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Posts Tagged ‘Nobel Prize in Chemistry’


Heroes in Basic Medical Research – Robert J. Lefkowitz

Author & Curator: Larry H Bernstein, MD, FCAP

Robert J. Lefkowitz, MD

Robert J. Lefkowitz MD, a Howard Hughes Medical Institute investigator who has spent his entire 39-year research career at the Duke University Medical Center, is sharing the 2012 Nobel Prize in Chemistry with Brian K. Kobilka of Stanford University School of Medicine, who was a post-doctoral fellow in Lefkowitz’s lab in the 1980s.

They are being recognized for their work on a class of cell surface receptors that have become the target of prescription drugs, including antihistamines, ulcer drugs and beta blockers to relieve hypertension, angina and coronary disease.

The receptors catch chemical signals from the outside and transmit their messages into the cell, providing the cell with information about changes occurring within the body. These particular receptors are called seven-transmembrane G protein-coupled receptors, or just “G-coupled receptors” for short. Serpentine in appearance, G-coupled receptors weave through the surface of the cell seven times.

The human genome contains code to make at least 1,000 different forms of these trans-membrane receptors, all of which are quite similar. The receptors also bear a strong resemblance to receptors that detect light in the eyes, smells in the nose and taste on the tongue. (See playlist of Lefkowitz science videos here.)

“Bob’s seminal discoveries related to G-protein coupled receptors ultimately became the basis for a great many medications that are in use today across many disease areas,” said Victor J. Dzau, MD, Chancellor for Health Affairs and CEO, Duke University Health System.  “He is an outstanding example of a physician-scientist whose impact can be seen in the lives of the countless patients who have benefited from his scientific discoveries. We are very proud of his magnificent achievements and grateful for his many contributions to Duke Medicine.”

After attending public elementary and junior high schools I entered The Bronx High School of Science (10th grade) in the autumn of 1956, graduating at age 16 in 1959. “Bronx Science” is one of several public high schools in New York City which admits students on the basis of a competitive examination. The student body, representing approximately the top 5% based on the exam, are gifted and interested in science and math. The accomplishments of graduates of this high school are quite remarkable. For example, I am the 8th Nobel Laureate to have graduated from this school, the 7 previous ones having received their prizes in Physics. For me, attending this school was a formative experience. Whereas in elementary and junior high school I was not greatly challenged, here I was among a group of remarkably bright, interesting and stimulating classmates. The curriculum featured many advanced classes at the college level. I was particularly drawn to chemistry and, as a result of taking these college level classes, I was able to receive full credit for two years of chemistry when I entered Columbia College in 1959. Thus I began as a college freshman with organic chemistry, a course generally taken by juniors.

The level of scholarship maintained by the student body was such that even with an average of about 94% my final class rank was about 100th out of 800. A classmate and friend at the time and at present, the famous geneticist David Botstein, had an almost identical average, a fact we tease each other about to this day.

Along with dozens of classmates, I moved on to Columbia University where I enrolled as a pre-medical student majoring in chemistry. The two year core curriculum in “Contemporary Civilization” was required of all students. With an emphasis on reading classic texts in history, philosophy, sociology and the political sciences and discussing these in small seminars, it was for me an opening to a whole new world. In addition, I took courses with and was exposed to, such intellectual giants as the literary critic Lionel Trilling, the cultural historian Jacques Barzun and the sociologist Daniel Bell, among others. I have very fond memories from this period of spending many hours in the public reading room at the 42nd Street New York Public Library, researching papers for those classes.

I also studied advanced Organic Chemistry with Cheves Walling and Physical Chemistry in a department which was strongly influenced by the then recently retired prominent physical organic chemist, Louis Hammett. However, the chemistry professor who had the most profound influence on me was actually a young Assistant Professor of Chemistry, Ronald Breslow. As a college senior I took an advanced seminar in biochemistry which he taught single handedly. This introduction to the chemistry of processes in living organisms really excited me in part, I suspect, because of his very lively teaching style. None of this, however, in any way diverted me from my goal of studying to become a practicing physician.

I greatly enjoyed my four years in medical school. I had dreamed about becoming a physician since grade school and now I was finally doing it. As a freshman immersed in the basic medical sciences I was able to deepen my interest in, and fascination with, biochemistry. Our biochemistry professors included a remarkable array of scholars (not that any of us appreciated that at the time). We heard lectures on metabolism from David Rittenberg, Chair of the Department; from David Shemin on porphyrins; from Irwin Chargaff on nucleic acids; and from David Nachmansohn on cholinergic neurotransmission.

One young professor left a lasting impression on me. Paul Marks was then a young academic hematologist who taught the Introduction to Clinical Medicine course in which we studied clinical problems for the first time, examined case histories, and looked at blood specimens. Not only was he a good clinician but he assigned readings from the basic science literature that were relevant in a very meaningful way to the cases we studied. This showed me how scientific information could be brought to bear on clinical problems. Among my classmates and friends in medical school was Harold Varmus, who was the co-recipient of the 1989 Nobel Prize for the discovery of oncogenes.

On July 1, 1968 I moved my family (now including the recently born Cheryl) to Rockville, Maryland to begin my research career at the NIH in nearby Bethesda, Maryland. I had been assigned, through a matching program, to work with Drs. Jesse Roth and Ira Pastan in the Clinical Endocrinology Branch of the National Institute of Arthritis and Metabolic Diseases (NIAMD), now known as NIDDK, the National Institute of Diabetes and Digestive and Kidney Diseases. I was a Clinical Associate, meaning that in addition to doing full time research ten months out of the year, for two months I also supervised a clinical endocrinology in-patient service. Because of this, I gained a remarkable exposure to unusual endocrine diseases which were under study at the time. An example of this was acromegaly.

It was the heyday of interest in second messenger signaling after the discovery of cAMP by Earl Sutherland. He would receive the Nobel Prize in Medicine and Physiology for this in 1971. One hormone after another was being shown to stimulate the enzyme adenylate cyclase thus increasing intracellular levels of cAMP. The idea that these different hormones might work through distinct receptors was talked about but was controversial. Moreover, at the time there were no direct methods for studying the receptors. I was assigned the challenging task of developing a radioligand binding method to study the putative receptors for adrenocorticotropic hormone (ACTH) in plasma membranes derived from an ACTH responsive adrenocortical carcinoma passaged in nude mice.

Recently, two Nobel Laureates, Mike Brown and Joe Goldstein, published a brief essay discussing the remarkable number of Nobel Laureates (9 so far) who have in common the fact that they came to the NIH as physicians during the brief space between 1964–1972 for postdoctoral research training. (1)

They dissect the unique convergence of circumstances which may have been responsible for this extraordinary result, including the quality of basic science mentors on the full time NIH staff, the competitiveness of “the best and the brightest” to obtain these positions during the Vietnam War years, and the now bygone emphasis on teaching of basic sciences in medical schools in the 1960s.

Lineages among Nobel Laureates are often commented upon. In my case, Jesse Roth had trained with Solomon Berson and Rosalyn Yalow whose development of radioimmunoassay led to the Nobel Prize in Medicine and Physiology to Yalow (1977) after Berson’s untimely death in 1972. Moreover, training in Ira Pastan’s laboratory contemporaneously with me was my medical school and house staff classmate and future Nobel Laureate, Harold Varmus. Ira had himself trained in the lab of another NIH career scientist, Earl Stadtman, who also trained a future Nobel Laureate, Mike Brown.

Dr. Edgar Haber, the Chief of Cardiology and a prominent immunochemist, allowed me to begin working in his lab. I was fascinated by receptors and what I saw as their potential to form the basis for a whole new field of research just waiting to be explored. I spent a great deal of time analyzing which receptor I should attempt to study. As an aspiring academic cardiologist I wanted to work on something related to the cardiovascular system. I also wanted a receptor known to be coupled to adenylate cyclase. I initially focused on two models, the cardiac glucagon and β-adrenergic receptors. However, my attention quickly became focused on the latter, for very practical reasons. Unlike the case for peptide hormones such as glucagon or ACTH, literally dozens, if not hundreds of analogs of adrenaline and noradrenaline, as well as their antagonists were available which could be chemically modified to develop the types of new tools which would need to be developed to study the receptors. These would include radioligands, photoaffinity probes, affinity chromatography matrices and the like. Moreover, the first β-adrenergic receptor blocker (“β-blocker”) had recently been approved for clinical use in the United States, adding further to the attractiveness of this target to me.

So in the early months of 1971 I began the quest to prove the existence of β-adrenergic receptors, to study their properties, to learn about their chemical nature, how they were regulated and how they functioned. This work has consumed me for the past forty years. Over the next several years in Boston, working mostly with membrane fractions derived from canine myocardium, I sought to develop radioligand binding approaches to tag the β-adrenergic receptors. I focused initially on the use of [3H]labeled catecholamines such as norepinephrine, which are agonists for the receptor. Specific saturable binding could be demonstrated, and I thought initially that we had developed a valid approach to label the receptors. However, it became increasingly clear over the next few years that the sites being labeled lacked many of the properties that would be expected for true physiological receptor binding sites. Coming to this realization was difficult.

During this time I also published some of the very first studies demonstrating GTP regulation of β-adrenergic receptor stimulated adenylate cyclase following after the work of Martin Rodbell on GTP regulation of glucagon sensitive adenylate cyclase. I was now a cardiology fellow. As at the NIH, nights on call were often spent in the lab doing experiments while hoping that my on call beeper would remain quiet. During these years, I had many stimulating and profitable discussions with Geoffrey Sharpe, a faculty member in the Nephrology Division with an interest in cell signaling and adenylate cyclase.

In work with postdoc Marc Caron in the spring of 1974, we succeeded in developing [3H]dihydroalprenolol. Contemporaneously, Gerald Aurbach at the NIH, and Alex Levitzki at the Hebrew University in Jerusalem also developed similar approaches using different radioligands. This was a watershed event because it finally opened the door to direct study of the receptors. Together with M.D./Ph.D. student Rusty Williams we developed comparable assays for the α-adrenergic receptors shortly thereafter.

Brian Kent Kobilka is an American physiologist and a corecipient of the 2012 Nobel Prize in Chemistry with Robert Lefkowitz for discoveries that reveal the inner workings of an important family G protein-coupled receptors.

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Heroes in Medical Research: Green Fluorescent Protein and the Rough Road in Science

Curator: Stephen J. Williams, Ph.D.

In this series, “Heroes in Medical Research”, I like to discuss the people who made some important contributions to science and medicine which underlie the great transformative changes but don’t usually get the notoriety given to Nobel Laureates or who seem to fly under the radar of popular news. Their work may be the development of research tools which allowed a great discovery leading to a line of transformative research, a moment of serendipity leading to discovery of a cure, or just contributions to the development of a new field or the mentoring of a new generation of scientists and clinicians. One such discovery, which has probably been pivotal in many of our research, is the discovery of the green fluorescent protein (GFP), commonly used as an invaluable tool to monitor protein for cellular expression and localization studies. Although the development of research tools, whether imaging tools, vectors, animal models, cell lines, and such are not heralded, they always assist in the pivotal discoveries of our time. The following is a heartwarming story by Discover Magazine’s Yudhijit Bhattacharjee behind Dr. Douglas Prasher’s discovery of the green fluorescent protein, his successful efforts to sequence the gene and subsequent struggles in science and finally scientific recognition for his work. In addition the story describes Dr. Prather’s perseverance, a trait necessary for every scientist.

http://discovermagazine.com/2011/apr/30-how-bad-luck-networking-cost-prasher-nobel

 

The following is a wonderful entry into Wikipedia about Dr. Prasher at:

http://en.wikipedia.org/wiki/Douglas_Prasher

including a listing of his publications including the seminal Science and PNAS publications1,2.

 

prasher

 

 

(Photo: Dr. Prasher in the lab at UCSD. Photo credit UCSD and John Galstaldo)

 

 

 

In summary, Dr. Prather had been working at Wood’s Hole in Massachusetts trying to discover, isolate, then clone the protein which allowed a species of jellyfish living in the cold waters of the North Pacific, Aequorea victoria, to emit a green glow. Eventually he cloned the GFP gene, but gave up on work to express the gene in mammalian cells. Before leaving Wood’s Hole he gave the gene to Dr. Roger Tsien, who with Dr. Martin Chalfie and Osamu Shimomura showed the utility of GFP as an intracellular tracer to visualize, in real time, the expression and localization of GFP-tagged proteins (all three shared the 2008 Nobel Prize for this work). Dr. Tsien however realized the importance of Douglas’s cloning work as pivotal for their research, contacted Douglas (who now due to the bad economy was working at a Toyota dealership in Alabama) and invited him to the Nobel Prize Award Ceremony in Sweden as his guest. Although Dr. Prasher had “left academic science” he never really stopped his quest for a scientific career, using his spare time to review manuscripts.

Other researchers have invited their colleagues who made important contributions to the ultimate Nobel work. One such guest was one of my colleagues Dr. Leonard Cohen, who worked with Dr. Irwin Rose and Avram Hershko at the Institute for Cancer Research in Philadelphia a cell-free system from clams to discover the mechanism how cyclin B is degraded during the exit from the cell cycle (from A. Hershko’s Nobel speech). Dr. Hershko had acknowledged a slew of colleagues and highlighted their contributions to the ultimate work. It shows how even small discoveries can contribute to the sphere of scientific knowledge and breakthrough.

Luckily, in the end, perseverance has paid off as Dr. Prasher is now using his talents in Roger Tsien‘s group at the University of California in San Diego.

References:

1. Chalfie, M., Tu, Y., Euskirchen, G., Ward, W.W., Prasher, D.C., Green fluorescent protein as a marker for gene expression. Science, 263(5148), 802-805 (1994).

 

2. Heim, R., Prasher, D.C., Tsien, R.Y., Wavelength mutations and posttranslational autoxidation of green fluorescent protein. Proc. Natl. Acad. Sci. USA, 91(26), 12501-12504 (1994).

More posts on this site on Heroes in Medical Research series include:

Heroes in Medical Research: Developing Models for Cancer Research

Heroes in Medical Research: Dr. Carmine Paul Bianchi Pharmacologist, Leader, and Mentor

Heroes in Medical Research: Dr. Robert Ting, Ph.D. and Retrovirus in AIDS and Cancer

Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin

 

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Cyber Experiments: 2013 Nobel Chemistry Prize: Martin Karplus, Michael Levitt and Arieh Warshel

Reporter: Aviva Lev-Ari, PhD, RN

Three win Nobel chemistry prize for cyber experiments
Wed, 10/09/2013 – 8:15am
Karl Ritter and Malin Rising, Associated Press

This photo shows a Webpage showing the laureates Martin Karplus, Michael Levitt and Arieh Warshel as winners of the 2013 Nobel Prize in chemistry, announced by the Royal Swedish Academy of Sciences in Stockholm. The prize was awarded for laying the foundation for the computer models used to understand and predict chemical processes. Photo: AP Photo/Claudio BrescianiThis photo shows a Webpage showing the laureates Martin Karplus, Michael Levitt and Arieh Warshel as winners of the 2013 Nobel Prize in chemistry, announced by the Royal Swedish Academy of Sciences in Stockholm. The prize was awarded for laying the foundation for the computer models used to understand and predict chemical processes. Photo: AP Photo/Claudio BrescianiSTOCKHOLM (AP) — Three U.S.-based scientists won the 2013 Nobel Prize in chemistry for developing powerful computer models that others can use to understand complex chemical interactions and create new drugs.

Research in the 1970s by Martin Karplus, Michael Levitt and Arieh Warshel has helped scientists develop programs that unveil chemical processes such as the purification of exhaust fumes or photosynthesis in green leaves, the Royal Swedish Academy of Sciences said. That kind of knowledge makes it possible to optimize catalysts for cars or design drugs and solar cells.

“This year’s prize is about taking the chemical experiment to cyberspace,” said Staffan Normark, the academy’s secretary.

Karplus, an 83-year-old U.S. and Austrian citizen, is affiliated with the Univ. of Strasbourg, France, and Harvard Univ. The academy said Levitt, 66, is a British, U.S. and Israeli citizen and a professor at the Stanford Univ. School of Medicine. Warshel, 72, is a U.S. and Israeli citizen affiliated with the Univ. of Southern California in Los Angeles.

Warshel told a news conference in Stockholm by telephone that he was “extremely happy” to have been woken up in the middle of the night in Los Angeles to find out he had won the prize and looks forward to collecting it in the Swedish capital in December.

“In short, what we developed is a way which requires computers to look, to take the structure of the protein and then to eventually understand how exactly it does what it does,” Warshel said.

When scientists wanted to simulate complex chemical processes on computers, they used to have to choose between software that was based on classical Newtownian physics or ones based on quantum physics. But the academy said the three laureates developed computer models that “opened a gate between these two worlds.”

The strength of their methods is that they can be used to study all kinds of chemistry, it said.

“Scientists can optimize solar cells, catalysts in motor vehicles or even drugs, to take but a few examples,” the academy said.

Working together at Harvard in the early 1970s, Karplus and Warshel developed a computer program that brought together classical and quantum physics. Warshel later joined forces with Levitt at the Weizeman institute in Rehovot, Israel, and at the Univ. of Cambridge in Britain, to develop a program that could be used to study enzymes.

Jeremy Berg, a prof. of computational and systems biology at the Univ. of Pittsburgh, said the winning work gives scientists a way to understand complicated reactions that involve thousands to millions of atoms.

“There are thousands of laboratories around the world using these methods, both for basic biochemistry and for things like drug design,” said Berg, former director of the National Institute of General Medical Sciences in Bethesda.

Many drug companies use computer simulations to screen substances for their potential as medicines, which lets them focus their chemistry laboratory work on those that look promising, he said.

Marinda Li Wu, president of the American Chemical Society, was equally enthusiastic about the award.

“I think it’s fabulous,” she said in a telephone interview. “They’re talking about the partnering of theoreticians with experimentalists, and how this has led to greater understanding.”

That is “bringing better understanding to problems that couldn’t be solved experimentally,” she said. “We’re starting as scientists to better understand things like how pharmaceutical drugs interact with proteins in our body to treat diseases. This is very, very exciting.”

Earlier this week, three Americans won the Nobel Prize in medicine for discoveries about how key substances are moved around within cells and the physics award went to British and Belgian scientists whose theories help explain how matter formed in the universe after the Big Bang.

Source: Associated Press

http://www.rdmag.com/news/2013/10/three-win-nobel-chemistry-prize-cyber-experiments?et_cid=3527874&et_rid=461755519&location=top

 

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Innovations in Israel – Nobel Prize in Chemistry 2004, 2011

Reporter: Aviva Lev-Ari, PhD, RN

 

Prof. Avram Hershko – Science as an Adventure –

Nobel Prize in Chemistry 2004

Prof. Avram Hershko shared the 2004 Nobel Prize in Chemistry with Aaron Ciechanover and Irwin Rose for “for the discovery of ubiquitin-mediated protein degradation.” He is a research professor in the Department of Biochemistry at the Technion’s Rappaport Faculty of Medicine in Haifa.

http://www.youtube.com/watch?v=lGJvsmG3mhw&list=PL8814C902ACB98559&feature=plcp

Prof. Aaron Ciechanover – Intracellular Proteolysis as a Future Drug Development Platform –

Nobel Prize in Chemistry 2004

Prof. Dan Shechtman  –  was awarded to Dan Shechtman “for the discovery of quasicrystals”.

 Nobel Prize in Chemistry 2011

On Dec. 10, 2011 as Prof. Dan Shechtman received his Nobel prize in chemistry, hundreds of Technion students gathered in the Zielony Student Union to watch the ceremony live in the Heller Cinema. A standing ovation was given to Prof. Shechtman when he received the prize.

http://www.youtube.com/watch?v=MGC1K255y0M&feature=relmfu

http://www.youtube.com/watch?v=EZRTzOMHQ4s&feature=relmfu

Daniel Shechtman is awarded the Nobel Prize for his discovery of quasicrystals. Discussed here by Professor Martyn Poliakoff and Sixty Symbols’ Professor Phil Moriarty.

http://www.youtube.com/watch?v=QiT00AUwQl8&feature=fvwrel

Technion and Albert Einstein

http://www.youtube.com/watch?v=gNZ6uNtSUHI&feature=relmfu

Technion Robots — Snake, Worm, Wall Crawling, Algorithms, Multi Agent

http://www.youtube.com/watch?v=8HHb3Z4n-4M&feature=relmfu

Prof. Judea Pearl and Ruth Pearl Interview Technion Harvey Prize

http://www.youtube.com/watch?v=32vGtL7T6Og&feature=context-chf&playnext=1&list=PLF3C1A9B99F462C37

http://www.youtube.com/technion

Technion-Cornell Innovation Institute – Craig Gotsman Interview

Interview with Prof. Craig Gotsman, Technion Computer Science professor and Founding Director of TCII-Technion-Cornell Innovation Institute. This institute is a joint venture of the Technion and Cornell University, and will be a key component of the new Cornell NYC Tech campus, a unique high-tech graduate school to be established in New York City. The goal of the entire NYC Tech campus, and the TCII within it, as conceived by Mayor Bloomberg, is to turn NYC into the high-tech capital of the world. This will be achieved by developing TCII into a fertile breeding ground for high-tech engineers. Google, New York will be the interim home of the Technion-Cornell Innovation Institute (TCII) and the CornellNYC Tech Campus. Google will initially provide 22,000 square feet, expandable to 58,000 square feet – free of charge – until the completion of the Roosevelt Island campus in 2017.

http://www.youtube.com/watch?v=-va_ncrYWes

Technion Cornell NYC Tech Campus Interior View

http://www.youtube.com/watch?v=HkN1aysdhdQ

Israel — One Hundred Years of Science and Technology

http://www.youtube.com/watch?v=GzilbrH3CcA&NR=1&feature=endscreen

Technion: The Start-Up Nation University

Saul Singer, co-author with Dan Senor of the best- selling book, “Start-Up Nation: The Story of Israel’s Economic Miracle” discusses the book and Technion’s critical contribution to Israel’s start-up scenehttp://www.startupnationbook.com/ . Featured in this film are Technion alumni, Shai Agassi founder and chief executive of Better Placehttp://www.betterplace.com/ and Uzia Galil, the founding father of Israeli high-tech http://www.uzia.com/management/ . Galil founded Elron Electronic Industries and Elbit computers.

ISRAEL START-UP NATION

http://www.youtube.com/watch?v=3JN1xwlKmoQ&feature=relmfuhttp://www.youtube.com/watch?v=-EQliG9Wsdo&feature=related

Israel: A Leader in Business Innovation

http://www.youtube.com/watch?v=KHLyANGmLjQ&feature=related

Israel in pictures

http://www.youtube.com/watch?v=T5gKq_p135Q&feature=related

Israel from the Air part 1

http://www.youtube.com/watch?v=3WFgeI3CXAU&feature=related

Israel from the Air part 2

http://www.youtube.com/watch?v=S08vOHhAWY8&feature=relmfu

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