of nature is. The experience of scientific inquiry teaches us that theprocess of answering a question inevitably creates even more questions; this has not changed in the 400 years since Harvey,and will not change in the future. For all the progress we have made, a true scientist has the humility to always keep in mindthat “all we know is still infinitely less than all that still remains unknown”.
11
volume 17, number 3, 2010
report on the xxxiii meeting of
the australasian section
(august 13-16, 2009; sydney, australia)
The Basic Science Lecture was presentedby Michael Clark (University of Tasmania,Australia) on the topic: ‘Microvasculardysfunction and diabetes: from animalmodels to human studies’, highlighting anovel action of insulin on microvascularperfusion. Beyond the 8 parallel streams ofthemed Symposia that ran from Friday toSunday, there was plenty of opportunity atthe meeting for delegates to present theirresearch at poster sessions (including“electronic posters” that could be con–tinuously accessed) and, for the first time,as five-minute mini-orals. These ‘speed
In 2009, the ISHR Australasian Section Annual Scientific Meeting was (as is nowusual) held jointly with the Cardiac Society of Australia and New Zealand (CSANZ).
The meeting, staged at the Sydney Convention and Exhibition Centre 13–16August, attracted over 2300 delegates. The meeting commenced with an indigenousWelcome to Country ceremony, providing the prelude to an action-packed programof symposia, breakfast theme sessions, free communications, mini orals, postersand workshops. This year, ISHR was particularly delighted to welcome severalinvited speakers well known on the ISHR International scene - David Eisner(University of Manchester), Elizabeth ‘Tish’ Murphy (NIH Bethesda), and ChristineSeidman (Harvard, Boston). All attracted robust attendance to the Basic Mechanismsstream and made excellent contributions to a number of sessions – both from thepodium and from the pews.
Basic Science Lecture - Michael Clark
Welcome to Country ceremony
science’ sessions were very popular, andproved an excellent way of quickly gaininga research snapshot – and left many of thepresenters enthusiastically breathless!
Putting together such a busy and suc–cessful meeting was the product of morethan a year’s hard work. In particular, theefforts of Peter Macdonald and ChrisSemsarian, as Chairs of the Local Organizingand Scientific Programme Committees, havebeen pivotal. Our ISHR appointees to thesecommittees (David Allen and Lea Delbridge)also worked hard behind the scenes andwere given plenty of scope by the Chairs toshape up the ISHR content.
ISHR strongly supports the participationof the younger members at our meetings,providing student travel awards, andincluding an ISHR Early Career ResearcherWorkshop in the programme. For 2009, thisworkshop was organized and chaired byJames Bell and Nader Ghaffari, the newlyappointed ISHR Council ECR repre–sentatives. Tish and David (as specialguests) were persuaded to be panelists ina discussion about ‘Finding the right post-doc position’ and had some wise, practical(and humorous) insights to offer whichwere much appreciated.
A number of Student prizes are awardedannually, the most prestigious of which isthe Student Investigator Oral Presentation
Award. This year, an independent panel offive judges shortlisted four applicants forthe award, based on assessment ofsubmitted abstracts. The winner ($1000)was Helena Viola (School of Biomedical,Biomolecular and Chemical Sciences,University of Western Australia). Herpresentation was titled ‘Evidence formitochondrial complex III as source ofsuperoxide production after transientexposure to H
2O
2’. The runner-up: ($500)
was Steven Weiss (John Curtin School ofMedical Research, Australian NationalUniversity) who presented his work‘Riluzole reduces ventricular arrhythmiasand myocardial damage in an open-chest
12
the news bulletin of the international society for heart research
You are warmly invited to join us at the2010 ISHR AUS-Section Meeting(joint meeting with CSANZ)
August 5-8, 2010Adelaide Convention CentreAdelaide, Australia
Details can be found at:www.csanz.edu.au
Tish Murphy and David Eisner (centre) help out the ISHR ECR Workshopconvenors Jim Bell (right) and Nader Ghaffar (left).
pig model of myocardial ischaemia-reperfusion’.
Students also had the opportunity to wina prize in the mini-oral and poster sessions.For the mini-oral prize, the winner wasLynette Pretorius (Baker IDI Heart andDiabetes Institute) and runner-up PeterPsaltis (Department of Medicine, Uni–versity of Adelaide). The poster prize winnerwas Ying-Yi Liu (Australian School ofAdvanced Medicine, Macquarie Univer–sity), with Nathan Dwyer (Royal HobartHospital) coming a close second.
The talented ISHR Student Investigator Oral Prize finaliasts(left to right) Steven Weiss, Nicholas Lam, Elisha Hamiltonand Helena Viola (winner).
The ISHR Australasian Section executive toasts special inter-national guests at the AGM and dinner – (right to left) David Saint,
Tish Murphy, Lea Delbridge, Julie McMullen, David Eisner.
With prizes to be awarded in three categories,judging turned out to be a rather complicatedand demanding task with over 30 presen–tations to be considered. Fortunately, thisprocess was most ably organized by IgorWendt who recruited a team of experts tohelp out on the judging panels. Our thanksto those Society members who assistedwith this task. All agreed that the studentpresentations were of a very high standard,and our prizewinners are to be congratulatedon their achievements.
Of course, the meeting included plenty of
opportunity for mixing and mingling, eatingand drinking and enjoying the ambience ofthe Sydney waterfront. The very convivialtwilight AGM and dinner was held atJordans Seafood Restaurant on DarlingHarbour. Finally, after all the science wasdone, our visitors were whisked away forone last cultural experience – to enjoy musicof the old and new worlds under the sailsof the iconic Opera House! We now turnour attention to 2010 – with the excitingprospects of a Congress in Kyoto and jointmeeting with CSANZ in Adelaide (seeinsert). In Adelaide we will welcome twonew ISHR ‘down-under’ visitors – JohnSolaro and Roberta Gottleib will help us puttogether another fantastic scientificprogramme.
Marie WardHelen KiriazisIgor Wendt �
13
volume 17, number 3, 2010
death and senescence, both are
problems - p53 causes cardiovascular
and metabolic diseases
(continued on page 14)
p53 Induces Heart Failure (4-7)Pressure overload initially induces cardiachypertrophy to reduce wall stress andmaintain normal cardiac function. At thisstage, vascular growth was enhanced inthe heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenicfactors. However, sustained pressureoverload induced an accumulation of p53,at least in part by DNA damage, whichinhibited the Hif-1 activity. Inhibition ofcardiac angiogenesis enhanced hypoxia,resulting in systolic dysfunction. Con–versely, promoting cardiac angiogenesisby introducing angiogenic factors or byinhibiting p53 accumulation developedhypertrophy further but restored cardiacdysfunction under chronic pressureoverload. These results suggest that thetumor suppressor protein p53 has a crucialfunction in the transition from cardiachypertrophy to heart failure by inhibitingangiogenesis (4).
Little attention has been paid to the DNAdamage response of cardiomyocytespossibly because cardiac cancer is veryrare. Doxorubicin is known to havecumulative dose-dependent cardiotoxicity.Doxorubicin, an anti-cancer drug, inducedp53 accumulation via oxidative stress-induced DNA damage of cardiomyocytesin vitro and in vivo. Doxorubicin-inducedcontractile dysfunction and myocyteapoptosis were attenuated in heterozygous
p53 deficient mice and cardiac-restrictedBcl-2 transgenic mice, suggesting thatmyocyte apoptosis plays a central roledownstream of p53 in doxorubicin cardio–toxicity (5). The results of two studiessuggest that p53 causes heart failure byinhibiting angiogenesis and inducingapoptosis of cardiomyocytes, but theremight be other mechanisms by which p53 isinvolved in the development of heart failure.It has been reported that p53 regulatesmitochondrial respiration with secondarychanges in glycolysis (6) and that p53induces inflammation such as upregulationof inflammatory cytokines (7).
p53 Induces Atherosclerosis (8-12)Ras has been reported to induce prematuresenescence of various types of cellsincluding vascular smooth muscle cells (8,9). As one of the many activators of Ras,angiotensin II also induced prematuresenescence of human vascular smoothmuscle cells with enhanced expressions ofproinflammatory cytokines and adhesionmolecules via the p53/p21-dependentpathway in vitro and in vivo. Loss of p21markedly ameliorated the induction ofproinflammatory molecules by angiotensinII and prevented the development ofatherosclerosis (10), suggesting thatangiotensin II promotes atherosclerosisby induction of vascular cell senescencevia upregulation of p53.
Many molecular mechanisms have beensuggested to contribute to human agingand its associated diseases. Recent geneticanalyses have demonstrated that reduction-of-function mutations in the signalingpathway of insulin/insulin-like growthfactor-1 (IGF-1)/phosphatidylinositol-3kinase (PI3K)/Akt (also known as proteinkinase B) extend the longevity of thenematode Caenorhabditis elegans (11).Although the signaling pathway of insulin/phosphatidylinositol-3 kinase/Akt isknown to play a critical role in glucosemetabolism and survival of mammalian cells,constitutive activation of Akt promotedsenescence-like arrest of cell growth via thep53/p21-dependent pathway (12). Aktinactivated a forkhead transcription factor,FOXO3a, which influenced p53 activity byupregulating the level of reactive oxygenspecies. In patients with type 2 diabetesand metabolic syndrome, blood insulinlevels are elevated because of the increasedresistance to insulin in the liver and skeletalmuscle. The elevated insulin may activatephosphatidylinositol-3 kinase/Akt signal–ing in vascular cells, which may lead toatherosclerosis (12). In diabetes, anothercandidate for vascular injury is high
DNA damage induces cell death or cell cycle arrest as well as infinite proliferationof cells (1-3). A variety of molecules and factors can induce DNA damage, such
as irradiation, ultraviolet light and anti-cancer drugs. Ischemia/reperfusion andmany neurohumoral factors, including catecholamine and angiotensin II, can induceDNA damage by increasing reactive oxygen species. The heart rarely forms cancer,probably because cardiomyocytes have little ability to proliferate after birth.Instead, cardiomyocytes show apoptosis or senescence in response to DNAdamage, which may result in heart failure. Cell senescence can also cause variouscardiovascular and metabolic diseases such as atherosclerosis and diabetes.
Issei Komuro
14
the news bulletin of the international society for heart research
(continued from page 13)
glucose. Treatment of human endothelialcells with high glucose decreased expres–sion of an NAD(+)-dependent deacetylaseSIRT1, a mammalian homolog of Sir2 (13).Downregulation of SIRT1 activated p53 byincreasing its acetylation. Introduction ofSIRT1, or disruption of p53, inhibited highglucose-induced endothelial senescenceand dysfunction. Likewise, activation ofSIRT1 prevented the hyperglycemia-induced vascular cell senescence andthereby protected against vascular dys–function in mice with diabetes (13).Expressions of p53 were increased in thelimbs of mice with diabetes and ischemia.p53 also inhibited angiogenesis at leastpartly by upregulating the axon-guidingmolecule semaphorin3E, which inhibitedthe action of VEGF (14).
p53 Causes Diabetes (15)Excessive calorie intake led to the accu–mulation of oxidative stress in the adiposetissue of mice with type 2 diabetes andpromoted senescence-like changes, suchas increased activity of senescence-associated b-galactosidase, increasedexpression of p53 and increased productionof proinflammatory cytokines. Inhibitionof p53 activity in adipose tissue markedlyameliorated these senescence-like changes,decreased the expression of proinflam–matory cytokines and improved insulinresistance in mice with type 2 diabetes.Conversely, upregulation of p53 in adiposetissue caused an inflammatory responsethat led to insulin resistance. Adipose tissuefrom individuals with diabetes also showedsenescence-like features. These resultsshow a previously unappreciated role ofadipose tissue p53 expression in theregulation of insulin resistance, and suggestthat cellular aging signals in adipose tissuecould be a new target for the treatment ofdiabetes (15).
Cells respond to DNA damage by activationof various protein kinases, such as ATM,ATR, CHK1 and 2, which reduce cyclin-
dependent kinase activity by variousmechanisms, some of which are mediatedby the activation of p53 (2, 3, 16).Accumulation of DNA damage can be animportant cause of cardiomyopathy. First,cardiomyocytes exhibit high mitochondrialrespiration and thus produce lots of reactiveoxygen species that can damage mito–chondrial and nuclear DNA. Second,cardiomyocytes are vulnerable to DNAdamage because of the limited capacity for
cell replacement after birth. Furthermore,cardiomyocytes, being in G
0, cannot repair
double-strand breaks by homologousrecombination and must use error-pronenon-homologous end-joining (17). Al–though the proliferative ability of cardio–myocytes is very limited, the transcriptionalactivity is very high. Since oxidative DNAdamage can block transcription, variousstresses that increase reactive oxygenspecies can induce cardiomyocyte degen–eration and death (18). The upregulatedp53 also induces apoptotic cell death andcellular senescence. Accumulating evi–dence has suggested that loss of cardio–myocytes, possibly accompanied bycardiomyocyte hypertrophy, may lead tocardiac dysfunction. Cardiac function isgradually impaired during aging. Senes–
cence of cardiomyocytes may causedysfunction, although the mechanisms areelusive. Expression patterns of variousproteins, such as contractile proteins andmetabolism-related proteins, may bechanged in senescent cardiomyocytes, orinflammatory cytokines may be upregu–lated in the senescent heart.
Aging, as well as hypertension anddiabetes, causes atherosclerosis. Vascular
cell senescence may be a common cause ofatherosclerosis by enhancing expressionof inflammatory cytokines and adhesionmolecules (19). Ross has mentioned thatatherosclerosis is an inflammatory disease(20). Vascular cell senescence may causeatherosclerosis by inducing inflammationof vessels. DNA damage, p53 and cellularsenescence could be novel targets ofcardiovascular and metabolic diseases (ref.2, Figure).
References1. Campisi J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol 2001;11: S27–S31.
2. Vazquez A, Bond EE, Levine AJ, et al. Thegenetics of the p53 pathway, apoptosis and
15
ISHR MEETINGS CALENDAR
volume 17, number 3, 2010
� May 13-16, 2010. XX World Congress of the ISHR. Kyoto International Conference Center, Kyoto, Japan. Website
www.ishr2010.com
� August 5-8, 2010. XXXIV Meeting of the Australasian Section (jointly with the Cardiac Society of Australia and New Zealand).
Adelaide, Australia. Website www.csanz.edu.au
� August 28 – September 1, 2010. Congress of the European Society of Cardiology. Stockholm, Sweden. Website www.escardio.org
� November 13-17, 2010. Scientific Sessions of the American Heart Association. Chicago, IL. Website www.scientificsessions.org
� May 22-25, 2011. XXXII Annual Meeting of the American Section. Philadelphia, PA, USA
� June 26-29, 2011. XXX Annual Meeting of the European Section. Haifa, Israel
cancer therapy. Nat Rev Drug Discov 2008; 7:979-987.
3. Evan GI, d’Adda di Fagagna F. Cellularsenescence: hot or what? Curr Opin Genet Dev2009; 19: 25-31.
4. Sano M, Minamino T, Toko H, et al. p53-induced inhibition of Hif-1 causes cardiacdysfunction during pressure overload. Nature2007; 446: 444-448.
5. Yoshida M, Shiojima I, Ikeda H, et al. Chronicdoxorubicin cardiotoxicity is mediated byoxidative DNA damage-ATM-p53-apoptosispathway and attenuated by pitavastatin throughthe inhibition of Rac1 activity. J Mol CellCardiol 2009; 47: 698-705.
6. Ma W, Sung HJ, Park JY, et al. A pivotal rolefor p53: balancing aerobic respiration andglycolysis. J Bioenerg Biomembr 2007; 39:243-246.
8. Serrano M, Lin AW, McCurrach ME, et al.Oncogenic ras provokes premature cellsenescence associated with accumulation ofp53 and p16INK4a. Cell 1997; 88: 593–602.
9. Minamino T, Yoshida T, Tateno K, et al. Rasinduces vascular smooth muscle cell senescenceand inflammation in human atherosclerosis.Circulation 2003; 108: 2264-2269.
10. Kunieda T, Minamino T, Nishi J, et al.Angiotensin II induces premature senescence
of vascular smooth muscle cells and acceleratesthe development of atherosclerosis via a p21-dependent pathway. Circulation 2006;114: 953-960.
11. Kenyon C, Chang J, Gensch E, et al. A C.elegans mutant that lives twice as long as wildtype. Nature 1993; 366: 461–464.
12. Miyauchi H, Minamino T, Tateno K, et al.Akt negatively regulates the in vitro lifespan ofhuman endothelial cells via a p53/p21-dependent pathway. EMBO J 2004; 23: 212-220.
13. Orimo M, Minamino T, Miyauchi H, et al.Protective role of SIRT1 in diabetic vasculardysfunction. Arterioscler Thromb Vasc Biol2009; 29: 889-894.
14. Moriya J, Minamino T, Tateno K, et al.Inhibition of semaphorin as a novel strategy fortherapeutic angiogenesis. Circ Res 2010; 106:391-398.
15. Minamino T, Orimo M, Shimizu I, et al. Acrucial role for adipose tissue p53 in theregulation of insulin resistance. Nat Med 2009;15: 1082-1087.
16. Meek DW. Tumour suppression by p53: arole for the DNA damage response? NatureReviews Cancer 2009; 9: 714-723.
17. Rass U, Ahel I, West SC. Defective DNArepair and neurodegenerative disease. Cell 2007;130: 991-1004.
18. Jackson SP, Bartek J. The DNA-damageresponse in human biology and disease. Nature2009; 461: 1071-1078.
19. Minamino T, Miyauchi H, Yoshida T, et al.Endothelial cell senescence in human athero–sclerosis: role of telomere in endothelialdysfunction. Circulation 2002; 105: 1541–1544.
20. Ross R. Atherosclerosis—an inflammatorydisease. N Engl J Med 1999; 340: 115-126.
Dr Isssei KomuroOsaka, Japan �
We are pleased to present thisarticle by Dr Issei Komuro as the
third in our series of articles written bymembers of the ISHR InternationalCouncil.
Previous articles in this series appear inHN&V issues 13:1 (Dr Piero Anversa,“Rebuilding the Heart: Reality orFantasy”) and 16:2 (Dr Fabio Di Lisa,“The Incessant Remodelling of Mito–chondrial Studies in CardiovascularResearch”).
The format for this series calls for eachmember of Council to submit one articlefor publication during his/her 6-yeartenure. The content of the article is atthe discretion of the author, but shouldbe of broad interest to members of theSociety.
16
HEART NEWS AND VIEWS
is the official News Bulletin of theInternational Society for HeartResearch and is published everyfourth month.
the news bulletin of the international society for heart research
HEART NEWS AND VIEWSis published thanks to
an unrestricted grant from Servier
a private French pharmaceutical company committedto therapeutic advances in cardiovascular medicine as
well as other key therapeutic areas. We have successfullydeveloped products in the field of cardiovascular diseases(ischemic heart disease, hypertension, and heart failure),
as well as in other major therapeutic fields. A numberof landmark studies like PROGRESS, EUROPA,
PREAMI, ADVANCE, HYVET, and BEAUTIFUL are,or have been, conducted with our support.
The dynamism of our research is ensured by consistentallocation of as much as over 25% of the annual turnover
of the Group to search for new molecules and developtheir therapeutic applications.
Servier is also the foundingfather of The European
Cardiologist Journal by
Fax and Dialogues in
Cardiovascular Medicine,
a quarterly publicationwith a worldwidecirculation edited byRoberto FERRARI
and David J. HEARSE.
Dialogues discusses in acomprehensive way issuesfrom the cutting edgeof basic research andclinical cardiology.
Visit the Web version at www.dialogues-cvm.org
The forthcoming issue, devoted toBIOLOGICAL CLOCKS AND THE HEART
will feature articles by:
G. K. Paschos and G. A. FitzGerald;D. E. Montgomery and D. E. Vaughan; A. J. Harmar;
R. V. Kondratov and M. P. Antoch
Biological Clocks and the Heart
Volume 15 • Number 1
2010
For further information onDialogues in Cardiovascular Medicine please contact:
Dr Irina Elyubaeva - Servier International35 rue de Verdun - 92284 Suresnes Cedex - France
