Posted in Atherogenic Processes & Pathology, Electrophysiology, Epigenetics and Cardiovascular Risks, Heart Failure (HF), HTN, Origins of Cardiovascular Disease, Pharmacotherapy of Cardiovascular Disease, Uncategorized on February 21, 2016| Leave a Comment »
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Objectives: At the end of the presentation, the audience should be able to describe appropriate interventions for identified arrhythmias.
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Posted in Cardiovascular Research, Frontiers in Cardiology and Cardiovascular Disorders, Heart Failure (HF), HTN, Pharmacotherapy of Cardiovascular Disease on February 21, 2016| Leave a Comment »
Reporter: Aviva Lev-Ari, PhD, RN
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An animated video on Mechanism of action of antihypertensive drugs for Ty and Final Year students. And also for those preparing for competitive exams.
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See on Scoop.it – Cardiotoxicity
Posted in HTN, Pharmacotherapy of Cardiovascular Disease on February 21, 2016| Leave a Comment »
Reporter: Aviva Lev-Ari, PhD, RN
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Dr Hisao Ogawa of Kumamoto University, Japan reported at a press conference and a hot-line session at the European Society of Cardiology 2015 Congress. The 3…
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Posted in Atherogenic Processes & Pathology, HTN, Pharmacotherapy of Cardiovascular Disease, Uncategorized on February 21, 2016| Leave a Comment »
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http://www.realbooknow.net/books
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Posted in Atherogenic Processes & Pathology, Endocrine Diseases, HTN, Pharmacotherapy of Cardiovascular Disease on February 21, 2016| Leave a Comment »
Reporter: Aviva Lev-Ari, PhD, RN
Parathyroid hormone levels may be elevated by use of some antihypertensive agents but reduced by others, analysis of the Multi-Ethnic Study of Atherosclerosis suggests.
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Posted in Acute Myocardial Infarction, Biological Networks, Ca2+ triggered activation, Calcium Signaling, Cardiomyopathy, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Clinical & Translational, Curation, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Frontiers in Cardiology and Cardiovascular Disorders, Gene Regulation, HTN, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Pharmacotherapy of Cardiovascular Disease, tagged angina, calcium channels, Hypertension, pharmacotherapy on December 11, 2015| Leave a Comment »
Calcium Channel Blocker Potential for Angina
Larry H. Bernstein, MD, FCAP, Curator
LPBI
Pranidipine
ANTHONY MELVIN CRASTO, PhD
https://newdrugapprovals.files.wordpress.com/2015/12/str116.jpg
Pranidipine , OPC-13340, FRC 8411
Acalas®
NDA Filing in Japan
A calcium channel blocker potentially for the treatment of angina pectoris and hypertension.
CAS No. 99522-79-9
see dipine series………..http://organicsynthesisinternational.blogspot.in/p/dipine-series.html
manidipine
PAPER
Der Pharmacia Sinica, 2014, 5(1):11-17
https://newdrugapprovals.files.wordpress.com/2015/12/str113.jpg
pelagiaresearchlibrary.com/der-pharmacia-sinica/vol5-iss1/DPS-2014-5-1-11-17.pdf
| Names | |
|---|---|
| IUPAC name
methyl (2E)-phenylprop-2-en-1-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
|
|
| Other names
2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-methyl O3-[(E)-3-phenylprop-2-enyl] ester
|
|
| Identifiers | |
99522-79-9  |
|
| ChEMBL | ChEMBL1096842  |
| ChemSpider | 4940726 |
| Jmol interactive 3D | Image |
| MeSH | C048161 |
| PubChem | 6436048 |
| UNII | 9DES9QVH58 |
| PATENT | SUBMITTED | GRANTED |
|---|---|---|
| Process for the preparation of 1,4 – dihydropyridines and novel 1,4-dihydropyridines useful as therapeutic agents [US2003230478] | 2003-12-18 | |
| Advanced Formulations and Therapies for Treating Hard-to-Heal Wounds [US2014357645] | 2014-08-19 | 2014-12-04 |
| METHODS OF TREATING CARDIOVASCULAR AND METABOLIC DISEASES [US2014322199] | 2012-08-06 | 2014-10-30 |
| Protein Carrier-Linked Prodrugs [US2014323402] | 2012-08-10 | 2014-10-30 |
| sGC STIMULATORS [US2014323448] | 2014-04-29 | 2014-10-30 |
| TREATMENT OF ARTERIAL WALL BY COMBINATION OF RAAS INHIBITOR AND HMG-CoA REDUCTASE INHIBITOR [US2014323536] | 2012-12-07 | 2014-10-30 |
| Agonists of Guanylate Cyclase Useful For the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders [US2014329738] | 2014-03-28 | 2014-11-06 |
| METHODS, COMPOSITIONS, AND KITS FOR THE TREATMENT OF CANCER [US2014335050] | 2012-05-25 | 2014-11-13 |
| ROR GAMMA MODULATORS [US2014343023] | 2012-09-18 | 2014-11-20 |
| High-Loading Water-Soluable Carrier-Linked Prodrugs [US2014296257] | 2012-08-10 | 2014-10-02 |
Synthesis, isolation and use of a common key intermediate for calcium antagonist inhibitors
Neelakandan K.a,b, Manikandan H.b , B. Prabhakarana*, Santosha N.a , Ashok Chaudharia *, Mukund Kulkarnic , Gopalakrishnan Mannathusamyb and Shyam Titirmarea
a API Research Centre, Emcure Pharmaceutical Limited, Hinjawadi, Pune, India bDepartment of Chemistry, Annamalai University, Chidhambaram, India cDepartment of Chemistry, Pune University, Pune, India _________________________________________________________________________________
Pelagia Research Library www.pelagiaresearchlibrary.com Der Pharmacia Sinica, 2014, 5(1):11-17
The compound (3) synthesized from Nitrobenzaldehyde, tertiary butyl acetoacetate and piperidine can be used as a common intermediate for the production of calcium channel blockers like Nicardipine hydrochloride (1) and Pranidipine hydrochloride (2) with high purity.
The last twenty years have witnessed discoveries of calcium antagonists associated with multicoated pharmacodynamics potential which include not only antihypertensive and antiarrhythmic effects of the drugs but also action against excessive calcium entry in the cell of cardiovascular system and subsequent cell damage. Among many classes of calcium channel blockers, 1,4-dihydropyrimidine based drug molecules represented by Felodipine, Clevidipine, Benidipine, Nicardipine and Pranidipine are by far the best to reduce systemic vascular resistance and arterial pressure.
The reported synthetic approaches however proceed with complicated work ups, laborious purification procedures, highly expensive chemicals and low overall yields. (Scheme-I).
Synthetic scheme of Nicardipine and Pranidipine In view of the draw backs associated with previous synthetic approaches there is a strong need for environmentfriendly high yielding process applicable to the multi-kilogram production of calcium antagonist inhibitors. Herein, we report a scalable synthesis for Nicardipine hydrochloride (1) and Pranidipine hydrochloride (2) in fairly high overall yield using key intermediate 3-nitro benzylidene acid (3).Compound (3) was synthesized in two steps using 3-nitrobenzaldehyde, tertiary butyl acetoacetate and piperidine as a base to furnish tertiary butyl ester derivative (10). This was followed by hydrolysis of (10) in TFA and DCM to furnish compound (3) which would serve as a precursor for synthesis of versatile calcium antagonist inhibitors (Scheme-II).
Reported routes for synthesis of Benidipine,1,2 Lercanadipine,3-6 Nimodipine,7-11 Barnidipine12-14 and Manidipine15-16 were explored in our laboratory which involve reaction of nitro benzaldehyde with tertiary butyl acetoacetate using piperidine as a base to get tertiary butyl ester derivative (10). This is further treated with respective reagents to get various calcium channel blockers as shown in scheme 4. Since reported procedures involve in-situ generation of intermediate (3) and its reaction with corresponding fragments, it results in the formation of by-products which ultimately decrease the yield and increase the cost of API.
A novel process of manufacturing benzylidine acid derivative (3) was developed. Use of this intermediate was demonstrated by synthesis of Nicardipine and Pranidipine. This protocol may be employed for synthesis of other calcium channel blockers. In conclusion, a highly efficient, reproducible and scalable process for the synthesis of calcium channel blockers has been developed using (3) as the key intermediate.
[1] US 63 365 (Kyowa Hakko; appl.15.4.1982; J-prior.17.4.1981). [2] US 4 448 964 (Kyowa Hakko;15.5.1984; J-prior.17.4.1981). [3] Leonardi, A. et al.: Eur. J. Med.Chem. (EJMCA5) 33,399 (1988). [4] EP 153 016 (Recordati Chem. and Pharm.; appl. 21.1.1985; GB-prior. 14.2.1984). [5] US 4 705 797 (Recordati;10.11.1987; GB-prior. 14.2.1984). [6] WO 9 635 668 (Recordati Chem. and Pharm.; appl. 9.5.1996; I-prior. 12.5.1995). [7] DOS 2 117 571 (Bayer; appl. 10.4.1971). [8] DE 2 117 573 (Bayer; prior.10.4.1971) [9] US 3 799 934 (Bayer;26.3.1974;D-prior.10.4.1971). [10] US 3 932 645 (Bayer;13.1.1976;D-prior.10.4.1971). [11] Meyer, H. et al.: Arzneim.-Forsch. (ARZNAD) 31, 407 (1981); 33, 106 (1983). [12] DE 2 904 552 (Yamanouchi Pharm.; appl. 7.2.1979; J-prior.14.2.1978). [13] US 4 220 649 (Yamanouchi;2.9.1980; J-prior.14.2.1978). [14] CN 85 107 590( Faming Zhuanli Sheqing Gonhali S.; appl. 11.10.1985; J-prior.24.1.1985). [15] EP 94 159 (Takeda; appl. 15.4.1983; J-prior. 10.5.1982). [16] US 4 892 875 (Takeda;9.1.1990; J-prior. 10.5.1982, 11.1.1983).
Posted in Atherogenic Processes & Pathology, Cardiovascular Research, Clinical & Translational, Curation, Diagnostics and Lab Tests, Epigenetics and Cardiovascular Risks, History and physical exam, HTN, Nutrition, Origins of Cardiovascular Disease, Population Health Management, Population Health Management, Nutrition and Phytochemistry, tagged blood pressure lowering, Clinical Trials, CVD risk, Hypertension on November 10, 2015| Leave a Comment »
Blood Pressure Lowering
Larry H. Bernstein, MD, FCAP, Curator
LPBI
Data analysis and publication of landmark NIH blood pressure study confirm that lower blood pressure target can reduce cardiovascular disease, deaths
NIH-supported researchers are reporting more details on a landmark study that announced preliminary findings in September showing a lower blood pressure target can save lives and reduce the risk of cardiovascular disease in a group of non-diabetic adults 50 years and older with high blood pressure. Results of the Systolic Blood Pressure Intervention Trial (SPRINT) appear in the current online issue of the New England Journal of Medicine and were discussed today at the American Heart Association 2015 Scientific Sessions in Orlando.
The study confirms that, in adults 50 years and older with high blood pressure, targeting a systolic blood pressure of less than 120 millimeters of mercury (mm Hg) reduced rates of cardiovascular events, such as heart attack and heart failure, as well as stroke, by 25 percent. Additionally, this target reduced the risk of death by 27 percent—as compared to a target systolic pressure of 140 mm Hg.
“SPRINT is part of a proud legacy of NIH-funded clinical trials that will change clinical practice and save lives for decades to come. These results reinforce the compelling public health importance of enhancing the awareness, treatment and control of hypertension in this country and around the world,” said Gary H. Gibbons, M.D., director of the National Heart, Lung, and Blood Institute (NHLBI), the primary sponsor of SPRINT.
The SPRINT study, which began in the fall of 2009, included more than 9,300 participants age 50 and older, recruited from about 100 medical centers and clinical practices throughout the United States and Puerto Rico. About 36 percent of participants were women, 58 percent were white, 30 percent were African-American, and 11 percent were Hispanic. The SPRINT study did not include patients with diabetes, prior stroke, or polycystic kidney disease, as other NIH trials were studying those particular populations. Approximately 28 percent were 75 or older and 28 percent had chronic kidney disease. The study tested a strategy of using blood pressure medications to achieve the targeted goals of less than 120 mm Hg (intensive treatment group) versus 140 mm Hg (standard treatment group). The NIH stopped the blood pressure intervention in August—a year earlier than planned—after it became apparent that this more intensive intervention was beneficial.
“When the benefits of the stronger intervention became apparent in SPRINT, we made a commitment to rapid public health communication and peer-reviewed publication of the study results,” Dr. Gibbons said. “We are pleased to present the details of the study’s potentially lifesaving findings at this time.”
In their report, investigators provided detailed data showing that both cardiovascular deaths and overall deaths were lower in the intensive treatment group.
Certain types of serious consequences were more common in the intensive group, including low blood pressure, fainting, electrolyte abnormalities, and acute kidney damage. However, other serious adverse events associated with lower blood pressure, such as slow heart rate and falls with injuries, did not increase in the intensive group. In patients with chronic kidney disease, there was no difference in the rate of serious decline in kidney function between the two blood pressure goal groups.
“The benefits of more intensive blood pressure lowering exceeded the potential for harm, regardless of gender or race/ethnicity,” said study co-author Paul Whelton, M.D., of Tulane University School of Public Health and Tropical Medicine in New Orleans, Louisiana. He is chair of the SPRINT Steering Committee.
In addition to its primary cardiovascular outcome, the study continues to examine kidney disease, cognitive function, and dementia among the SPRINT participants; however, these results are not yet available as additional information will be collected and analyzed over the next year.
“Although the study provides strong evidence that a lower blood pressure target saves lives, patients and their health care providers may want to wait to see how guideline groups incorporate this study and other scientific reports into any future hypertension guidelines. In the meantime, patients should talk to their health care providers to determine whether this lower goal is best for their individual care,” said study co-author Lawrence Fine, M.D., Chief, Clinical Applications and Prevention Branch at NHLBI.
“It’s also important to remember that healthy lifestyle changes can make a difference in controlling high blood pressure,” Dr. Fine added. He emphasized the importance of following a healthy diet, being physically active, maintaining a healthy weight, as well as learning to check your blood pressure.
In addition to primary sponsorship by the NHLBI, SPRINT is co-sponsored by the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the National Institute on Aging.
Part of the National Institutes of Health, the National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at http://www.nhlbi.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
NIH…Turning Discovery Into Health®
Landmark NIH study shows intensive blood pressure management may save lives
September 11, 2015, 10:30 AM EDT
Lower blood pressure target greatly reduces cardiovascular complications and deaths in older adults
More intensive management of high blood pressure, below a commonly recommended blood pressure target, significantly reduces rates of cardiovascular disease, and lowers risk of death in a group of adults 50 years and older with high blood pressure. This is according to the initial results of a landmark clinical trial sponsored by the National Institutes of Health called the Systolic Blood Pressure Intervention Trial (SPRINT). The intervention in this trial, which carefully adjusts the amount or type of blood pressure medication to achieve a target systolicpressure of 120 millimeters of mercury (mm Hg), reduced rates of cardiovascular events, such as heart attack and heart failure, as well as stroke, by almost a third and the risk of death by almost a quarter, as compared to the target systolic pressure of 140 mm Hg.
“This study provides potentially lifesaving information that will be useful to health care providers as they consider the best treatment options for some of their patients, particularly those over the age of 50,” said Gary H. Gibbons, M.D., director of the National Heart, Lung, and Blood Institute (NHLBI), the primary sponsor of SPRINT. “We are delighted to have achieved this important milestone in the study in advance of the expected closure date for the SPRINT trial and look forward to quickly communicating the results to help inform patient care and the future development of evidence-based clinical guidelines.”
High blood pressure, or hypertension, is a leading risk factor for heart disease, stroke, kidney failure, and other health problems. An estimated 1 in 3 people in the United States has high blood pressure.
The SPRINT study evaluates the benefits of maintaining a new target for systolic blood pressure, the top number in a blood pressure reading, among a group of patients 50 years and older at increased risk for heart disease or who have kidney disease. A systolic pressure of 120 mm Hg, maintained by this more intensive blood pressure intervention, could ultimately help save lives among adults age 50 and older who have a combination of high blood pressure and at least one additional risk factor for heart disease, the investigators say.
The SPRINT study, which began in the fall of 2009, includes more than 9,300 participants age 50 and older, recruited from about 100 medical centers and clinical practices throughout the United States and Puerto Rico. It is the largest study of its kind to date to examine how maintaining systolic blood pressure at a lower than currently recommended level will impact cardiovascular and kidney diseases. NIH stopped the blood pressure intervention earlier than originally planned in order to quickly disseminate the significant preliminary results.
The study population was diverse and included women, racial/ethnic minorities, and the elderly. The investigators point out that the SPRINT study did not include patients with diabetes, prior stroke, or polycystic kidney disease, as other research included those populations.
When SPRINT was designed, the well-established clinical guidelines recommended a systolic blood pressure of less than 140 mm Hg for healthy adults and 130 mm Hg for adults with kidney disease or diabetes. Investigators designed SPRINT to determine the potential benefits of achieving systolic blood pressure of less than 120 mm Hg for hypertensive adults 50 years and older who are at risk for developing heart disease or kidney disease.
Between 2010 and 2013, the SPRINT investigators randomly divided the study participants into two groups that differed according to targeted levels of blood pressure control. The standard group received blood pressure medications to achieve a target of less than 140 mm Hg. They received an average of two different blood pressure medications. The intensive treatment group received medications to achieve a target of less than 120 mm Hg and received an average of three medications.
“Our results provide important evidence that treating blood pressure to a lower goal in older or high-risk patients can be beneficial and yield better health results overall,” said Lawrence Fine, M.D., chief, Clinical Applications and Prevention Branch at NHLBI. “But patients should talk to their doctor to determine whether this lower goal is best for their individual care.”
The study is also examining kidney disease, cognitive function, and dementia among the patients; however, those results are still under analysis and are not yet available as additional information will be collected over the next year. The primary results of the trial will be published within the next few months.
In addition to primary sponsorship by the NHLBI, SPRINT is co-sponsored by the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the National Institute on Aging.
Posted in HTN, Pharmacotherapy of Cardiovascular Disease on October 9, 2015| Leave a Comment »
Low dose beta-blockers as effective as high dose after a heart attack
Reporter: Aviva Lev-Ari, PhD, RN
In a surprising new finding, heart attack patients treated with a substantially lower dosage of beta-blockers than used in earlier clinical trials showing their effectiveness survived at the same rate, or even better, than …
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Posted in Chemical Biology and its relations to Metabolic Disease, Clinical & Translational, Curation, Discovery process, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Gastroenterology, Genetics & Innovations in Treatment, Genome Biology, HTN, Pharmacotherapy of Cardiovascular Disease, tagged colonic epithelial cells, platelets, stem cells on September 8, 2015| Leave a Comment »
Mature cells can be reprogrammed to become pluripotent – John Gurdon and Shinya Yamanaka
Larry H. Bernstein, MD, FCAP, Curator
Leaders in Pharmaceutical Innovation
Series E: 2; 7.1
In 1962, John B. Gurdon successfully cloned frogs. He took the nucleus of an adult frog cell – the part of the cell that holds the DNA – and put it into a frog egg cell. The egg was able to develop into a normal tadpole. These experiments showed that an adult, specialised cell still had the information needed to form a new tadpole. The same technique was later used to produce the famous cloned sheep, Dolly.
In 2006, Shinya Yamanaka’s work again took the scientific community by surprise and changed the way researchers think about how cells develop.Yamanaka showed that adult, fully specialised mouse cells could be reprogrammed to become cells that behave like embryonic stem cells – so-called induced pluripotent stem cells, which can develop into all types of cells in the body.
Gurdon and Yamanaka’s work is celebrated and explained in the award-winning documentary, Stem Cell Revolutions, by Clare Blackburn and Amy Hardie. The short clip above is taken from the film and links Gurdon and Yamanaka’s work (click the red button on the image above to watch the clip). Amy Hardie, who directed the film, commented: “So many scientists have said that Shinya Yamanaka has overturned our understanding of basic developmental biology. And he has – with the discovery of iPS cells. What Shinya Yamanaka himself points out and we were able to show in our film, Stem Cell Revolutions, is the lineage from John Gurdon who cloned frogs in Cambridge. Shinya’s groundbreaking discovery would not have been possible without Gurdon’s pioneering work.
Proc Natl Acad Sci U S A. 2013 Apr 9; 110(15): 5740–5741.
Published online 2013 Mar 28. doi: 10.1073/pnas.1221823110
Sir John Bertrand Gurdon, FRS, FMedSci (born 2 October 1933), is an English developmental biologist. He is best known for his pioneering research in nuclear transplantation[2][3][4] and cloning.[1][5][6][7] He was awarded the Lasker Award in 2009. In 2012, he and Shinya Yamanaka were awarded the Nobel Prize for Physiology or Medicine for the discovery that mature cells can be converted to stem cells.[8]
The Nobel Prize in Physiology or Medicine 2012
Sir John B. Gurdon, Shinya Yamanaka
ohn Bertrand Gurdon (JBG), born 2 October 1933, was brought up in a comfortable home by his parents (fig.1) on the Surrey/Hampshire border in a village, Frensham in South England, endowed with a large amount of National Trust heathland and ponds. His mother, Marjorie Byass, was from an East Yorkshire farming family. Brought up on a farm, and educated in that region, she became a physical training teacher working for some time in an American private school. When her son and daughter (Caroline, who trained as a nurse) had been raised, she gave much time to the regional administration of the “Women’s Institute,” a voluntary organisation for educating women.
His father, William Gurdon, was from a longstanding Suffolk family whose ancestors go back to 1199 (fig. 2; Muskett, 1900; Cunnington, 2008); with the family motto “virtus viget in arduis” [virtue flourishes in adversity].
Figure 2. Paternal lineage of JBG.
Many of them had distinguished careers in government and as regional administrators, including Sir Adam Gurdon [Muskett, 1900]. JBG’s ancestors lived in a stately home, Assington Hall, in West Suffolk (fig. 3).
Figure 3. Assington Hall, Suffolk. Burnt down in 1957.
His grandfather had to leave the family home through lack of money to maintain it, due to repeal of the Corn Laws (1846) so that tenant farmers could no longer pay their rent, because of foreign imports. Assington Hall was requisitioned by the army during World War II, and was burnt down in a supposedly accidental fire in 1957. The remaining part of the house was partly restored and part of the original home, including its minarets, is still present in Assington. One of JBG’s ancestors married again after his first wife died and the outcome of a second marriage yielded a distinguished lawyer who accepted the hereditary title of Baron Cranworth. JBG’s father left school at the age of 16 and took a position in a rice broking firm in Burma. He was an early volunteer in the First World War and was decorated with the Distinguished Conduct Medal (DCM) before being commissioned to an officer rank. After that he led a career in banking in Assam and East India. He retired, in his forties, and in retirement, he gave much time to the transcribing of professional textbooks (especially legal) into Braille for the blind as voluntary work.
World War II started in 1939 when JBG was aged six. It was a time of austerity. Limited rations of food were managed by his mother, and the garden was used to raise chickens. He did not see luxuries like a banana or an orange until well after the end of the war. At the age of eight he was sent to a local private school, Frensham Heights. In an intelligence test at that age, he was asked to draw an orange. He started drawing the stalk by which the orange would hang from a tree, reasoning that an orange would not exist in space. The teacher tore up the piece of paper and reported to his parents that he was mentally subnormal and would need special teaching. The teacher meant to say, draw a circle. He was moved to another private school in the village, namely Edgeborough, where he thrived. At that age he had an intense interest in plants and insects. In most of his spare time he collected butterflies and moths and raised their caterpillars.
At the age of 13, he started school at Eton as a boarder. He found life there intensely uncomfortable, because senior boys acted as despots, administering punishments for trivial misdemeanours. As a means of survival, he took up squash, and as a result of hard work rather than ability, he became eventually the school captain in this sport. While at school he continued his interest in Lepidoptera, raising large numbers of moths from their larval stage.
Gurdon attended Edgeborough and then Eton College, where he ranked last out of the 250 boys in his year group at biology, and was in the bottom set in every other science subject. A schoolmaster wrote a report stating “I believe he has ideas about becoming a scientist; on his present showing this is quite ridiculous.”[9] Gurdon explains it is the only document he ever framed; Gurdon also told a reporter “When you have problems like an experiment doesn’t work, which often happens, it’s nice to remind yourself that perhaps after all you are not so good at this job and the schoolmaster may have been right.”[10]
It was during his first term of being taught Science at the school, at the age of 15, that he received a totally damning report from the Biology master (fig. 4). This report resulted from JBG being placed in the bottom position of the lowest form in a group of 250 students of the same age. The report, sent to his housemaster, resulted in him being taken off any further study of Science of any kind at the school. For the rest of his school days, for the next three years, he was given no Science teaching and was placed in a class which studied Ancient Greek, Latin and a modern language, a course intended for those judged to be unsuited for studying any subject in depth.
Entrance to University was a problem: having sat the Entrance examination in Latin and Greek, the Admissions tutor at Christ Church Oxford University told JBG that he would be accepted for Entrance on condition that he did not plan to study the subject in which he took the Entrance (Classics). Later the Admissions tutor admitted that he had under-filled the college and had his mind on other things; he was Hugh Trevor-Roper, later Lord Dacre, and author of The Last Days of Hitler. In due course it emerged that JBG’s acceptance for Christ Church involved a complicated arrangement between JBG’s uncle, at that time a Fellow of Christ Church, JBG’s school housemaster and a friend of his uncle, Sir John Masterman, who was Master of Worcester College, Oxford and in charge of the wartime Enigma operation at Bletchley, agreeing to accept the housemaster’s son. Such a manoeuvre, and admission to Oxford on those terms, could never happen now. At that time, 1952, it was not very easy to fill a college with paying students. Before entering University, JBG had to take a year off to learn elementary Biology with a private tutor, generously funded by his parents who had already paid several years of Eton fees. He was told that he could formally enter the Department of Zoology course at Oxford if he passed the elementary exams in Physics, Chemistry and Biology in a preliminary year. He survived this and started the course in Zoology at Oxford in 1953. The course was extremely oldfashioned, by today’s standards. A major part of the teaching involved learning Palaeontology, and the names of skeletal parts of dinosaurs. JBG later became a personal friend of Sir Alister Hardy, the Head of that department, through his Oxford aunt (see later).
As the Zoology course came to an end, JBG enquired about the possibility of doing a PhD in Entomology, in accord with his continuing interest in insects. While still a student, he had got permission to go to Oxford University’s nature reserve, namely Wytham Woods, with his butterfly net. No butterflies were to be seen, but he caught the only moving thing, which was a kind of fly. He used the taxonomic reference works to try to identify this “fly.” Having realised that the fly was a Hymenopteron, he was still unable to identify it. He therefore went to the Natural History Museum in London for help. They pronounced that it was in fact a species of sawfly new to Britain. This must have been intensely irritating to the Professor of Entomology, whose main research project was to identify animals and plants in Wytham Woods. JBG was later rejected for PhD work in Entomology. This was a great blessing because the work he would have done in Entomology was not well regarded and had very little, if any, analytical component to it. By his immense good fortune, he was invited to do a PhD with the Oxford University lecturer who taught Developmental Biology, Dr Michael Fischberg.
Fischberg was born in St Petersburg, Russia, in 1919. He was educated in Switzerland and was a PhD student of E. Hadorn. Hadorn in turn was a student of F. Baltzer, who was a student of H. Spemann, himself a student of T. Boveri. This German-Swiss lineage of eminent Developmental Biologists turns out to be the background of a great many of the successful Developmental Biologists of the mid-1950s. Most of those that did not have this background can trace their own training back to R. G. Harrison (1870–1959) of the USA, who pioneered cell culture. Having finished his PhD with Hadorn, Fischberg took a position in the Institute of Animal Genetics under Waddington in Edinburgh, from where he accepted his appointment in the Oxford Zoology department, headed by Professor Sir Alister Hardy, an eminent marine biologist [Royal Society memoirs].
Starting his PhD work in 1956, Fischberg suggested to JBG that he should try to carry out somatic cell nuclear transfer in Xenopus, a procedure for this having been recently published by Briggs and King (1952). The advisability and technical problems that arose at this point are described in the accompanying papers (Gurdon 2013 a,b). Once these technical obstacles had been overcome, largely as a result of good luck, JBG’s work proceeded extraordinarily fast; strongly motivated by early success, he became an intensely hard worker. By the end of his PhD he had succeeded in obtaining normal development of intestinal epithelium cell nuclei transplanted to enucleated eggs of Xenopus. When these tadpoles had eventually reached sexual maturity, he was able to publish a paper entitled “Fertile intestine nuclei.”This was the first decisive evidence that all cells of the body contain the same complete set of genes. This answered a long-standing and important question in the field of Developmental Biology. However it also showed very clearly, as was commented on in JBG’s papers at the time, the remarkable ability of eggs to reprogram somatic cell nuclei back to an embryonic state. Eventually this phenomenon attracted increasingly large interest, and led to the idea of cell replacement using accessible adult cells, such as skin. A key future discovery was that of Martin Evans (Nobel Prize, 2006) that a permanently proliferating embryonic stem cell line could be established from mouse embryos. Under appropriate conditions these cells could be caused to differentiate into all different cell types. The combination of somatic cell nuclear transfer and the derivation of embryonic stem cells in mammals made it realistic to think of cell replacement for human diseases. A huge boost for this idea was later provided by Takahashi and Yamanaka (2006), with their discovery that the overexpression of certain transcription factors can also yield embryonic stem cells from adult somatic tissue. The accompanying Nobel lecture provides more detail of the later scientific part of JBG’s career.
A visit by the Nobel Laureate George Beadle to the Fischberg Group in the Oxford Zoology department in 1960 led to an offer from the California Institute of Technology (CalTech) (previous chairman George Beadle) for JBG to do postdoctoral work there. Fischberg very wisely advised JBG to accept the CalTech offer of postdoctoral work rather than offers from other nuclear transplant labs. Stimulated by his mother’s adventurous spirit, JBG decided to buy a secondhand Chevrolet in New York and drive across the USA to California, using the famous Route 66 (now replaced). He gave lectures as he travelled across the USA and stopped at laboratories of Briggs and King, Alexander Brink (paramutation) etc. He had hoped to become a post-doctoral student of R. Dulbecco at CalTech (Nobel Prize), but the chairman of that department advised against this because JBG had no training in virology. Therefore JBG did his postdoctoral work with Robert Edgar on Bacteriophage Genetics. JBG found he had no aptitude at all for Phage Genetics and decided to return to Britain after one year at CalTech. Nevertheless, that year at CalTech was extremely formative because it provided some acquaintance with Molecular Biology, which had so far entirely escaped his training. During that year he met Sturtevant, a student of Morgan, who pioneered the whole field of Drosophila Genetics. He also got to know Ed Lewis (future Nobel Laureate). Thanks to James Ebert (director of the Department of Embryology, Carnegie Institute of Washington, in Baltimore) JBG visited various labs in the USA at the end of his post-doctoral period and met Donald Brown in Baltimore on that visit. Meantime, the success of the nuclear transfer work in Oxford had led to Michael Fischberg being offered a head of department professorship in Geneva, Switzerland. JBG was offered the teaching position in Oxford vacated by M. Fischberg. JBG returned from California to England via Japan and many other countries over a two-month period. One month of that time he spent in Japan and met Tokindo Okada and made other friends in Japan, including M. Furusawa and subsequently Koichiro Shiokawa.
While doing graduate and postdoctoral work in Oxford, JBG made other contacts and friendships. His mother’s sister lived in Oxford, and he spent much time at her house and visiting famous gardens, fostering a lifelong interest in plants. Through that connection he met Miriam Rothschild, and became a lifelong friend of hers (Van Emden and Gurdon, 2006). This friendship contained, through Miriam Rothschild’s generosity, ski mountaineering holidays based in her house in Wengen. JBG had achieved the British ski club’s Gold standard ski medal, again through relentless practice rather than any natural ability. Also, in accord with his interest in the open air and dogged determination, he became a reasonably accomplished ice figure skater.
Nobel Lecture by Sir John B. Gurdon (42 minutes)
Sir John B. Gurdon delivered his Nobel Lecture on 7 December 2012 at Karolinska Institutet in Stockholm. He was introduced by Professor Urban Lendahl, Chairman of the Nobel Committee for Physiology or Medicine.
Credits: Sveriges Television AB (production)
Copyright © Nobel Media AB 2012
The Nobel Prize in Physiology or Medicine 2012 Lecture (pdf)
Nuclear transfer
In 1958, Gurdon, then at the University of Oxford, successfully cloned a frog using intact nuclei from the somatic cells of a Xenopus tadpole.[14][15] This work was an important extension of work of Briggs and King in 1952 on transplanting nuclei from embryonic blastula cells[16] and the successful induction of polyploidy in fish Stickleback, Gasterosteus aculatus, in 1956 by Har Swarup reported in Nature.[17] However, he could not yet conclusively show that the transplanted nuclei derived from a fully differentiated cell. This was finally shown in 1975 by a group working at the Basel Institute for Immunology in Switzerland.[18] They transplanted a nucleus from an antibody-producing lymphocyte (proof that it was fully differentiated) into an enucleated egg and obtained living tadpoles.
Gurdon’s experiments captured the attention of the scientific community and the tools and techniques he developed for nuclear transfer are still used today. The term clone[19] (from the ancient Greek word κλών (klōn, “twig”)) had already been in use since the beginning of the 20th century in reference to plants. In 1963 the British biologist J. B. S. Haldane, in describing Gurdon’s results, became one of the first to use the word “clone” in reference to animals.
Messenger RNA expression
Gurdon and colleagues also pioneered the use of Xenopus (genus of highly aquatic frog) eggs and oocytes to translate microinjected messenger RNA molecules,[20] a technique which has been widely used to identify the proteins encoded and to study their function.
Recent research
Gurdon’s recent research has focused on analysing intercellular signalling factors involved in cell differentiation, and on elucidating the mechanisms involved in reprogramming the nucleus in transplantation experiments, including the role of histone variants,[21][22] and demethylation of the transplanted DNA.[23]
Reprogramming of Mature Cells
Our lives begin when a fertilized egg divides and forms new cells that, in turn, also divide. These cells are identical in the beginning, but become increasingly varied over time. As a result of this process, our cells become specialized for their location in the body – perhaps in a nerve, a muscle, or a kidney. It was long thought that a mature or specialized cell could not return to an immature state, but this has been proven incorrect.
In 1962, John Gurdon removed the nucleus of a fertilized egg cell from a frog and replaced it with the nucleus of a mature cell taken from a tadpole’s intestine. This modified egg cell grew into a new frog, proving that the mature cell still contained the genetic information needed to form all types of cells. In 2006, Shinya Yamanaka succeeded in identifying a small number of genes within the genome of mice that proved decisive in this process. When activated, skin cells from mice could be reprogrammed to immature stem cells, which, in turn, can grow into all types of cells within the body. In the long-term, these discoveries may lead to new medical treatments.
Shinya Yamanaka
A winding road to pluripotency
http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/yamanaka-lecture.pdf
http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/ypdfamanaka-lecture_slides.
Nobel Lecture
In 1989, however, my life took a new turn from clinical medicine in orthopedic surgery to basic science research for two reasons. First, I found that I was not a very talented surgeon. Second, I saw many patients suffering from intractable diseases and injuries, which even highly talented surgeons and physicians were not able to cure. For example, I had encountered patients suffering from spinal cord injuries, amyotrophic lateral sclerosis and osteosarcomas. Furthermore, I lost my father due to liver cirrhosis during my residency. Basic medical research is the only way to find cures for these patients. For these reasons, I decided to go back to school. I became a Ph.D. student at Osaka City University Medical School in April of 1989.
A scandal involving Japanese stem-cell research took a surprising turn Monday when the nation’s most revered researcher in the field, Nobel Prize laureate Shinya Yamanaka, apologized for what he described as poor record-keeping.
The apology came after months of soul-searching in Japan over research ethics. A researcher at the prestigious Riken institute, Haruko Obokata, apologized earlier this month after admitting errors in a paper in the journal Nature that described a possible new method of creating stem cells.
Last week, the head of the Riken panel investigating Dr. Obokata had to resign from the panel after admitting that a paper he co-authored used some of the same improper methods of cutting and pasting images that he had criticized in Dr. Obokata’s work.
On Monday evening, Dr. Yamanaka, a professor at Kyoto University, spoke at a news conference after questions arose about an image in a 2000 paper on which he was the lead author. In the paper, Dr. Yamanaka, then at Nara University, described a protein that played a role in turning embryo cells into cells specific to a part of the body.
The university said it conducted an investigation after Dr. Yamanaka informed administrators about allegations he discovered online that an image in the paper was doctored.
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