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Nobel Prize in Physiology or Medicine 2013 for Cell Transport: James E. Rothman of Yale University; Randy W. Schekman of the University of California, Berkeley; and Dr. Thomas C. Südhof of Stanford University

Reporter: Aviva Lev-Ari, PhD, RN

Comments by Graduate Students of the nobel Prize Recipients and other in NYT, 10/7/2013:

I had the privilege of meeting Randy Schekman a few times when I was a postdoc at Berkeley. In addition to pioneering the understand of cellular trafficking, he was also a great colleague and educator (of undergrads, grad students, postdocs). Hats off to a wonderful scientist who also pays it forward to future generations as a mentor!

Last couple years, including this year, the Nobel for Physiology or Medicine Award has been dominated by Cell Biologists. I think this highlights how understanding cells is really the key to most medicine.
Paul Knoepfler
http://www.ipscell.com

I guess UC Berkeley will have to add a few more Nobel Laureate Parking Spots on their campus now!
Yes, in parking-challenged Berkeley campus, some of the best parking spots are reserved for the Nobel Laureate Faculty. They have so many winners, and rather spotty on-campus parking, so they don’t want such brains to go hunt for parking. They reason that the Laureates should be doing better things, like more research, or assisting newer researchers and students. A most elegant solution!
I don’t think there is any other institution anywhere in the world that has dedicated parking for their Nobel-winning employees. Or has so many Nobels on the payroll. But then, there is just one Cal.
This prize is another testament to UC Berkeley’s standing.
Congratulations to the scientists, and a big thank you to their institutions that allowed them the freedom and resources to pursue their ideas.

Randy Schekman awarded 2013 Nobel Prize in Physiology or Medicine

By Robert Sanders, Media Relations | October 7, 2013

BERKELEY —

ScheckmanRandy Schekman, who will share the 2013 Nobel Prize in Physiology or Medicine (Peg Skorpinski photo)

Randy W. Schekman, professor of molecular and cell biology at the University of California, Berkeley, has won the 2013 Nobel Prize in Physiology or Medicine for his role in revealing the machinery that regulates the transport and secretion of proteins in our cells. He shares the prize with James E. Rothman of Yale University and Thomas C. Südhof of Stanford University.

Discoveries by Schekman about how yeast secrete proteins led directly to the success of the biotechnology industry, which was able to coax yeast to release useful protein drugs, such as insulin and human growth hormone. The three scientists’ research on protein transport in cells, and how cells control this trafficking to secrete hormones and enzymes, illuminated the workings of a fundamental process in cell physiology.

Schekman is UC Berkeley’s 22nd Nobel Laureate, and the first to receive the prize in the area of physiology or medicine.

In a statement, the 50-member Nobel Assembly lauded Rothman, Schekman and Südhof for making known “the exquisitely precise control system for the transport and delivery of cellular cargo. Disturbances in this system have deleterious effects and contribute to conditions such as neurological diseases, diabetes, and immunological disorders.”

“My first reaction was, ‘Oh, my god!’ said Schekman, 64, who was awakened at his El Cerrito home with the good news at 1:30 a.m. “That was also my second reaction.”

Be part of our developing story on Storify and Twitter: Tweet your congratulations to Professor Schekman, using hashtag #BerkeleyNobel.

Also see:

Happy ending for Berkeley’s newest Nobel winner

Schekman and Rothman separately mapped out one of the body’s critical networks, the system in all cells that shuttles hormones and enzymes out and adds to the cell surface so it can grow and divide. This system, which utilizes little membrane bubbles to ferry molecules around the cell interior, is so critical that errors in the machinery inevitably lead to death.

“Ten percent of the proteins that cells make are secreted, including growth factors and hormones, neurotransmitters by nerve cells and insulin from pancreas cells,” said Schekman, a Howard Hughes Medical Institute Investigator and a faculty member in the Li Ka Shing Center for Biomedical and Health Sciences.

Schekman on the phoneSchekman takes a call at home after getting the news. (Carol Ness photo)

In what some thought was a foolish decision, Schekman decided in 1976, when he first joined the College of Letters and Science at UC Berkeley, to explore this system in yeast. In the ensuing years, he mapped out the machinery by which yeast cells sort, package and deliver proteins via membrane bubbles to the cell surface, secreting proteins important in yeast communication and mating. Yeast also use the process to deliver receptors to the surface, the cells’ main way of controlling activities such as the intake of nutrients like glucose.

In the 1980s and ’90s, these findings enabled the biotechnology industry to exploit the secretion system in yeast to create and release pharmaceutical products and industrial enzymes. Today, diabetics worldwide use insulin produced and discharged by yeast, and most of the hepatitis B vaccine used around the world is secreted by yeast. Both systems were developed by Chiron Corp. of Emeryville, Calif., now part of Novartis International AG, during the 20 years Schekman consulted for the company.

Various diseases, including some forms of diabetes and a form of hemophilia, involve a hitch in the secretion system of cells, and Schekman is now investigating a possible link to Alzheimer’s disease.

“Our findings have aided people in understanding these diseases,” said Schekman.

Based on the machinery discovered by Schekman and Rothman, Südhof subsequently discovered how nerve cells release signaling molecules, called neurotransmitters, which they use to communicate.

For his scientific contributions, Schekman was elected to the National Academy of Sciences in 1992, received the Gairdner International Award in 1996 and the Lasker Award for basic and clinical research in 2002. He was elected president of the American Society for Cell Biology in 1999. On Oct. 3, Schekman received the Otto Warburg Medal of the German Society for Biochemistry and Molecular Biology, which is considered the highest German award in the fields of biochemistry and molecular biology.

Schekman, formerly editor of the journal Proceedings of the National Academy of Sciences, currently is editor-in-chief of the new open access journal eLife.

Schekman and his wife, Nancy Walls, have two adult children.

MORE INFORMATION

SOURCE

tanford Report, October 7, 2013

Thomas Südhof wins Nobel Prize in Physiology or Medicine

Neuroscientist Thomas Südhof, MD, professor of molecular and cellular physiology at the Stanford School of Medicine, won the 2013 Nobel Prize in Physiology or Medicine.

BY KRISTA CONGER

Steve FischThomas SudhofThomas Sudhof won the 2013 Nobel Prize in Physiology or Medicine.

Neuroscientist Thomas Südhof, MD, professor of molecular and cellular physiology at the Stanford University School of Medicine, won the 2013 Nobel Prize in Physiology or Medicine.

He shared the prize with James Rothman, PhD, a former Stanford professor of biochemistry, andRandy Schekman, PhD, who earned his doctorate at Stanford under the late Arthur Kornberg, MD, another winner of the Nobel Prize in Physiology or Medicine.

The three were awarded the prize “for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells.” Rothman is now a professor at Yale University, and Schekman is a professor at UC-Berkeley.

“I’m absolutely surprised,” said Südhof, who was in the remote town of Baeza in Spain to attend a conference and give a lecture. “Every scientist dreams of this. I didn’t realize there was chance I would be awarded the prize. I am stunned and really happy to share the prize with James Rothman and Randy Schekman.”

The three winners will share a prize that totals roughly $1.2 million, with about $413,600 going to each.

Robert Malenka, MD, Stanford’s Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences, is at the conference with Südhof, a close collaborator. “He’s dazed, tired and happy,” Malenka said by phone. “The only time I’ve seen him happier was when his children were born.”

Südhof, the Avram Goldstein Professor in the School of Medicine, received the award for his work in exploring how neurons in the brain communicate with one another across gaps called synapses. Although his work has focused on the minutiae of how molecules interact on the cell membranes, the fundamental questions he’s pursuing are large.

“The brain works by neurons communicating via synapses,” Südhof said in a phone conversation this morning. “We’d like to understand how synapse communication leads to learning on a larger scale. How are the specific connections established? How do they form? And what happens in schizophrenia and autism when these connections are compromised?” In 2009, he published research describing how a gene implicated in autism and schizophrenia alters mice’s synapses and produces behavioral changes in the mice, such as excessive grooming and impaired nest building, that are reminiscent of these human neuropsychiatric disorders.

Lloyd Minor, MD, dean of the School of Medicine, said, “Thomas Südhof is a consummate citizen of science. His unrelenting curiosity, his collaborative spirit, his drive to ascertain the minute details of cellular workings, and his skill to carefully uncover these truths — taken together it’s truly awe-inspiring.

“He has patiently but relentlessly probed one of the fundamental questions of medical science — perhaps the fundamental question in neuroscience: How nerve cells communicate with each other. The answer is at the crux of human biology and of monumental importance to human health. Dr. Südhof’s receipt of this prize is inordinately well-deserved, and I offer him my heartfelt congratulations. His accomplishment represents what Stanford Medicine and the biomedical revolution are all about.”

The Nobel committee called Südhof on his cell phone after trying his home in Menlo Park, Calif. His wife, Lu Chen, PhD, associate professor of neurosurgery and of psychiatry and behavioral sciences, then gave the committee his cell phone number to reach him in Spain.

“The phone rang three times before I decided to go downstairs and pick it up,” Chen said. “I thought it was one of my Chinese relatives who couldn’t figure out the time zone.”

Chen and Südhof have two young children, and Südhof has four adult children from a previous marriage. “I was very surprised,” Chen said, “but he’s more concerned about how I’ll get the kids up this morning in time for school.”

“I was expecting a call from a colleague about the conference I’m here to attend, so I pulled off in a parking lot,” said Südhof, who was driving from Madrid to Baeza at the time he received the announcement. “I hadn’t slept at all the previous night, and I certainly wasn’t expecting a call from the Nobel committee.”

On the day he got the call from the Nobel committee, he was scheduled to give a talk at a conference, Membrane Traffic at the Synapse: The Cell Biology of Synaptic Plasticity, held in a 17th-century building that now serves as a conference center.

“Professor Sudhof’s contributions to the understanding of how cells operate have been of enormous importance to medicine, and to his own work in understanding how connections form within the human brain,” said Stanford President John Hennessy. “The recognition by the Nobel committee is a remarkable achievement.”

Südhof, who is also a Howard Hughes Medical Institute investigator, has spent the past 30 years prying loose the secrets of the synapse, the all-important junction where information, in the form of chemical messengers called neurotransmitters, is passed from one neuron to another. The firing patterns of our synapses underwrite our consciousness, emotions and behavior. The simple act of taking a step forward, experiencing a fleeting twinge of regret, recalling an incident from the morning commute or tasting a doughnut requires millions of simultaneous and precise synaptic firing events throughout the brain and peripheral nervous system.

Even a moment’s consideration of the total number of synapses in the typical human brain adds up to instant regard for that organ’s complexity. Coupling neuroscientists’ ballpark estimate of 200 billion neurons in a healthy adult brain with the fact that any single neuron may share synaptic contacts with as few as one or as many as 1 million other neurons (the median is somewhere in the vicinity of 10,000) suggests that your brain holds perhaps 2 quadrillion synapses — 10,000 times the number of stars in the Milky Way.

“The computing power of a human or animal brain is much, much higher than that of any computer,” said Südhof. “A synapse is not just a relay station. It is not even like a computer chip, which is an immutable element. Every synapse is like a nanocomputer all by itself. The amount of neurotransmitter released, or even whether that release occurs at all, depends on that particular synapse’s previous experience.”

Much of a neuron can be visualized as a long, hollow cord whose outer surface conducts electrical impulses in one direction. At various points along this cordlike extension are bulbous nozzles known as presynaptic terminals, each one housing myriad tiny, balloon-like vesicles containing neurotransmitters and each one abutting a downstream (or postsynaptic) neuron.

When an electrical impulse traveling along a neuron reaches one of these presynaptic terminals, calcium from outside the neuron floods in through channels that open temporarily, and a portion of the neurotransmitter-containing vesicles fuse with the surrounding bulb’s outer membrane and spill their contents into the narrow gap separating the presynaptic terminal from the postsynaptic neuron’s receiving end.

Südhof, along with other researchers worldwide, has identified integral protein components critical to the membrane fusion process. Südhof purified key protein constituents sticking out of the surfaces of neurotransmitter-containing vesicles, protruding from nearby presynaptic-terminal membranes, or bridging them. Then, using biochemical, genetic and physiological techniques, he elucidated the ways in which the interactions among these proteins contribute to carefully orchestrated membrane fusion: As a result, synaptic transmission is today one of the best-understood phenomena in neuroscience.

Südhof, who was born in Germany in 1955, received an MD in 1982 from Georg-August-Universität in Göttingen. He came to Stanford in 2008 after 25 years at the University of Texas Southwestern Medical Center at Dallas, where he first worked as a postdoctoral fellow at the laboratories of Michael Brown, MD, and Joseph Goldstein, MD.. Brown and Goldstein were awarded the Nobel Prize in Physiology or Medicine in 1985 for their work in understanding the regulation of cholesterol metabolism. In 1986, Südhof established his own laboratory at the university.

Südhof became an HHMI investigator in 1991, and moved to Stanford as a professor in molecular and cellular physiology in 2008.

The proteins Südhof has focused on for close to three decades are disciplined specialists. They recruit vesicles, bring them into “docked” positions near the terminals, herd calcium channels to the terminal membrane, and, cued by calcium, interweave like two sides of a zipper and force the vesicles into such close contact with terminal membranes that they fuse with them and release neurotransmitters into the synaptic gap. Although these specialists perform defined roles at the synapses, similar proteins, discovered later by Südhof and others, play comparable roles in other biological processes ranging from hormone secretion to fertilization of an egg during conception to immune cells’ defense against foreign invaders.

“We’ve made so many major advances during the past 50 years in this field, but there’s still much more to learn,” said Südhof, who in a 2010 interview with The Lancet credited his bassoon instructor as his most influential teacher for helping him to learn the discipline to practice for hours on end. “Understanding how the brain works is one of the most fundamental problems in neuroscience.”

Südhof’s accomplishments also earned him the 2013 Lasker Basic Medical Research Award. He is a member of the National Academy of Sciences, the Institute of Medicine and the American Academy of Arts & Sciences. He also is a recipient of the 2010 Kavli Prize in neuroscience.

In the Lancet interview, Südhof defined basic research as an approach often neglected in the pursuit of medicine. “This ‘solid descriptive science,’ like neuroanatomy or biochemistry, [are] disciplines that cannot claim to immediately understand functions or provide cures, but which form the basis for everything we do.”

Südhof said this morning he is excited to speak with his family about the prize, although it may be too much for his youngest children, ages 3 and 4, to grasp. “I will try to explain it to them,” he said. “It will be a wonderful occasion.” He noted that he has already received congratulatory calls from two of his four adult children. For them, the news may have come as less of a surprise.

“The Nobel prize became an inevitable topic of conversation when Tom won the Lasker award,” Chen said. “But the two of us share a feeling that one should never work for prizes.”

“Everyone has pegged him as a potential Nobel prize winner for many years,” said Malenka, who described the scene at the conference during the lunch hour. “It was just a matter of time. The attendees were clapping and cheering for him.”

Although he plans to return to the United States as soon as possible, Südhof has no plans to let the award slow his research — or even his plans for the day. He responded to an inquiry with a characteristically low-key reply. “Well, I think I’ll go ahead and give my talk.”

SOURCE

Rothman Lab

Membrane fusion is a fundamental biological process for organelle formation, nutrient uptake, and the secretion of hormones and neurotransmitters.

It is central to vesicular transport, storage, and release in many areas of endocrine and exocrine physiology, and imbalances in these processes give rise to important diseases, such as diabetes.

We employ diverse biophysical, biochemical, and cell biological approaches to characterize the fundamental participants in intracellular transport processes.

flippedcellfull
Time lapse images of fusing flipped-SNARE cells.

SNARE Overview

Over 30 years ago, we observed what we interpreted to be vesicular transport in crude extracts of tissue culture cells. In subsequent years we found that we had reconstituted vesicle trafficking in the Golgi, including the process of membrane fusion. Using this assay as a guide, we purified as a required factor the NEM-Sensitive Fusion protein (NSF). This led to the purification of the Soluble NSF Attachment Factor (SNAP), which bound NSF to Golgi membranes, and then with these tools discovered that the receptors for SNAP in membranes were actually complexes of proteins (which we called SNAREs) which we envisioned could potentially partner as a bridge between membranes to contribute to the process of membrane fusion and provide specificity to it (as captured in the ‘SNARE hypothesis’ proposed at the time).

We now know that organisms have a large family of SNARE proteins that indeed form cognate partnerships in just this way, and that NSF is an ATPase that (using SNAP as an adaptor protein) disrupts the SNARE complex after fusion is complete so its subunits can be recycled for repeated use. Recombinant cognate SNAREs introduced into artificial bilayers or expressed ectopically on the outside of cells ( “flipped SNAREs”) spontaneously and efficiently result in membrane (or cell) fusion, demonstrating that the SNARE complex is not only necessary but is sufficient for fusion. There are many proteins known and rapidly being discovered which closely regulate this vital process, but the muscle – if not always the brains – is in the SNAREs. Compartmental specificity is encoded to a remarkable degree in the functional partnering of SNARE proteins, a fact which is in no way inconsistent with the emerging contribution of upstream regulatory components (like rabGTPases and tethering complexes) to domain/compartment specificity.

Current Research & Projects

Our lab is working to elucidate the underlying mechanisms of vesicular transport within cells and the secretion of proteins and neurotransmitters.

Projects include:

  1. The biochemical and biophysical mechanisms of vesicle budding and fusion;
  2. Cellular regulation of vesicle fusion in exocytosis and synaptic transmission;
  3. Structural and functional organization of the Golgi apparatus from a cellular systems view.

We take an interdisciplinary approach which includes cell-free biochemistry, single molecule biophysics, high resolution optical imaging of single events/single molecules in the cell and in cell-free formats.

The overall goal is to understand transport pathways form structural mechanism to cellular physiology. The latter is facilitated by high throughput functional genomics at the cellular level (see Yale Center for High Throughput Cell Biology).

SNAREpins

We have a strong interest in new lab members who bring backgrounds in chemistry, physics, and engineering.

SOURCE

http://medicine.yale.edu/cellbio/rothman/index.aspx

3 Americans Win Joint Nobel Prize in Medicine

Reuters

From left: Randy W. Schekman, Thomas C. Südhof and James E. Rothman.

<nyt_byline>

By 
Published: October 7, 2013 151 Comments

Three Americans won the Nobel Prize in Physiology or Medicine Monday for discovering the machinery that regulates how cells transport major molecules in a cargo system that delivers them to the right place at the right time in cells.

Science Twitter Logo.
 

The Karolinska Institute in Stockholmannounced the winners: James E. Rothman of Yale University; Randy W. Schekman of the University of California, Berkeley; and Dr. Thomas C. Südhof of Stanford University.

The molecules are moved around cells in small packages called vesicles, and each scientist discovered different facets that are needed to ensure that the right cargo is shipped to the correct destination at precisely the right time.

Their research solved the mystery of how cells organize their transport system, the Karolinska committee said. Dr. Schekman discovered a set of genes that were required for vesicle traffic. Dr. Rothman unraveled protein machinery that allows vesicles to fuse with their targets to permit transfer of cargo. Dr. Südhof revealed how signals instruct vesicles to release their cargo with precision.

The tiny vesicles, which have a covering known as membranes, shuttle the cargo between different compartments or fuse with the membrane. The transport system activates nerves. It also controls the release of hormones.

Disturbances in this exquisitely precise control system cause serious damage that, in turn, can contribute to conditions like neurological diseases, diabetes and immunological disorders.

Dr. Schekman, 64, who was born in St. Paul, used yeast cells as a model system when he began his research in the 1970s. He found that vesicles piled up in parts of the cell and that the cause was genetic. He went on to identify three classes of genes that control different facets of the cell’s transport system. Dr. Schekman studied at the University of California in Los Angeles and at Stanford University, where he obtained his Ph.D. in 1974.

In 1976, he joined the faculty of the University of California, Berkeley, where he is currently professor in the Department of Molecular and Cell Biology. Dr. Schekman is also an investigator at the Howard Hughes Medical Institute.

Dr. Rothman, 63, who was born in Haverhill, Mass., studied vesicle transport in mammalian cells in the 1980s and 1990s. He discovered that a protein complex allows vesicles to dock and fuse with their target membranes. In the fusion process, proteins on the vesicles and target membranes bind to each other like the two sides of a zipper. The fact that there are many such proteins and that they bind only in specific combinations ensures that cargo is delivered to a precise location.

The same principle operates inside the cell and when a vesicle binds to the cell’s outer membrane to release its contents. Dr. Rothman received a Ph.D. from Harvard Medical School in 1976, was a postdoctoral fellow at Massachusetts Institute of Technology, and moved in 1978 to Stanford University, where he started his research on the vesicles of the cell. Dr. Rothman has also worked at Princeton University, Memorial Sloan-Kettering Cancer Institute and Columbia University.

In 2008, he joined the faculty of Yale University where he is currently professor and chairman in the Department of Cell Biology. Some of the genes Dr. Schekman discovered in yeast coded for proteins correspond to those Dr. Rothman identified in mammals. Collectively, they mapped critical components of the cell´s transport machinery.

Dr. Südhof, 57, who was born in Göttingen, Germany, studied neurotransmission, the process by which nerve cells communicate with other cells in the brain. At the time he set out to explore the field 25 years ago, much of it was virgin scientific territory. Researchers had not identified a single protein in the neurotransmission process.

Dr. Südhof helped transform what had been a rough outline into a number of molecular activities to provide insights into the elaborate mechanisms at the crux of neurological activities, from the simplest to the most sophisticated. He did so by systematically identifying, purifying and analyzing proteins that can rapidly release chemicals that underlie the brain’s activities. The transmission process can take less than a thousandth of a second.

Dr. Südhof studied at the Georg-August-Universität in Göttingen, where he received a medical degree in 1982 and a doctorate in neurochemistry the same year. In 1983, he moved to the University of Texas Southwestern Medical Center in Dallas. Dr. Südhof, who has American citizenship, became an investigator at the Howard Hughes Medical Institute in 1991 and was appointed professor of molecular and cellular physiology at Stanford University in 2008.

All three scientists have won other awards, including the Lasker Prize, for their research.

<nyt_correction_bottom>

This article has been revised to reflect the following correction:

Correction: October 7, 2013

An earlier version of this article misstated Randy W. Schekman’s age. He is 64, not 65.

SOURCE

http://www.nytimes.com/2013/10/08/health/3-win-joint-nobel-prize-in-medicine.html?_r=0

Nobel for Cell Transport

October 07, 2013

This year’s Nobel Prize in Physiology or Medicine is going jointly to three scientists for their work figuring out how cells transport their cargo, according to the Karolinska Institute. They will share the $1.25 million prize.

“Imagine hundreds of thousands of people who are traveling around hundreds of miles of streets; how are they going to find the right way? Where will the bus stop and open its doors so that people can get out?” says Nobel committee secretary Goran Hansson, according to the Associated Press. “There are similar problems in the cell.”

By studying yeast cells with defective vesicles, Randy Schekman from the University of California, Berkeley, uncovered three classes of genes that control transportation within the cell, the New York Times adds. Schekman was awakened in California by the call from Stockholm. “I wasn’t thinking too straight. I didn’t have anything elegant to say,” he tells the AP. “All I could say was ‘Oh my God,’ and that was that.” Schekman adds that he called his lab manager to arrange a celebration in the lab.

Meanwhile, Yale University’s James Rothman discovered a protein complex that allows vesicles to bind to their intended membrane targets, getting the vesicle contents to a specific location. Rothman notes that he recently lost funding for work building on his discovery, and says that he hopes that having won the Nobel will help him when he reapplies.

And Thomas Südhof at Stanford University systematically studied how nerve cells communicate, finding that vesicles full of neurotransmitters bind to cell membranes to release their contents through a molecular mechanism that responds to the presence of calcium ions. He was on his way to a give a talk when he got his call. “I got the call while I was driving and like a good citizen I pulled over and picked up the phone,” Südhof says to the AP. “To be honest, I thought at first it was a joke. I have a lot of friends who might play these kinds of tricks.”

SOURCE

Other related articles published on these Open Access Online Scientific Journal include the following:

The Series on Cardiovascular Disease and the role of Calcium Signaling consists of the following articles:

Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/

Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

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Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

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 and Aviva Lev-Ari, PhD, RN

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Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

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Part V: Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

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Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

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Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

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From Molecular Biology to Translational Medicine: How Far Have We Come, and Where Does It Lead Us?

The Initiation and Growth of Molecular Biology and Genomics, Part I

Curator: Larry H Bernstein, MD, FCAP

Introduction and purpose

This material will cover the initiation phase of molecular biology, Part I; to be followed by the Human Genome Project, Part II; and concludes with Ubiquitin, it’s Role in Signaling and Regulatory Control, Part III.
This article is first a continuation of a previous discussion on the role of genomics in discovery of therapeutic targets titled Directions for genomics in personalized medicine https://pharmaceuticalintelligence.com/2013/01/27/directions-for-genomics-in-personalized-medicine/

The previous article focused on key drivers of cellular proliferation, stepwise mutational changes coinciding with cancer progression, and potential therapeutic targets for reversal of the process. It also covers the race to delineation of the Human Genome, discovery methods and fundamental genomic patterns that are ancient in both animal and plant speciation.

This article reviews the web-like connections between early and later discoveries, as significant finding has led to novel hypotheses and many more findings over the last 75 years. This largely post WWII revolution has driven our understanding of biological and medical processes at an exponential pace owing to successive discoveries of chemical structure, the basic building blocks of DNA and proteins, of nucleotide and protein-protein interactions, protein folding, allostericity, genomic structure, DNA replication, nuclear polyribosome interaction, and metabolic control. In addition, the emergence of methods for copying, removal and insertion, and improvements in structural analysis as well as developments in applied mathematics have transformed the research framework.

In the Beginning

During the Second World War we had the discoveries of physics and the emergence out of the Manhattan Project of radioactive nuclear probes from E.O. Lawrence University of California Berkeley Laboratory. The use of radioactive isotopes led to the development of biochemistry and isolation of nucleotides, nucleosides, enzymes, and filling in of details of pathways for photosynthesis, for biosynthesis, and for catabolism.
Perhaps a good start of the journey is a student of Neils Bohr named Max Delbruck (September 4, 1906 – March 9, 1981), who won the Nobel prize for discovering that bacteria become resistant to viruses (phages) as a result of genetic mutations, founded a new discipline called Molecular Biology, lifting the experimental work in Physiology to a systematic experimentation in biology with the rigor of Physics using radiation and virus probes on selected cells. In 1937 he turned to research on the genetics of Drosophila melanogaster at Caltech, and two years later he coauthored a paper, “The growth of bacteriophage”, reporting that the viruses replicate in one step, not exponentially. In 1942, he and Salvador Luria of Indiana University demonstrated that bacterial resistance to virus infection is mediated by random mutation. This research, known as the Luria-Delbrück experiment, notably applied mathematics to make quantitative predictions, and earned them the 1969 Nobel Prize in Physiology or Medicine, shared with Alfred Hershey. His inferences on genes’ susceptibility to mutation was relied on by physicist Erwin Schrödinger in his 1944 book, What Is Life?, which conjectured genes were an “aperiodic crystal” storing code-script and influenced Francis Crick and James D. Watson in their 1953 identification of cellular DNA’s molecular structure as a double helix.

Watson-Crick Double Helix Model

A new understanding of heredity and hereditary disease was possible once it was determined that DNA consists of two chains twisted around each other, or double helixes, of alternating phosphate and sugar groups, and that the two chains are held together by hydrogen bonds between pairs of organic bases—adenine (A) with thymine (T), and guanine (G) with cytosine (C). Modern biotechnology also has its basis in the structural knowledge of DNA—in this case the scientist’s ability to modify the DNA of host cells that will then produce a desired product, for example, insulin.
The background for the work of the four scientists was formed by several scientific breakthroughs:

  1. the progress made by X-ray crystallographers in studying organic macromolecules;
  2. the growing evidence supplied by geneticists that it was DNA, not protein, in chromosomes that was responsible for heredity;
  3. Erwin Chargaff’s experimental finding that there are equal numbers of A and T bases and of G and C bases in DNA;
  4. and Linus Pauling’s discovery that the molecules of some proteins have helical shapes.

In 1962 James Watson (b. 1928), Francis Crick (1916–2004), and Maurice Wilkins (1916–2004) jointly received the Nobel Prize in physiology or medicine for their 1953 determination of the structure of deoxyribonucleic acid (DNA), performed with a knowledge of Chargaff’s ratios of the bases in DNA and having  access to the X-ray crystallography of Maurice Wilkins and Rosalind Franklin at King’s College London. Because the Nobel Prize can be awarded only to the living, Wilkins’s colleague Rosalind Franklin (1920–1958), who died of cancer at the age of 37, could not be honored.
Of the four DNA researchers, only Rosalind Franklin had any degrees in chemistry. Franklin completed her degree in 1941 in the middle of World War II and undertook graduate work at Cambridge with Ronald Norrish, a future Nobel Prize winner. She returning to Cambridge after a year of war service, presented her work and received the PhD in physical chemistry. Franklin then learned the  X-ray crystallography in Paris and rapidly became a respected authority in this field. Returning to returned to England to King’s College London in 1951, her charge was to upgrade the X-ray crystallographic laboratory there for work with DNA.

bt2304  Rosalind Franklin, crystallographer

Cold Spring Harbor Laboratory

I digress to the beginnings of the Cold Spring Harbor Laboratory. A significant part of the Laboratory’s life revolved around education with its three-week-long Phage Course, taught first in 1945 by Max Delbruck, the German-born, theoretical-physicist-turned-biologist. James D Watson first came to Cold Spring Harbor Laboratory with his thesis advisor, Salvador Luria, in the summer of 1948. Over its more than 25-year history, the Phage Course was the training ground for many notable scientists. The Laboratory’s annual scientific Symposium, has provided a unique highly interactive education about the exciting field of “molecular” biology. The 1953 symposium featured Watson coming from England to give the first public presentation of the DNA double helix. When he became the Laboratory’s director in 1968 he was determined to make the Laboratory an important center for advancing molecular biology, and he focused his energy on bringing large donations to the enterprise CSHNL. It became a magnate for future discovery at which James D. Watson became the  Director in 1968, and later the Chancellor. This contribution has as great an importance as his Nobel Prize discovery.

Biochemistry and Molecular Probes comes into View

Moreover, at the same time, the experience of Nathan Kaplan and Martin Kamen at Berkeley working with radioactive probes was the beginning of an establishment of Lawrence-Livermore Laboratories role in metabolic studies, as reported in the previous paper. A collaboration between Sid Collowick, NO Kaplan and Elizabeth Neufeld at the McCollum Pratt Institute led to the transferase reaction between the two main pyridine nucleotides.  Neufeld received a PhD a few years later from the University of California, Berkeley, under William Zev Hassid for research on nucleotides and complex carbohydrates, and did postdoctoral studies on non-protein sulfhydryl compounds in mitosis. Her later work at the NIAMDG on mucopolysaccharidoses. The Lysosomal Storage Diseases opened a new chapter on human genetic diseases when she found that the defects in Hurler and Hunter syndromes were due to decreased degradation of the mucopolysaccharides. When an assay became available for α-L-iduronidase in 1972, Neufeld was able to show that the corrective factor for Hurler syndrome that accelerates degradation of stored sulfated mucopolysaccharides was α-L-iduronidase.

______________________________________________________

The Hurler Corrective Factor. Purification and Some Properties (Barton, R. W., and Neufeld, E. F. (1971) J. Biol. Chem. 246, 7773–7779)
The Sanfilippo A Corrective Factor. Purification and Mode of Action (Kresse, H., and Neufeld, E. F. (1972) J. Biol. Chem. 247, 2164–2170)
_______________________________________________________

I mention this for two reasons:
[1] We see a huge impetus for nucleic acids and nucleotides research growing in the 1950’s with a post WWII emergence of work on biological structure.
[2] At the same time, the importance of enzymes in cellular metabolic processes runs parallel to that of the genetic code.

In 1959 Arthur Kornberg was a recipient of the Nobel prize for Physiology or Medicine based on his discovery of “the mechanisms in the biological synthesis of deoxyribonucleic acid” (DNA polymerase) together with Dr. Severo Ochoa of New York University. In the next 20 years Stanford University Department of Biochemistry became a top rated graduate program in biochemistry. Today, the Pfeffer Lab is distinguished for research into how human cells put receptors in the right place through Rab GTPases that regulate all aspects of receptor trafficking. Steve Elledge (1984-1989) at Harvard University is one of  its graduates from the 1980s.

Transcription –RNA and the ribosome

In 2006, Roger Kornberg was awarded the Nobel Prize in Chemistry for identifying the role of RNA polymerase II and other proteins in transcribing DNA. He says that the process is something akin to a machine. “It has moving parts which function in synchrony, in appropriate sequence and in synchrony with one another”. The Kornbergs were the tenth family with closely-related Nobel laureates.  The 2009 Nobel Prize in Chemistry was awarded to Venki Ramakrishnan, Tom Steitz, and Ada Yonath for crystallographic studies of the ribosome. The atomic resolution structures of the ribosomal subunits provide an extraordinary context for understanding one of the most fundamental aspects of cellular function: protein synthesis. Research on protein synthesis began with studies of microsomes, and three papers were published on the atomic resolution structures of the 50S and 30S the atomic resolution of structures of ribosomal subnits in 2000. Perhaps the most remarkable and inexplicable feature of ribosome structure is that two-thirds of the mass is composed of large RNA molecules, the 5S, 16S, and 23S ribosomal RNAs, and the remaining third is distributed among ~50 relatively small and innocuous proteins. The first step on the road to solving the ribosome structure was determining the primary structure of the 16S and 23S RNAs in Harry Noller’s laboratory. The sequences were rapidly followed by secondary structure models for the folding of the two ribosomal RNAs, in collaboration with Carl Woese, bringing the ribosome structure into two dimensions. The RNA secondary structures are characterized by an elaborate series of helices and loops of unknown structure, but other than the insights offered by the structure of transfer RNA (tRNA), there was no way to think about folding these structures into three dimensions. The first three-dimensional images of the ribosome emerged from Jim Lake’s reconstructions from electron microscopy (EM) (Lake, 1976).

Ada Yonath reported the first crystals of the 50S ribosomal subunit in 1980, a crucial step that would require almost 20 years to bring to fruition (Yonath et al., 1980). Yonath’s group introduced the innovative use of ribosomes from extremophilic organisms. Peter Moore and Don Engelman applied neutron scattering techniques to determine the relative positions of ribosomal proteins in the 30S ribosomal subunit at the same time. Elegant chemical footprinting studies from the Noller laboratory provided a basis for intertwining the RNA among the ribosomal proteins, but there was still insufficient information to produce a high resolution structure, but Venki Ramakrishnan, in Peter Moore’s laboratory did it with deuterated ribosome reconstitutions. Then the Yale group was ramping up its work on the H. marismortui crystals of the 50S subunit. Peter Moore had recruited long-time colleague Tom Steitz to work on this problem and Steitz was about to complete the final event in the pentathlon of Crick’s dogma, having solved critical structures of DNA polymerases, the glutaminyl tRNA-tRNA synthetase complex, HIV reverse transcriptase, and T7 RNA polymerase. In 1999 Steitz, Ramakrishnan, and Yonath all presented electron density maps of subunits at approximately 5 Å resolution, and the Noller group presented 10 Å electron density maps of the Thermus 70S ribosome. Peter Moore aptly paraphrased Churchill, telling attendees that this was not the end, but the end of the beginning. Almost every nucleotide in the RNA is involved in multiple stabilizing interactions that form the monolithic tertiary structure at the heart of the ribosome.
Williamson J. The ribosome at atomic resolution. Cell 2009; 139:1041-1043.    http://dx.doi.org/10.1016/j.cell.2009.11.028/      http://www.sciencedirect.com/science/article/pii/S0092867409014536

This opened the door to new therapies.  For example, in 2010 it was reported that Numerous human genes display dual coding within alternatively spliced regions, which give rise to distinct protein products that include segments translated in more than one reading frame. To resolve the ensuing protein structural puzzle, we identified human genes with alternative splice variants comprising a dual coding region at least 75 nucleotides in length and analyzed the structural status of the protein segments they encode. The inspection of their amino acid composition and predictions by the IUPred and PONDR® VSL2 algorithms suggest a high propensity for structural disorder in dual-coding regions.
Kovacs E, Tompa P, liliom K, and Kalmar L. Dual coding in alternative reading frames correlates with intrinsic protein disorder. PNAS 2010.   http://www.jstor.org/stable/25664997   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851785
http://www.pnas.org/content/107/12/5429.full.pdf


In 2012, it was shown that drug-bound ribosomes can synthesize a distinct subset of cellular polypeptides. The structure of a protein defines its ability to thread through the antibiotic-obstructed tunnel. Synthesis of certain polypeptides that initially bypass translational arrest can be stopped at later stages of elongation while translation of some proteins goes to completion. (Kannan K, Vasquez-Laslop N, and Mankin AS. Selective Protein Synthesis by Ribosomes with a Drug-Obstructed Exit Tunnel. Cell 2012; 151; 508-520.) http://dx.doi.org/10.1016/j.cell.2012.09.018     http://www.sciencedirect.com/science/article/pii/S0092867412011257

Mobility of genetic elements

Barbara McClintock received the Nobel Prize for Medicine for the discovery of the mobility of genetic elements, work that been done in that period. When transposons were demonstrated in bacteria, yeast and other organisms, Barbara rose to a stratospheric level in the general esteem of the scientific world, but she was uncomfortable about the honors. It was sufficient to have her work understood and acknowledged. Prof. Howard Green said of her, “There are scientists whose discoveries greatly transcend their personalities and their humanity. But those in the future who will know of Barbara only her discoveries will know only her shadow”.
“In Memoriam – Barbara McClintock”. Nobelprize.org. 5 Feb 2013   http://www.nobelprize.org/nobel_prizes/medicine/laureates/1983/mcclintock-article.html/

She introduced her Nobel Lecture in 1983 with the following observation: “An experiment conducted in the mid-nineteen forties prepared me to expect unusual responses of a genome to challenges for which the genome is unprepared to meet in an orderly, programmed manner. In most known instances of this kind, the types of response were not predictable in advance of initial observations of them. It was necessary to subject the genome repeatedly to the same challenge in order to observe and appreciate the nature of the changes it induces…a highly programmed sequence of events within the cell that serves to cushion the effects of the shock. Some sensing mechanism must be present in these instances to alert the cell to imminent danger, and to set in motion the orderly sequence of events that will mitigate this danger”. She goes on to consider “early studies that revealed programmed responses to threats that are initiated within the genome itself, as well as others similarly initiated, that lead to new and irreversible genomic modifications. These latter responses, now known to occur in many organisms, are significant for appreciating how a genome may reorganize itself when faced with a difficulty for which it is unprepared”.

An experiment with Zea conducted in the summer of 1944 alerted her to the mobility of specific components of genomes involved the entrance of a newly ruptured end of a chromosome into a telophase nucleus. This experiment commenced with the growing of approximately 450 plants in the summer of 1944, each of which had started its development with a zygote that had received from each parent a chromosome with a newly ruptured end of one of its arms. The design of the experiment required that each plant be self-pollinated to isolate from the self-pollinated progeny new mutants that were expected to appear, and confine them to locations within the ruptured arm of a chromosome. Each mutant was expected to reveal the phenotype produced by a minute homozygous deficiency. Their modes of origin could be projected from the known behavior of broken ends of chromosomes in successive mitoses. Forty kernels from each self-pollinated ear were sown in a seedling bench in the greenhouse during the winter of 1944-45.

Some seedling mutants of the type expected overshadowed by segregants exhibiting bizarre phenotypes. These were variegated for type and degree of expression of a gene. Those variegated expressions given by genes associated with chlorophyll development were startingly conspicuous. Within any one progeny chlorophyll intensities, and their pattern of distribution in the seedling leaves, were alike. Between progenies, however, both the type and the pattern differed widely.

The effect of X-rays on chromosomes

Initial studies of broken ends of chromosomes began in the summer of 1931. By 1931, means of studying the beads on a string hypothesis was provided by newly developed methods of examining the ten chromosomes of the maize complement in microsporocytes in meiosis. The ten bivalent chromosomes are elongated in comparison to their metaphase lengths. Each chromosome

  • is identifiable by its relative length,
  • by the location of its centromere, which is readily observed at the pachytene stage, and
  • by the individuality of the chromomeres strung along the length of each chromosome.

At that time maize provided the best material for locating known genes along a chromosome arm, and also for precisely determining the break points in chromosomes that had undergone various types of rearrangement, such as translocations, inversions, etc.
The recessive phenotypes in the examined plants arose from loss of a segment of a chromosome that carried the wild-type allele, and X-rays were responsible for inducing these deficiencies. A conclusion of basic significance could be drawn from these observations:

  1. broken ends of chromosomes will fuse, 2-by-2, and
  2. any broken end with any other broken end.

This principle has been amply proved in a series of experiments conducted over the years. In all such instances the break must sever both strands of the DNA double helix. This is a “double-strand break” in modern terminology. That two such broken ends entering a telophase nucleus will find each other and fuse, regardless of the initial distance that separates them, soon became apparent.

During the summer of 1931 she had seen plants in the maize field that showed variegation patterns resembling the one described for Nicotiana.  Dr. McClintock was interested in selecting the variegated plants to determine the presence of a ring chromosome in each, and in the summer of 1932 with Dr. Stadler’s generous cooperation from Missouri, she had the opportunity to examine such plants. Each plant had a ring chromosome, but It was the behavior of this ring that proved to be significant. It revealed several basic phenomena. The following was noted:

In the majority of mitoses

  • replication of the ring chromosome produced two chromatids completely free from each other
  • could separate without difficulty in the following anaphase.
  • sister strand exchanges do occur between replicated or replicating chromatids
  • the frequency of such events increases with increase in the size of the ring.
  • these exchanges produce a double-size ring with two centromeres.
  • Mechanical rupture occurs in each of the two chromatid bridges formed at anaphase by passage of the two centromeres on the double-size ring to opposite poles of the mitotic spindle.
  • The location of a break can be at any one position along any one bridge.
  • The broken ends entering a telophase nucleus then fuse.
  • The size and content of each newly constructed ring depend on the position of the rupture that had occurred in each bridge.
  1. The conclusion was that cells sense the presence in their nuclei of ruptured ends of chromosomes
  2. then activate a mechanism that will bring together and then unite these ends
  3. this will occur regardless of the initial distance in a telophase nucleus that separated the ruptured ends.

The ability of a cell to

  • sense these broken ends,
  • to direct them toward each other, and
  • then to unite them so that the union of the two DNA strands is correctly oriented,
  • is a particularly revealing example of the sensitivity of cells to all that is going on within them.

Evidence from gave unequivocal support for the conclusion that broken ends will find each other and fuse. The challenge is met by a programmed response. This may be necessary, as

  1. both accidental breaks and
  2. programmed breaks may be frequent.
  3. If not repaired, such breaks could lead to genomic deficiencies having serious consequences.

A cell capable of repairing a ruptured end of a chromosome must sense the presence of this end in its nucleus. This sensing

  • activates a mechanism that is required for replacing the ruptured end with a functional telomere.
  • that such a mechanism must exist was revealed by a mutant that arose in the stocks.
  • this mutant would not allow the repair mechanism to operate in the cells of the plant.

Entrance of a newly ruptured end of a chromosome into the zygote is followed by the chromatid type of breakage-fusion-bridge cycle throughout mitoses in the developing plant.
This suggested that the repair mechanism in the maize strains is repressed in cells producing

  • the male and female gametophytes and
  • also in the endosperm,
  • but is activated in the embryo.

The extent of trauma perceived by cells

  • whose nuclei receive a single newly ruptured end of a chromosome that the cell cannot repair,
  • and the speed with which this trauma is registered, was not appreciated until the winter of 1944-45.

By 1947 it was learned that the bizarre variegated phenotypes that segregated in many of the self-pollinated progenies grown on the seedling bench in the fall and winter of 1944-45, were due to the action of transposable elements. It seemed clear that

  • these elements must have been present in the genome,
  • and in a silent state previous to an event that activated one or another of them.

She concluded that some traumatic event was responsible for these activations. The unique event in the history of these plants relates to their origin. Both parents of the plants grown in 1944 had contributed a chromosome with a newly ruptured end to the zygote that gave rise to each of these plants.
Detection of silent elements is now made possible with the aid of DNA cloning method. Silent AC (Activator) elements, as well as modified derivatives of them, have already been detected in several strains of maize. When other transposable elements are cloned it will be possible to compare their structural and numerical differences among various strains of maize. In any one strain of maize the number of silent but potentially transposable elements, as well as other repetitious DNAs, may be observed to change, and most probably in response to challenges not yet recognized.
Telomeres are especially adapted to replicate free ends of chromosomes. When no telomere is present, attempts to replicate this uncapped end may be responsible for the apparent “fusions” of the replicated chromatids at the position of the previous break as well as for perpetuating the chromatid type of breakage-fusion-bridge cycle in successive mitoses.
In conclusion, a genome may react to conditions for which it is unprepared, but to which it responds in a totally unexpected manner. Among these is

  • the extraordinary response of the maize genome to entrance of a single ruptured end of a chromosome into a telophase nucleus.
  • It was this event that was responsible for activations of potentially transposable elements that are carried in a silent state in the maize genome.
  • The mobility of these activated elements allows them to enter different gene loci and to take over control of action of the gene wherever one may enter.

Because the broken end of a chromosome entering a telophase nucleus can initiate activations of a number of different potentially transposable elements,

  • the modifications these elements induce in the genome may be explored readily.

In addition to

modifying gene action, these elements can

  • restructure the genome at various levels,
  • from small changes involving a few nucleotides,
  • to gross modifications involving large segments of chromosomes, such as
  1. duplications,
  2. deficiencies,
  3. inversions,
  4. and other reorganizations.

In the future attention undoubtedly will be centered on the genome, and with greater appreciation of its significance as a highly sensitive organ of the cell,

  • monitoring genomic activities and correcting common errors,
  • sensing the unusual and unexpected events,
  • and responding to them,
  • often by restructuring the genome.

We know about the elements available for such restructuring. We know nothing, however, about

  • how the cell senses danger and instigates responses to it that often are truly remarkable.

Source: 1983 Nobel Lecture. Barbara McClintock. THE SIGNIFICANCE OF RESPONSES OF THE GENOME TO CHALLENGE.

In 2009 the Nobel Prize in Physiology or Medicine was awarded to Elizabeth Blackburn, Carol Greider and Jack Szoztak for the discovery of Telomerase. This recognition came less than a decade after the completion of the Human Genome Project previously discussed. Prof. Blackburn acknowledges a strong influence coming from the work of Barbara McClintock. The discovery is tied to the pond organism Tetrahymena thermophila, and studies of yeast cells. Blackburn was drawn to science after reading the biography of Marie Curie by her daughter, Irina, as a child. She recalls that her Master’s mentor while studying the metabolism of glutamine in the rat liver, thought that every experiment should have the beauty and simplicity of a Mozart sonata. She did her PhD at the distinguished Laboratory for Molecular Biology at Cambridge, the epicenter of molecular biology sequencing the regions of bacteriophage phiX 174, a single stranded DNA bacteriophage. Using Fred Sanger’s methods to piece together RNA sequences she showed the first sequence of a 48 nucleotide fragment to her mathematical-gifted Cambridge cousin, who pointed out repeats of DNA sequence patterns! She worked on the sequencing of the DNA at the terminal regions of  the short “minichromosomes” of the ciliated protozoan Tetrahymena thermophile at Yale in 1975. She continued her research begun at Yale at UCSF funded by the NIH based on an intriguing audiogram showing telomeric DNA in Tetrahymena.
I describe the work as follows:

  • Prof. Blackburn incorporated 32P isotope labelled deoxynucleoside residues into the rDNA molecules for DNA repair enzymatic reactions and found that
  • the end regions were selectively labeled by combinations of 32P isotope radiolabled nucleoside triphosphate, and by mid-year she had an audiogram of the depurination products.
  • The audiogram showed sequences of 4 cytosine residues flanked by either an adenosine or a guanosine residue.
  • In 1976 she had deduced a sequence consisting of a tandem array of CCCAA repeats, and subsequently separated the products on a denaturing gel electrophoresis that appeared as tiger stripes extending up the gel.
  • The size of each band was 6 bases more than the band below it.

Telomere must have a telomerase!

The discovery of the telomerase enzyme activity was done by the Prize co-awardee, Carol Greider. They were trying to decipher the structure right at the termini of telomeres of both cliliated protozoans and yeast plasmids. The view that in mammalian telomeres there is a long protruding G-rich strand does not take into account the clear evidence for the short C strand repeat oligonucleotides that she discovered. This was found for both the Tetrahymena rDNA minichromosome molecules and linear plasmids purified from yeast.
In contrast to nucleosomal regions of chromosomes, special regions of DNA, for example

  • promoters that must bind transcription initiation factors that control transcription, have proteins other than the histones on them.
  • The telomeric repeat tract turned out to be such a non-nucleosomal region.

They  found that by clipping up chromatin using an enzyme that cuts the linker between neighboring nucleosomes,

  • it cut up the bulk of the DNA into nucleosome-sized pieces
  • but left the telomeric DNA tract as a single protected chunk.

The resulting complex of the telomeric DNA tract plus its bound cargo of protective proteins behaved very differently, from nucleosomal chromatin, and concluded that it had no histones or nucleosomes.

Any evidence for a protein on the bulk of the rDNA molecule ends, such as their behavior in gel electrophoresis and the appearance of the rDNA molecules under the electron microscope, was conspicuously lacking. This was reassuring that there was no covalently attached protein at the very ends of this minichoromosome. Despite considerable work, she was unable to determine what protein(s) would co-purify with the telomeric repeat tract DNA of Tetrahymena. It was yeast genetics and approaches done by others that turned out to provide the next great leaps forward in understanding telomeric proteins. Carol Greider, her colleague, noticed the need to scale up the telomerase activity preparations and they used a very large glass column for preparative gel filtration chromatography.

Jack W Szostak at the Howard Hughes Medical Institue at Harvard shared in the 2009 Nobel Prize. He became interested in molecular biology taking a course on the frontiers of Molecular Biology and reading about the experiments of Meselson-Stahl barely a decade earlier, and learned how the genetic code had been unraveled. The fact that one could deduce, from measurements of the radioactivity in fractions from a centrifuge tube, the molecular details of DNA replication, transcription and translation was astonishing. A highlight of his time at McGill was the open-book, open-discussion final exam in this class, in which the questions required the intense collaboration of groups of students.

At Cornell, Ithaca, he collaborated with  John Stiles and they came up with a specific idea to chemically synthesize a DNA oligonucleotide of sufficient length that it would hybridize to a single sequence within the yeast genome, and then to use it as an mRNA and gene specific probe. At the time, there was only one short segment of the yeast genome for which the DNA sequence was known,

  • the region coding for the N-terminus of the iso-1 cytochrome c protein,

intensively studied by Fred Sherman
The Sherman lab, in a tour de force of genetics and protein chemistry, had isolated

  • double-frameshift mutants in which the N-terminal region of the protein was translated from out-of-frame codons.
  • Protein sequencing of the wild type and frame-shifted mutants allowed them to deduce 44 nucleotides of DNA sequence.

If they could prepare a synthetic oligonucleotide that was complementary to the coding sequence, they could use it to detect the cytochrome-c mRNA and gene. At the time, essentially all experiments on mRNA were done on total cellular mRNA. Ray Wu was already well known for determining the sequence of the sticky ends of phage lambda, the first ever DNA to be sequenced, and his lab was deeply involved in the study of enzymes that could be used to manipulate and sequence DNA more effectively, but would not take on a project from another laboratory. So John went to nearby Rochester to do postdoctoral work with Sherman, and he was able to transfer to Ray Wu’s laboratory. In order to carry out his work, Ray Wu sent him to Saran Narang’s lab in Ottawa, and he received training there under Keichi Itakura, who synthesized the Insulin gene. A few months later, he received several milligrams of our long sought 15-mer. In collaboration with John Stiles and Fred Sherman, who sent us RNA and DNA samples from appropriate yeast strains, they were able to use the labeled 15-mer as a probe to detect the cyc1 mRNA, and later the gene itself. He notes that one of the delights of the world of science is that it is filled with people of good will who are more than happy to assist a student or colleague by teaching a technique or discussing a problem. He remained in Ray’s lab after completion of the PhD upon the arrival of Rodney Rothstein from Sherman’s lab in Rochester, who introduced him to yeast genetics, and he was prepared for the next decade of work on yeast.

  • first in recombination studies, and
  • later in telomere studies and other aspects of yeast biology.

His studies of recombination in yeast were enabled by the discovery, in Gerry Fink’s lab at Cornell, of a way to introduce foreign DNA into yeast. These pioneering studies of yeast transformation showed that circular plasmid DNA molecules could on occasion become integrated into yeast chromosomal DNA by homologous recombination.

  • His studies of unequal sister chromatid exchange in rDNA locus resulted in his first publication in the field of recombination.

The idea that you could increase transformation frequency by cutting the input DNA was pleasingly counterintuitive and led us to continue our exploration of this phenomenon. He gained an appointment to the Sidney-Farber Cancer Institute due to the interest of Prof. Ruth Sager, who gathered together a great group of young investigators. In work spearheaded by his first graduate student, Terry Orr-Weaver, on

  • double-strand breaks in DNA
  • and their repair by recombination (and continuing interaction with Rod Rothstein),
  • they were attracted to what kinds of reactions occur at the DNA ends.

It was at a Gordon Conference that he was excited hearing a talk by Elizabeth Blackburn on her work on telomeres in Tetrahymena.

  • This led to a collaboration testing the ability of Tetrahymena telomers to function in yeast.
  • He performed the experiments himself, and experienced the thrill of being the first to know that our wild idea had worked.
  • It was clear from that point on that a door had been opened and that they were going to be able to learn a lot about telomere function from studies in yeast.
  • Within a short time he was able to clone bona fide yeast telomeres, and (in a continuation of the collaboration with Liz Blackburn’s lab)
  • they obtained the critical sequence information that led (them) to propose the existence of the key enzyme, telomerase.

A fanciful depiction evoking both telomere dynamics and telomere researchers, done by the artist Julie Newdoll in 2008, elicits the idea of a telomere as an ancient Sumarian temple-like hive, tended by a swarm of ancient Sumarian Bee-goddesses against a background of clay tablets inscribed with DNA sequencing gel-like bands.
Dr. Blackburn recalls owing much to Barbara McClintock for her scientific findings, but also, Barbara McClintock also gave her advice in a conversation with her in 1977, during which

  • she had unexpected findings with the rDNA end sequences.
  • Dr. McClintock urged her to trust in intuition about the scientific research results.

This advice was surprising then because intuitive thinking was not something that she accepted to be a valid aspect of being a biology researcher.
MLA style: “Elizabeth H. Blackburn – Biographical”. Nobelprize.org. 5 Feb 2013. http://www.nobelprize.org/nobel_prizes/medicine/laureates/2009/blackburn.html

Summary:

In this Part I of a series of 3, I have described the

  • emergence of Molecular Biology and
  • closely allied work on the mechanism of Cell Replication and
  • the dependence of metabolic processes on proteins and enzymatic conversions through a surge of
  • post WWII research that gave birth to centers for basic science research in biology and medicine in both US and in England, which was preceded by work in prewar Germany. This is to be followed by further developments related to the Human Genome Project.
  • Transcription initiation (Photo credit: Wikipedia)
  • Schematic relationship between biochemistry, genetics, and molecular biology (Photo credit: Wikipedia)
  • Central dogma of molecular biology (Photo credit: Wikipedia)

 

Transcription initiation

Transcription initiation (Photo credit: Wikipedia)

Schematic relationship between biochemistry, g...

Schematic relationship between biochemistry, genetics, and molecular biology (Photo credit: Wikipedia)

Central dogma of molecular biology

Central dogma of molecular biology (Photo credit: Wikipedia)

 

 

 

                        Nucleotides_1.svg

 

 

 

Related References on the Open Access On;ine Scientific Journal

Big Data in Genomic Medicine lhb
https://pharmaceuticalintelligence.com/2012/12/17/big-data-in-genomic-medicine/

BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair S Saha
http://pharmaceuticalintelligence.com/2012/12/04/brca1-a-tumour-suppressor-in-breast-and-ovarian-cancer-functions-in-transcription-ubiquitination-and-dna-repair/

Computational Genomics Center: New Unification of Computational Technologies at Stanford A Lev-Ari
http://pharmaceuticalintelligence.com/2012/12/03/computational-genomics-center-new-unification-of-computational-technologies-at-stanford/

Personalized medicine gearing up to tackle cancer ritu saxena
http://pharmaceuticalintelligence.com/2013/01/07/personalized-medicine-gearing-up-to-tackle-cancer/

Differentiation Therapy – Epigenetics Tackles Solid Tumors SJ Williams
http://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/

Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment A Lev-Ari
http://pharmaceuticalintelligence.com/2013/01/17/mechanism-involved-in-breast-cancer-cell-growth-function-in-early-detection-treatment/

The Molecular pathology of Breast Cancer Progression Tilde Barliya
http://pharmaceuticalintelligence.com/2013/01/10/the-molecular-pathology-of-breast-cancer-progression/

Gastric Cancer: Whole-genome reconstruction and mutational signatures A Lev-Ari
http://pharmaceuticalintelligence.com/2012/12/24/gastric-cancer-whole-genome-reconstruction-and-mutational-signatures-2/

Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1 (pharmaceuticalintelligence.com) A Lev-Ari
http://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomarkers-and-personalized-medicine-part-1/

LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment: Part 2 A Lev-Ari
http://pharmaceuticalintelligence.com/2013/01/13/leaders-in-genome-sequencing-of-genetic-mutations-for-therapeutic-drug-selection-in-cancer-personalized-treatment-part-2/

Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research: Part 3 A Lev-Ari
http://pharmaceuticalintelligence.com/2013/01/13/personalized-medicine-an-institute-profile-coriell-institute-for-medical-research-part-3/

Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders @ http://pharmaceuticalintelligence.com ALA
http://pharmaceuticalintelligence.com/2013/01/13/7000/Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders/
GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial” A Lev-Ari
http://pharmaceuticalintelligence.com/2012/11/14/gsk-for-personalized-medicine-using-cancer-drugs-needs-alacris-systems-biology-model-to-determine-the-in-silico-effect-of-the-inhibitor-in-its-virtual-clinical-trial/

Recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes in serous endometrial tumors S Saha
http://pharmaceuticalintelligence.com/2012/11/19/recurrent-somatic-mutations-in-chromatin-remodeling-and-ubiquitin-ligase-complex-genes-in-serous-endometrial-tumors/

Human Variome Project: encyclopedic catalog of sequence variants indexed to the human genome sequence A Lev-Ari
http:///pharmaceuticalintelligence.com/2012/11/24/human-variome-project-encyclopedic-catalog-of-sequence-variants-indexed-to-the-human-genome-sequence/

Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition sjwilliams
http://pharmaceuticalintelligence.com/2012/11/30/histone-deacetylase-inhibitors-induce-epithelial-to-mesenchymal-transition-in-prostate-cancer-cells/

Inspiration From Dr. Maureen Cronin’s Achievements in Applying Genomic Sequencing to Cancer Diagnostics A Lev-Ari
http://pharmaceuticalintelligence.com/2013/01/10/inspiration-from-dr-maureen-cronins-achievements-in-applying-genomic-sequencing-to-cancer-diagnostics/

The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953 A Lev-Ari
http://pharmaceuticalintelligence.com/2013/01/09/the-cancer-establishments-examined-by-james-watson-co-discover-of-dna-wcrick-41953/

Squeezing Ovarian Cancer Cells to Predict Metastatic Potential: Cell Stiffness as Possible Biomarker pkandala
http://pharmaceuticalintelligence.com/2012/12/08/squeezing-ovarian-cancer-cells-to-predict-metastatic-potential-cell-stiffness-as-possible-biomarker/

Hypothesis – following on James Watson lhb
http://pharmaceuticalintelligence.com/2013/01/27/novel-cancer-h…ts-are-harmful/

Otto Warburg, A Giant of Modern Cellular Biology lhb
http://pharmaceuticalintelligence.com/2012/11/02/otto-warburg-a-giant-of-modern-cellular-biology/

Is the Warburg Effect the cause or the effect of cancer: A 21st Century View? lhb
http://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-century-view/

Predicting Tumor Response, Progression, and Time to Recurrence lhb
http://pharmaceuticalintelligence.com/2012/12/20/predicting-tumor-response-progression-and-time-to-recurrence/

Directions for genomics in personalized medicine lhb
http://pharmaceuticalintelligence.com/2013/01/27/directions-for-genomics-in-personalized-medicine/

How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis. SJ Williams
http://pharmaceuticalintelligence.com/2012/10/31/how-mobile-elements-in-junk-dna-prote-cancer-part1-transposon-mediated-tumorigenesis/

Advances in Separations Technology for the “OMICs” and Clarification of Therapeutic Targets lhb ‎
http://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification-of-therapeutic-targets/

Mitochondrial Damage and Repair under Oxidative Stress lhb
http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

Mitochondria: More than just the “powerhouse of the cell” Ritu Saxena
http://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

Mitochondrial mutation analysis might be “1-step” away Ritu Saxena
http://pharmaceuticalintelligence.com/2012/08/14/mitochondrial-mutation-analysis-might-be-1-step-away/

RNA interference with cancer expression lhb
http://pharmaceuticalintelligence.com/2012/10/26/mrna-interference-with-cancer-expression/

What can we expect of tumor therapeutic response? lhb
http://pharmaceuticalintelligence.com/2012/12/05/what-can-we-expect-of-tumor-therapeutic-response/

Expanding the Genetic Alphabet and linking the genome to the metabolome
http://pharmaceuticalintelligence.com/2012/09/24/expanding-the-genetic-alphabet-and-linking-the-genome-to-the-metabolome/

Breast Cancer, drug resistance, and biopharmaceutical targets lhb
http://pharmaceuticalintelligence.com/2012/09/18/breast-cancer-drug-resistance-and-biopharmaceutical-targets/

Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression Analysis A Lev-Ari
http://pharmaceuticalintelligence.com/2012/12/24/breast-cancer-genomic-profiling-to-predict-survival-combination-of-histopathology-and-gene-expression-analysis/

Gastric Cancer: Whole-genome reconstruction and mutational signatures A Lev-Ari
http://pharmaceuticalintelligence.com/2012/12/24/gastric-cancer-whole-genome-reconstruction-and-mutational-signatures-2/

Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis lhb
http://pharmaceuticalintelligence.com/2012/10/30/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-proteolysis-and-cell-apoptosis/

Identification of Biomarkers that are Related to the Actin Cytoskeleton lhb
http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/

Genomic Analysis: FLUIDIGM Technology in the Life Science and Agricultural Biotechnology A Lev-Ari
http://pharmaceuticalintelligence.com/2012/08/22/genomic-analysis-fluidigm-technology-in-the-life-science-and-agricultural-biotechnology/

Interview with the co-discoverer of the structure of DNA: Watson on The Double Helix and his changing view of Rosalind Franklin A Lev-Ari
https://pharmaceuticalintelligence.com/2012/11/09/interview-with-the-co-discoverer-of-the-structure-of-dna-watson-on-the-double-helix-and-his-changing-view-of-rosalind-franklin/

Winning Over Cancer Progression: New Oncology Drugs to Suppress Passengers Mutations vs. Driver Mutations A Lev-Ari
https://pharmaceuticalintelligence.com/2013/02/05/winning-over-cancer-progression-new-oncology-drugs-to-suppress-driver-mutations-vs-passengers-mutations/

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Reporter: Aviva Lev-Ari, PhD, RN

On August 16, 2012 I received an e-mail on New@NEJM.org from this e-mail, I selected to post HERE, the

Cardiology Panel — NEJM Dialogue in Medicine, June 22, 2012

https://pharmaceuticalintelligence.com/2012/08/16/cardiology-panel-nejm-dialogue-in-medicine-june-22-2012/

While listening to the 1:35 minutes of the Video of the Cardiology Panel, the Nobel Prize for Nitric Oxide was mentioned. In light of the thrust, this Scientific Web Site has related to Nitric Oxide in Health and in Disease, I decided to cite here the entire Letter from the Nobel Prize Web Site.

October 12, 1998

The Nobel Assembly at Karolinska Institutet has today decided to award
the Nobel Prize in Physiology or Medicine for 1998 jointly to

Robert F. Furchgott, Louis J. Ignarro and Ferid Murad

for their discoveries concerning “nitric oxide as a signalling molecule in the cardiovascular system”.

Summary

Nitric oxide (NO) is a gas that transmits signals in the organism. Signal transmission by a gas that is produced by one cell, penetrates through membranes and regulates the function of another cell represents an entirely new principle for signalling in biological systems. The discoverers of NO as a signal molecule are awarded this year’s Nobel Prize.

Robert F Furchgott, pharmacologist in New York, studied the effect of drugs on blood vessels but often achieved contradictory results. The same drug sometimes caused a contraction and at other occasions a dilatation. Furchgott wondered if the variation could depend on whether the surface cells (the endothelium) inside the blood vessels were intact or damaged. In 1980, he demonstrated in an ingenious experiment that acetylcholine dilated blood vessels only if the endothelium was intact. He concluded that blood vessels are dilated because the endothelial cells produce an unknown signal molecule that makes vascular smooth muscle cells relax. He called this signal molecule EDRF, the endothelium-derived relaxing factor, and his findings led to a quest to identify the factor.

Ferid Murad, MD and pharmacologist now in Houston, analyzed how nitroglycerin and related vasodilating compounds act and discovered in 1977 that they release nitric oxide, which relaxes smooth muscle cells. He was fascinated by the concept that a gas could regulate important cellular functions and speculated that endogenous factors such as hormones might also act through NO. However, there was no experimental evidence to support this idea at the time.

Louis J Ignarro, pharmacologist in Los Angeles, participated in the quest for EDRF’s chemical nature. He performed a brilliant series of analyses and concluded in 1986, together with and independently of Robert Furchgott, that EDRF was identical to NO. The problem was solved and Furchgott’s endothelial factor identified.

When Furchgott and Ignarro presented their conclusions at a conference in July, 1986, it elicited an avalanche of research activities in many different laboratories around the world. This was the first discovery that a gas can act as a signal molecule in the organism.

Background

Nitric oxide protects the heart, stimulates the brain, kills bacteria, etc.
It was a sensation that this simple, common air pollutant, which is formed when nitrogen burns, for instance in automobile exhaust fumes, could exert important functions in the organism. It was particularly surprising since NO is totally different from any other known signal molecule and so unstable that it is converted to nitrate and nitrite within 10 seconds. NO was known to be produced in bacteria but this simple molecule was not expected to be important in higher animals such as mammals.

Further research results rapidly confirmed that NO is a signal molecule of key importance for the cardiovascular system and it was also found to exert a series of other functions. We know today that NO acts as a signal molecule in the nervous system, as a weapon against infections, as a regulator of blood pressure and as a gatekeeper of blood flow to different organs. NO is present in most living creatures and made by many different types of cells.
– When NO is produced by the innermost cell layer of the arteries, the endothelium, it rapidly spreads through the cell membranes to the underlying muscle cells. Their contraction is turned off by NO, resulting in a dilatation of the arteries. In this way, NO controls the blood pressure and its distribution. It also prevents the formation of thrombi.
– When NO is formed in nerve cells, it spreads rapidly in all directions, activating all cells in the vicinity. This can modulate many functions, from behaviour to gastrointestinal motility.
– When NO is produced in white blood cells (such as macrophages), huge quantities are achieved and become toxic to invading bacteria and parasites.

Importance in medicine today and tomorrow
Heart: In atherosclerosis, the endothelium has a reduced capacity to produce NO. However, NO can be furnished by treatment with nitroglycerin. Large efforts in drug discovery are currently aimed at generating more powerful and selective cardiac drugs based on the new knowledge of NO as a signal molecule.

Shock: Bacterial infections can lead to sepsis and circulatory shock. In this situation, NO plays a harmful role. White blood cells react to bacterial products by releasing enormous amounts of NO that dilate the blood vessels. The blood pressure drops and the patient may become unconscious. In this situation, inhibitors of NO synthesis may be useful in intensive care treatment.

Lungs: Intensive care patients can be treated by inhalation of NO gas. This has provided good results and even saved lives. For instance, NO gas has been used to reduce dangerously high blood pressure in the lungs of infants. But the dosage is critical since the gas can be toxic at high concentrations.

Cancer: White blood cells use NO not only to kill infectious agents such as bacteria, fungi and parasites, but also to defend the host against tumours. Scientists are currently testing whether NO can be used to stop the growth of tumours since this gas can induce programmed cell death, apoptosis.

Impotence: NO can initiate erection of the penis by dilating the blood vessels to the erectile bodies. This knowledge has already led to the development of new drugs against impotence.

Diagnostic analyses: Inflammatory diseases can be revealed by analysing the production of NO from e.g. lungs and intestines. This is used for diagnosing asthma, colitis, and other diseases.

NO is important for the olfactory sense and our capacity to recognise different scents. It may even be important for our memory.

Nitroglycerin
Alfred Nobel invented dynamite, a product in which the explosion-prone nitroglycerin is curbed by being absorbed in kieselguhr, a porous soil rich in shells of diatoms. When Nobel was taken ill with heart disease, his doctor prescribed nitroglycerin. Nobel refused to take it, knowing that it caused headache and ruling out that it could eliminate chest pain. In a letter, Nobel wrote: It is ironical that I am now ordered by my physician to eat nitroglycerin. It has been known since last century that the explosive, nitroglycerin, has beneficial effects against chest pain. However, it would take 100 years until it was clarified that nitroglycerin acts by releasing NO gas.

TO CITE THIS PAGE:
MLA style: “Physiology or Medicine for 1998 – Press Release”. Nobelprize.org. 16 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/1998/press.html

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