eClinical Forum Fall Meeting

 

The eClinical Forum just completed its Fall meeting held at the corporate headquarters of Biogen-Idec in Cambridge, MA. The Forum started in 2000, was the idea of a group of people who were keen to create something unique – a group run by its members for its members. Independence, openness and public dissemination have been hallmarks of its success. Pharmaceutical, healthcare, regulatory, academic and support industry members participate in open discussion, networking and exchange that provides the practical information, approach and learning experiences required to maximize the success of eClinical initiatives. Many eClinical Forum deliverables are made freely available within the public domain.

 

Presenters were from a broad array of DM, IT, clinical and regulatory experts. Pharma companies included (in alphabetical order), Allergan, Array BioPharma, Biogen-Idec, Boehringer Ingelheim, Bristol-Meyers Squibb, Cubist, Merck, Novartis and Pfizer, and a broad spectrum of top notch service providers. Dean Gittleman of Target Health presented an update on behalf of the EDC Hosting Task Force and Jules Mitchel presented a provocative presentation on “Challenges and Recommendations When Implementing New eSystems.“ Our thanks go to Suzanne Bishop and Richard Perkins who “run the show.“ If you are interested in joining or attending a meeting, please let us know.

 

20141027-17

26 October 2014 – Leaves Changing Very Slowly in Central Park – © Target Health Inc.

 

ON TARGET is the newsletter of Target Health Inc., a NYC-based, full-service, contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services to the pharmaceutical and device industries, including the paperless clinical trial.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchelor Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

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RNA Polymerase Transcription

 

20141027-14

Image of RNA polymerase from the journal Science.

 

RNA Polymerase transcribes genetic information into a message that can be read by the ribosome to produce protein. The research group of Professor Roger Kornberg of Stanford University has studied the structure of this 12-subunit and half-megadalton size macromolecular machine using diffraction data collected by the Stanford Synchrotron Radiation Lightsource (SSRL). A key step in gene 1) ___ is the “transcription” of the DNA sequences comprising the genes into messenger RNAs. Transcription is the first step and a key control point in gene expression. Transcriptional regulation underlies all aspects of cellular metabolism including oncogenesis (cancer) and morphogenesis (development). RNA polymerase II (Pol II) is a large (550 kDa) complex of 12 subunits that is at the heart of the transcription mechanism. Gene expression, and therefore RNA pol II, is regulated by a number of proteins, in particular initiation and transcription factors.

 

The interpretation of the structural and biochemical experiments have resulted in a number of breakthrough publications. Jean Marx, as reported in of Science Magazine (Science Apr 20 2001: 411-414), describes this remarkable structure in the following way:

 

“If any enzyme does the cell’s heavy lifting, it’s RNA polymerase II. Its job: getting the synthesis of all the proteins in higher cells under way by copying their genes into RNAs, and doing it at just the right time and in just the right amounts. As such, pol II, as the enzyme is called, is the heart of the machinery that controls everything that 2) ___ do from differentiating into all the tissues of a developing embryo to responding to everyday stresses. Now, cell biologists can get their best look yet at just how the pol II enzyme of yeast and, by implication, of other higher organisms performs its critical role.”

 

 

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Simplified diagram of mRNA synthesis and processing. Enzymes not shown.

 

Transcription is the first step of gene expression, in which a particular segment of 3) ___ is copied into RNA by the enzyme RNA polymerase. Both RNA and DNA are nucleic 4) ___, which use base pairs of nucleotides as a complementary language. The two can be converted back and forth from DNA to RNA by the action of the correct enzymes. During transcription, a DNA sequence is read by an RNA polymerase, which produces a complementary, antiparallel RNA strand called a primary transcript. The stretch of DNA transcribed into an RNA molecule is called a transcription unit and encodes at least one gene. If the gene transcribed, encodes a protein, messenger RNA (mRNA) will be transcribed; the mRNA will in turn serve as a template for the protein’s synthesis through translation. Alternatively, the transcribed gene may encode for either non-coding RNA (such as microRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), or other ribozymes. Overall, RNA helps synthesize, regulate, and process 5) ___; it therefore plays a fundamental role in performing functions within a cell. In eukaryotes, RNA polymerase, and therefore the initiation of transcription, requires the presence of a core promoter sequence in the DNA. Promoters are regions of DNA that promote transcription and, in eukaryotes, are found at -30, -75, and -90 base pairs upstream from the transcription start site (abbreviated to TSS). Core promoters are sequences within the promoter that are essential for transcription initiation. RNA polymerase is able to bind to core promoters in the presence of various specific transcription factors. One strand of the DNA, the template strand (or noncoding strand), is used as a template for RNA synthesis. As transcription proceeds, RNA polymerase traverses the template 6) ___ and uses base pairing complementary with the DNA template to create an RNA copy.

 

 

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In bacteria, transcription begins with the binding of RNA polymerase to the promoter in DNA. RNA polymerase is a core enzyme consisting of five subunits. Transcription inhibitors can be used as 7) ___ against, for example, pathogenic bacteria (antibacterials) and fungi (antifungals). An example of such an antibacterial is rifampicin, which inhibits prokaryotic DNA transcription into mRNA by inhibiting DNA-dependent RNA polymerase by binding its beta-subunit.

 

Prokaryotes (bacteria) have no 8) ___ and eukaryotic transcription is more complex than prokaryotic transcription. For instance, in eukaryotes the genetic material (DNA), and therefore transcription, is primarily localized to the nucleus, where it is separated from the cytoplasm (in which translation occurs) by the nuclear membrane. This allows for the temporal regulation of gene expression through the sequestration of the RNA in the nucleus, and allows for selective transport of mature RNAs to the cytoplasm. Bacteria on the other hand do not have a distinct nucleus that separates DNA from ribosome and mRNA is translated into protein as soon as it is transcribed. The coupling between the two processes provides an important mechanism for prokaryotic gene regulation.

 

Transcription is the process of copying genetic information stored in a DNA strand into a transportable complementary strand of RNA. Eukaryotic transcription takes place in the nucleus of the cell and proceeds in three sequential stages: initiation, elongation, and termination. The transcriptional machinery that catalyzes this complex reaction has at its core three multi-subunit RNA polymerases. RNA polymerase I is responsible for transcribing RNA that codes for genes that become structural components of the ribosome, a protein responsible for the translation of RNA into proteins.

 

Protein coding genes are transcribed into messenger RNAs (mRNAs) that carry the information from DNA to the site of protein synthesis. Although mRNAs possess great diversity, they are not the most abundant RNA species made in the cell. The so-called non-coding RNAs account for the large majority of the transcriptional output of a cell. These non-coding 9) ___ perform a variety of important cellular functions. Eukaryotic transcription is the elaborate process that eukaryotic cells use to copy genetic information stored in DNA into units of RNA replica. Gene transcription occurs in both eukaryotic and prokaryotic cells. Unlike prokaryotic RNA polymerase that initiates the transcription of all different types of RNA, RNA polymerase in eukaryotes (including humans) comes in three variations, each encoding a different type of gene. A eukaryotic cell has a nucleus that separates the processes of transcription and translation. Eukaryotic transcription occurs within the nucleus where DNA is packaged into nucleosomes and higher order chromatin structures. The complexity of the eukaryotic genome necessitates a great variety and complexity of gene expression control.

 

A molecule that allows the genetic material to be realized as a protein was first hypothesized by Fran?ois Jacob and Jacques Monod. Arthur Kornberg and Severo Ochoa won a Nobel Prize in Physiology or Medicine in 1959 for developing a process for synthesizing RNA in vitro with polynucleotide phosphorylase, which was useful for cracking the genetic 10) ___. RNA synthesis by RNA polymerase was established in vitro at several laboratories by 1965; however, the RNA synthesized by these enzymes had properties that suggested the existence of an additional factor needed to terminate transcription correctly. In 1972, Walter Fiers became the first person to actually prove the existence of the terminating enzyme. Roger D. Kornberg won the 2006 Nobel Prize in Chemistry “for his studies of the molecular basis of eukaryotic transcription”.

 

Cell Overview (http://vcell.ndsu.nodak.edu/animations/flythrough/movie-flash.htm)

 

Animation of gene transcription (http://highered.mheducation.com/olc/dl/120069/bio06.swf)

 

Transcription (http://vcell.ndsu.nodak.edu/animations/transcription/movie-flash.htm)

 

ANSWERS:

1) expression; 2) cells; 3) DNA; 4) acids; 5) protein; 6) strand; 7) antibiotics; 8) nucleus; 9) RNAs; 10) code

 

Arthur Kornberg MD (father)/Roger Kornberg (son) Both Won Nobel Prizes

 

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Arthur Kornberg (1918 – 2007) – He and his son are the sixth father and son to win Nobel Prizes

 

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Roger Kornberg, left, the Nobel Laureate in Chemistry for 2006, pauses after a press conference to listen to his father Arthur Kornberg, the 1959 Nobel Laureate in Medicine

 

Arthur Kornberg was an American biochemist who, together with Dr. Severo Ochoa of New York University, won the Nobel Prize in Physiology or Medicine in 1959 for their discovery of “the mechanisms in the biological synthesis of deoxyribonucleic acid (DNA)“. Kornberg was also awarded the Paul-Lewis Award in Enzyme Chemistry from the American Chemical Society in 1951, L.H.D. degree from Yeshiva University in 1962, as well as National Medal of Science in 1979. Kornberg’s primary research interests were in biochemistry, especially enzyme chemistry, DNA synthesis/replication, and studying the nucleic acids which control heredity in animals, plants, bacteria and viruses.

 

Born in New York City, Arthur Kornberg was the son of Jewish parents Joseph and Lena (n?e Katz) Kornberg, who emigrated to New York from Austrian Galicia (now part of Poland) in 1900 before they were married. His paternal grandfather had changed the family name from Queller (also spelled Kweller) to avoid the draft by taking on the identity of someone who had already completed military service. Joseph worked as a sewing machine operator in the sweat shops of the Lower East side of New York for almost 30 years, and when his health failed, he opened a small hardware store in Brooklyn, where Arthur assisted customers at the age of nine. Joseph spoke at least six languages although he had no formal education.

 

Arthur Kornberg was educated first at Abraham Lincoln High School and then at City College in New York City. He received at B. Sc. in 1937, followed by an M.D. at the University of Rochester in 1941. Kornberg had a mildly elevated level of bilirubin in his blood – jaundice due to a hereditary genetic condition known as Gilbert’s syndrome – and while at medical school he took a survey of fellow students to discover how common the condition was. The results were published in Kornberg’s first research paper in 1942. His internship was at Strong Memorial Hospital in Rochester, New York, between 1941-1942. After completing his medical training he joined the armed services as a Lieutenant in the United States Coast Guard, serving as a ship’s doctor in 1942. Rolla Dyer, the Director of National Institutes of Health, had noticed his paper and invited him to join the research team at the Nutrition Laboratory of the NIH. From 1942 to 1945, Kornberg’s work was the feeding of specialized diets to rats to discover new vitamins. The feeding of rats was boring work, and Kornberg became fascinated by enzymes. He then transferred to Dr Severo Ochoa’s laboratory at New York University in 1946, and took summer courses at Columbia University to fill out the gaps in his knowledge of organic and physical chemistry while learning the techniques of enzyme purification at work. He became Chief of the Enzyme and Metabolism Section at NIH from 1947-1953, working on understanding of ATP production from NAD and NADP. This led to his work on how DNA is built up from simpler molecules. In 1953 he became Professor and Head of the Department of Microbiology, at Washington University in St. Louis, until 1959. Here he continued experimenting with the enzymes which created DNA. In 1956 he isolated the first DNA polymerizing enzyme, now known as DNA polymerase I. This won him the Nobel prize in 1959.

 

In 1960, Kornberg received an LL.D. again from City College, followed by a D.Sc. at the University of Rochester in 1962. He became Professor and Executive Head of the Department of Biochemistry, Stanford University, Stanford in 1959. In a 1997 interview with Sally Smith Hughes, Arthur Kornberg (referring to Josh Lederberg) stated: “Lederberg really wanted to join my department. I knew him; he’s a genius, but he’d be unable to focus and to operate within a small family group like ours, and so, I was instrumental in establishing a department of genetics [at Stanford] of which he would be chairman.“

 

Kornberg’s mother died of gas gangrene from a spore infection after a routine gall bladder operation in 1939. This started his lifelong fascination with spores, and he devoted some of his research efforts to understanding them while at Washington University. From 1962 to 1970, in the midst of his work on DNA synthesis, Kornberg devoted half his research effort to determining how DNA is stored in the spore, what replication mechanisms are included, and how the spore generates a new cell.

 

The Arthur Kornberg Medical Research Building at the University of Rochester Medical Center was named in his honor in 1999. Until his death, Kornberg maintained an active research laboratory at Stanford and regularly published peer reviewed scientific journal articles. For several years the focus of his research was the metabolism of inorganic polyphosphate. The “Kornberg school“ of biochemistry refers to Arthur Kornberg’s many graduate students and post-doctoral fellows, i.e., his intellectual children, and the trainees of his trainees, i.e., his intellectual grandchildren. Kornberg’s intellectual children include I. Robert Lehman, Charles C. Richardson, Randy Schekman, William T. Wickner, James Rothman, Arturo Falaschi and Ken-ichi Arai.

 

On November 21, 1943, Kornberg married Sylvy Ruth Levy, also a biochemist. She worked closely with Kornberg and contributed significantly to the discovery of DNA polymerase. The day after he was awarded the Nobel prize, she was quoted in a newspaper as saying “I was robbed.“ Arthur and Sylvy Kornberg had three sons: Roger David Kornberg (1947), Thomas B. Kornberg (1948), and Kenneth Andrew Kornberg (1950). Roger is Professor of Structural Biology at Stanford University, and the 2006 laureate of the Nobel Prize in Chemistry. Thomas discovered DNA polymerase II and III in 1970 and is now a professor at the University of California, San Francisco. Kenneth is an architect specializing in the design of biomedical and biotechnology laboratories and buildings.

 

When he was in his eighties, Kornberg continued to conduct research full-time at Department of Biochemistry at Stanford. He died on October 26, 2007 at Stanford Hospital from respiratory failure.

 

Roger D. Kornberg wins the 2006 Nobel Prize in Chemistry

 

 

20141027-12

Roger David Kornberg (born April 24, 1947) is an American biochemist and professor of structural biology at Stanford University School of Medicine. Kornberg was awarded the Nobel Prize in Chemistry in 2006 for his studies of the process by which genetic information from DNA is copied to RNA, “the molecular basis of eukaryotic transcription.“ “Kornberg“ was born in St. Louis, Missouri, the eldest of three sons of biochemist Arthur Kornberg, who won the Nobel Prize in 1959, and Sylvy Ruth (Levy), also a biochemist. He earned his bachelor’s degree in chemistry from Harvard University in 1967 and his Ph.D. in chemical physics from Stanford in 1972. He became a postdoctoral fellow at the Laboratory of Molecular Biology in Cambridge, England and then an Assistant Professor of Biological Chemistry at Harvard Medical School in 1976, before moving to his present position as Professor of Structural Biology at Stanford Medical School in 1978. His closest collaborator has been his wife, Professor Yahli Lorch. He has two younger brothers: Thomas B. Kornberg (b. 1948) -biochemist who was the first person to purify and characterize DNA polymerase II and DNA polymerase III; and Kenneth Andrew Kornberg (b. 1950) – architect specializing in the design of biomedical and biotechnology laboratories and buildings.

Some Background of the Science

All organisms are controlled by their genes, which are coded by DNA, which is copied to RNA, which creates proteins, which are sequences of amino acids. DNA resides in the nucleus. When a cell expresses a gene, it copies (transcribes) that gene’s DNA sequence onto a messenger RNA (mRNA) sequence. mRNA is transported out of the nucleus to ribosomes. The ribosomes read the mRNA and translate the code into the right amino acid sequence to make that gene’s protein. The DNA is transcribed to mRNA by an enzyme, RNA polymerase II, with the help of many other proteins. Using yeast, Kornberg identified the role of RNA polymerase II and other proteins in transcribing DNA, and he created three-dimensional images of the protein cluster using X-ray crystallography. Polymerase II is used by all organisms with nuclei, including humans, to transcribe DNA.

 

 

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X-ray crystallography shows the arrangement of water molecules in ice, revealing the hydrogen bonds (1) that hold the solid together. Few other methods can determine the structure of matter with such precision (resolution).

 

Kornberg and his research group have made several fundamental discoveries concerning the mechanisms and regulation of eukaryotic transcription. While a graduate student working with Harden McConnell at Stanford in the late 1960s, he discovered the “flip-flop“ and lateral diffusion of phospholipids in bi-layer membranes. While a postdoctoral fellow working with Aaron Klug and Francis Crick at the MRC in the 1970s, Kornberg discovered the nucleosome as the basic protein complex packaging chromosomal DNA in the nucleus of eukaryotic cells (chromosomal DNA is often termed “Chromatin“ when it is bound to proteins in this manner, reflecting Walther Flemming’s discovery that certain structures within the cell nucleus would absorb dyes and become visible under a microscope). Within the nucleosome, Kornberg found that roughly 200 bp of DNA are wrapped around an octamer of histone proteins.

 

Announcement of Roger Kornberg’s winning of Nobel Prize sent out by Stanford University:

 

The Royal Swedish Academy of Sciences awarded Roger Kornberg, PhD, of the Stanford University School of Medicine, the 2006 Nobel Prize in Chemistry for his work in understanding how DNA is converted into RNA, a process known as transcription. In 2001 Kornberg published the first molecular snapshot of the protein machinery responsible – RNA polymerase – in action. The finding helped explain how cells express all the information in the human genome, and how that expression sometimes goes awry, leading to cancer, birth defects and other disorders.

 

“I’m simply stunned. There are no other words,“ said Kornberg after the 2:30 a.m. call. “It’s such astonishing news.“ The scene at Kornberg’s house was one of controlled chaos, with nonstop telephone calls from well-wishers and media. Kornberg, who is also the Mrs. George A. Winzer Professor in Medicine, is the School of Medicine’s second Nobel Prize winner this week. On Monday, Andrew Fire, PhD, professor of pathology and of genetics, was a winner of the 2006 Nobel Prize in Physiology or Medicine for his work on RNA interference. Together the two awards serve as a clarion announcement of RNA’s arrival in the scientific and medical spotlight. “Roger has been one of my role models for many years,“ said Fire. “We did our post-docs at Cambridge in the same institute, and he’s been a tremendous help to me since I came to Stanford in 2003. Our fields are interestingly intertwined.“ Kornberg’s research, and latest award, is a family affair: his father Arthur Kornberg, PhD, was awarded the Nobel Prize in Physiology or Medicine in 1959 for studies of how genetic information is transferred from one DNA molecule to another. The Kornbergs are the sixth father-son team to win Nobel Prizes, in addition to one father-daughter team. “I have felt for some time that he richly deserved it,“ said the elder Kornberg after hearing about his son’s award. “His work has been awesome.“ Arthur Kornberg is the Emma Pfeiffer Merner Professor of Biochemistry, Emeritus, at the School of Medicine. He learned of the award from a nephew in LaJolla, Calif., who had been called accidentally by someone looking for Roger. “Roger Kornberg is one of our nation’s treasured scientists,“ said Philip Pizzo, MD, dean of the School of Medicine. “He has dedicated his life and career to using the powerful tools of structural biology to elucidate the molecular mechanism of transcription. His remarkable studies have been acclaimed for their elegance and technical sophistication as well as the unique insights they have yielded. His work has deepened our understanding of the ?message of life’ and how it contributes to both normal and abnormal human development, health and disease.“

 

Kornberg emphasized that the work required many contributions. “I am indebted to my colleagues,“ he said. “This is not something that I did alone, or even with a small number of people. It is the result of the hard work, insight and inspiration of very many exceptionally talented Stanford students and post-docs.“ Selective transcription of a cell’s tens of thousands of genes determines whether it becomes a neuron, a liver cell or a stem cell – and whether it develops normally or becomes a runaway cancer. The picture of RNA polymerase at work provided an atomic-level window into how the protein complex unzips and then re-zips the double-stranded DNA like a Ziploc bag after using the internal code to build a specific RNA molecule. It was a thing of beauty for biologists around the world. “We were astonished by the intricacy of the complex, the elegance of the architecture, and the way that such an extraordinary machine evolved to accomplish these important purpose,“ said Kornberg of the images he and his colleagues created. “RNA polymerase gives a voice to genetic information that, on its own, is silent.“ Learning how that voice is amplified – and shushed – through the selective expression of genes is a critical stepping stone to many areas of biological and medical research.

 

The path to the pictures involved a highly specialized field at the intersection of chemistry, biology and physics called crystallography. The technique, as much art as science, is the same one used by Francis Crick and James Watson to determine the double-stranded nature of DNA. In general, it involves evaporating a concentrated solution of a molecule until all that’s left are highly structured crystals somewhat like the crust of salt left behind by drying seawater. Extremely bright X-rays are then able to pinpoint the position of individual atoms and the data are used to produce a computer-generated representation of the molecule. Successfully crystallizing one molecule is a feat worth congratulating. Capturing the 10 subunits of RNA polymerase in action on the DNA was unthinkable. “It was a technical tour de force that took about 20 years of work to accomplish,“ said Joseph Puglisi, PhD, professor and chair of the department of structural biology at the School of Medicine. “Like other great scientists, Roger doesn’t quit. He’s stubborn. A lot of scientists would have given up after five years.“ Kornberg’s determination, coupled with his expertise in both crystallography and biochemistry, finally cracked the code. “I’m a biochemist and he’s a biochemist, but beyond that he’s a crystallographer, a structural chemist and a geneticist,“ said Arthur Kornberg. Roger Kornberg devised a way to first initiate the process of transcription in a test tube and then stall it by withholding one of the building blocks of RNA. Crystallizing the frozen complex showed the relative positions of the polymerase, the DNA template and the growing RNA strand.

 

“Professor Kornberg’s seminal research on transcription has been an exceptional contribution to the body of knowledge in fundamental biology,“ said Stanford University President John Hennessy. “His work settled long-open questions about how genes communicate the information needed to make proteins and will help us understand a variety of diseases that can be caused by a failure in the transcription process. For the second time this week, a colleague’s achievement reminds us of the unique role universities have in advancing basic knowledge. We are proud to claim Professor Kornberg and his father Arthur as members of the Stanford family. I offer Roger warm congratulations on behalf of the entire university community.“

 

Prior to beginning his work studying the molecular mechanism of transcription, Kornberg discovered the nucleosome, the basic unit from which all chromosomes are made. In 1974, as a junior scientist at Cambridge University, he proposed that the massive amounts of DNA contained in every cell could be compactly stored by wrapping it in its condensed form – the chromosome – around eight histone protein “spools“ to form nucleosome “beads.“ Kornberg and his wife and collaborator Yahli Lorch, PhD, associate professor of structural biology at Stanford, were instrumental in identifying the nucleosome as fundamental to transcription. Since then, it has been recognized that disruptions involving the nucleosome underlie many cancers and other diseases.

 

“Roger was a scientist from the beginning; He never showed any other interest,“ said his brother, Thomas Kornberg, PhD, a professor of biochemistry at the University of California-San Francisco. “Both my parents had fine scientific minds and taught by example how to approach questions and problems in a logical, dispassionate way,“ Roger Kornberg once said. “Science was a part of dinner conversation and an activity in the afternoons and on weekends. Scientific reasoning became second nature. Above all, the joy of science became evident to my brothers and me.“ Kornberg was able to indulge his scientific bent early as a high school student working in the laboratory of Paul Berg, a colleague of his father’s at Stanford who won the Nobel Prize in Chemistry in 1980. The senior Kornberg said his son’s winning did not come entirely out of the blue. He had mentioned the chemistry prize yesterday in a conversation with his son, who had just returned from a trip to Jerusalem. “I talked to him at length and couldn’t help but discuss this possibility – I know he’s been shortlisted in previous years,“ said the elder Kornberg. “He dismissed it, saying it was a possibility but he didn’t expect it, but that’s the way it goes.“ Arthur Kornberg said he had not imagined decades ago, when his son first began his career as a biochemist, that there would be a second Nobel laureate in the family. “Of course not,“ he remarked. “But nature is so broad, profound and mysterious – one doesn’t know where it leads. And I would say among the people I know – and I have trained many hundreds – he has the clearest vision, sense of purpose and direction.“ Pizzo paid tribute to the contributions of both father and son to Stanford. “Arthur Kornberg played a major role in transforming the Stanford University School of Medicine into a research-intensive powerhouse,“ Pizzo said. “He was clearly productive in both his professional life and his private life – since he is the father of remarkably talented children, including Roger – who has sustained a legacy of brilliance and commitment to science and the deepening of our understanding of human life.“

 

Roger Kornberg received his undergraduate degree in chemistry from Harvard in 1967 and his doctorate in chemistry from Stanford in 1972, studying the motion of lipids in cell membranes. He was a postdoctoral fellow and member of the scientific staff at the Laboratory of Molecular Biology in Cambridge, U.K., from 1972 to 1975. He joined Harvard Medical School in 1976 as an assistant professor in biological chemistry. Kornberg returned to Stanford in 1978 as a professor in structural biology. He served as department chair from 1984 until 1992. Kornberg is an elected member of the National Academy of Sciences and of the American Academy of Arts and Sciences, and an honorary member of the Japanese Biochemical Society. He is editor of the Annual Reviews of Biochemistry. He has written more than 180 peer-reviewed journal articles. His previous honors and awards include the Eli Lilly Award (1981), the Passano Award (1982), the Harvey Prize (1997), the Gairdner International Award (shared in 2000 with Robert Roeder), the Welch Award (2001) and the Grand Prix of the French Academy of Sciences (2002). “One of the benefits of the recognition of work such as ours is that it encourages continued support of fundamental issues like this one,“ said Kornberg. “Many of the major advances in human health have their origins in the pursuit of basic biological knowledge.“ His funding sources agree. “Through decades of elegant, state-of-the art studies in biochemistry and structural biology, Roger Kornberg has revealed the mechanism underlying how cells transcribe genetic information,“ said Jeremy M. Berg, PhD, director of the National Institute of General Medical Sciences, which has funded Kornberg’s research since 1979. “This knowledge sheds light on a fundamental process that is key to health and disease. The achievement also demonstrates the power of innovative approaches to probe the many complicated molecular assemblies essential to life.“ Despite the kudos, wining such a prestigious award can create complications: Kornberg was scheduled to fly to Pittsburgh this evening to receive the Dickson Prize in Medicine. When he called to cancel his flight, the Travelocity operator wanted to know the reason for the cancellation. There was a pause, and a gulp. “Well,“ he said. “I just won the Nobel Prize in Chemistry.“ There’s no word yet as to the operator’s response, but perhaps he can roll the ticket over to his upcoming trip to Sweden. “I’m looking forward to being in Stockholm, where we have many friends,“ said Arthur Kornberg, remembering his own award 47 years ago. “They put on a great party.“

 

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Rapid Agent Restores Pleasure-Seeking Ahead of Other Antidepressant Action

 

A cardinal symptom of both depression and bipolar disorder is anhedonia, or the loss of the ability to look forward to pleasurable activities.  Ketamine, a drug not approved by the U.S. Food and Drug Administration as a treatment for depression, appears to reverse anhedonia. Ketamine is mostly used in veterinary practice, and abuse can lead to hallucinations, delirium and amnesia.

 

Long used as an anesthetic and sometimes club drug, ketamine and its mechanism-of-action have lately been the focus of research into a potential new class of rapid-acting antidepressants that can lift mood within hours instead of weeks. According to an article published online in the journal Translational Psychiatry (14 Oct 2014), ketamine, being evaluated as a fast-acting mood-lifter, restored pleasure-seeking behavior independent of – and ahead of – its other antidepressant effects. Within 40 minutes after a single infusion of ketamine, treatment-resistant depressed bipolar disorder patients experienced a reversal of a key symptom, including loss of interest in pleasurable activities, which lasted up to 14 days. Brain scans traced the agent’s action to boosted activity in areas at the front and deep in the right hemisphere of the brain. This approach is consistent with the NIMH’s Research Domain Criteria project, which calls for the study of functions — such as the ability to seek out and experience rewards — and their related brain systems that may identify subgroups of patients in one or multiple disorder categories.

 

Based on their previous studies, the authors expected ketamine’s therapeutic action against anhedonia would be traceable — like that for other depression symptoms – to effects on a mid-brain area linked to reward-seeking and that it would follow a similar pattern and time course. To find out, the drug or a placebo was infused into 36 patients in the depressive phase of bipolar disorder, and any resultant mood changes were detected using rating scales for anhedonia and depression. By isolating scores on anhedonia items from scores on other depression symptom items, the authors discovered that ketamine was triggering a strong anti-anhedonia effect sooner — and independent of – the other effects. Levels of anhedonia plummeted within 40 minutes in patients who received ketamine, compared with those who received placebo — and the effect was still detectable in some patients two weeks later. Other depressive symptoms improved within 2 hours. The anti-anhedonic effect remained significant even in the absence of other antidepressant effects, suggesting a unique role for the drug. Next, the authors scanned a subset of the ketamine-infused patients, using positron emission tomography (PET), which shows what parts of the brain are active by tracing the destinations of radioactively-tagged glucose — the brain’s fuel. The scans showed that ketamine jump-started activity not in the middle brain area they had expected, but rather in the dorsal (upper) anterior cingulate cortex, near the front middle of the brain and putamen, deep in the right hemisphere.

 

According to the authors, boosted activity in these areas may reflect increased motivation towards or ability to anticipate pleasurable experiences. Depressed patients typically experience problems imagining positive, rewarding experiences — which would be consistent with impaired functioning of this dorsal anterior cingulate cortex circuitry. However, confirmation of these imaging findings must await results of a similar NIMH ketamine trial nearing completion in patients with unipolar major depression.

 

Other evidence suggests that ketamine’s action in this circuitry is mediated by its effects on the brain’s major excitatory neurotransmitter, glutamate, and downstream effects on a key reward-related chemical messenger, dopamine. The findings add to mounting evidence in support of the antidepressant efficacy of targeting this neurochemical pathway. Ongoing research is exploring, for example, potentially more practical delivery methods for ketamine and related experimental antidepressants, such as a nasal spray.

 

Unexpected Role for Stem Cells in the Brain

 

The olfactory bulb is located in the front of the brain and receives information directly from the nose about odors in the environment. Neurons in the olfactory bulb sort that information and relay the signals to the rest of the brain, at which point we become aware of the smells we are experiencing. Olfactory loss is often an early symptom in a variety of neurological disorders, including Alzheimer’s and Parkinson’s diseases. In a process known as neurogenesis, adult-born neuroprogenitor cells are generated in the subventricular zone deep in the brain and migrate to the olfactory bulb where they assume their final positions. Once in place, they form connections with existing cells and are incorporated into the circuitry.

 

For decades, it was thought that neurons in the brain were born only during the early development period and could not be replenished. More recently, however, cells have been discovered with the ability to divide and turn into new neurons in specific brain regions. The function of these neuroprogenitor cells remains an intense area of research. Recently, scientists at the National Institutes of Health (NIH) reported that newly formed brain cells in the mouse olfactory system — the area that processes smells — play a critical role in maintaining proper connections. The results were published in the October 8 issue of the Journal of Neuroscience. Using two types of specially engineered mice, the authors were able to specifically target and eliminate the stem cells that give rise to these new neurons in adults, while leaving other olfactory bulb cells intact. This level of specificity had not been achieved previously.

 

In the first set of mouse experiments, the authors first disrupted the organization of olfactory bulb circuits by temporarily plugging a nostril in the animals, to block olfactory sensory information from entering the brain. This laboratory previously showed that this form of sensory deprivation causes certain projections within the olfactory bulb to dramatically spread out and lose the precise pattern of connections that show under normal conditions. These studies also showed that this widespread disrupted circuitry could re-organize itself and restore its original precision once the sensory deprivation was reversed. However, in the current study, it was revealed that once the nose is unblocked, if new neurons are prevented from forming and entering the olfactory bulb, the circuits remain in disarray. To further explore this idea, the research team also eliminated the formation of adult-born neurons in mice that did not experience sensory deprivation. It was found that the olfactory bulb organization began to break down, resembling the pattern seen in animals blocked from receiving sensory information from the nose. And then the authors observed a relationship between the extent of stem cell loss and amount of circuitry disruption, indicating that a greater loss of stem cells led to a larger degree of disorganization in the olfactory bulb.

 

According to the authors, it is generally assumed that the circuits of the adult brain are quite stable and that introducing new neurons alters the existing circuitry, causing it to re-organize. However, in this case, the circuitry appears to be inherently unstable requiring a constant supply of new neurons not only to recover its organization following disruption but also to maintain or stabilize its mature structure. The authors continued that It’s actually quite amazing that despite the continuous replacement of cells within this olfactory bulb circuit, under normal circumstances its organization does not change. The authors speculate that new neurons in the olfactory bulb may be important to maintain or accommodate the activity-dependent changes in the system, which could help animals adapt to a constantly varying environment.

 

FDA Approves 2 Drugs to Treat Idiopathic Pulmonary Fibrosis

 

Idiopathic pulmonary fibrosis is a condition in which the lungs become progressively scarred over time. As a result, patients with IPF experience shortness of breath, cough, and have difficulty participating in everyday physical activities. Current treatments for IPF include oxygen therapy, pulmonary rehabilitation, and lung transplant.

 

The FDA has approved Esbriet (pirfenidone) and Ofev (nintedanib) for the treatment of idiopathic pulmonary fibrosis (IPF).

 

The FDA granted both products fast track, priority review, orphan product, and breakthrough designations. As a result, Esbriet and Ofev were approved ahead of the product’s prescription drug user fee goal date of Nov. 23, 2014, and January 2, 2015, respectively, the dates the FDA was scheduled to complete the review of the drug applications.

 

Esbriet acts on multiple pathways that may be involved in the scarring of lung tissue. Its safety and effectiveness were established in three clinical trials of 1,247 patients with IPF. Ofev is a kinase inhibitor that blocks multiple pathways that may be involved in the scarring of lung tissue. Its safety and effectiveness were established in three clinical trials of 1,231 patients with IPF. For both drugs, the decline in forced vital capacity – the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible – was significantly reduced in patients receiving Ofev compared to patients receiving placebo.

 

Esbriet is not recommended for patients who have severe liver problems, end-stage kidney disease, or who require dialysis. Esbriet should be taken with food to minimize the potential for nausea and dizziness. Patients should avoid or minimize exposure to sunlight and sunlamps and wear sunscreen and protective clothing, as Esbriet may cause patients to sunburn more easily. Ofev is not recommended for patients who have moderate to severe liver problems. Ofev can cause birth defects or death to an unborn baby. Women should not become pregnant while taking Ofev. Women who are able to get pregnant should use adequate contraception during and for at least three months after the last dose of Ofev.

 

The most common side effects of Esbriet are nausea, rash, abdominal pain, upper respiratory tract infection, diarrhea, fatigue, headache, dyspepsia, dizzines, vomiting, decreased/loss of appetite, gastro-esophageal reflux disease, sinusitis, insomnia, decreased weight, and arthralgia. The most common side effects of Ofev are diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevation, decreased appetite, headache, decreased weight, and high blood pressure.

 

Esbriet is manufactured for InterMune, Inc., Brisbane, California and Ofev is distributed by Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.

 

Apple Harvest Cake with Amaretto

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Apples are plentiful and delicious, this time of year. ©Joyce Hays, Target Health Inc.

 

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Look at the Amaretto oozing out. ©Joyce Hays, Target Health Inc.

 

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Gather together, all the ingredients. Apple harvest is still going on, so this is the time of year to get out your best apple recipes. This apple cake is one of mine. ©Joyce Hays, Target Health Inc.

 

Apples

 

4 small apples, washed, halved, peeled and cored (depending on the apple size, you may or may not use all of the apples)

2 Tablespoons fresh lemon juice

2 Tablespoons granulated Splenda

 

Cake

 

1/4 cup plus 1 Tablespoon unsalted butter, at room temperature

1/4 cup plus 2 Tablespoons (6 tablespoons) granulated Splenda

1/4 cup honey

1 teaspoon vanilla

3 large eggs, separated

2 pinches of Kosher or sea salt

2 teaspoons baking powder

1 and ? cups almond flour

 

Topping, After Cake Has Cooled (optional)

 

1/4 cup honey, plus your favorite rum or liqueur

Pinch salt

 

Directions

 

Preheat oven to 350 degrees.

Coat a 9-inch spring-form cake pan with canola spray. Line the bottom of the pan with a round of parchment paper.

 

Prepare apples: First of all, as you can see in the photo, there are now a plethora of varieties to choose from, so chose your favorite from those locally grown. First I used regular size apples, then I tried a tiny variety, just to fit more apples onto the cake.

 

 

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Cutting parallel thin apple slices, here, without cutting all the way through the apple. ©Joyce Hays, Target Health Inc.

 

Place peeled, halved and cored apples cut-side-down on cutting board. With a sharp knife, create parallel thin slices, but only cut halfway through, so each apple half stays together. If you slip and cut through, don’t worry about it. Cut the slices as thin as you can.

 

In a bowl, toss apples with lemon juice and 2 Tablespoons granulated Splenda.

 

Prepare cake: With your electric beaters, beat butter and 1/4 cup plus 2 tablespoons granulated Splenda, in a bowl until fluffy. Add honey and beat until combined. Add vanilla and egg yolks, and keep beating until just combined. Slowly, add baking powder and salt to cake batter, and mix briefly for a few seconds, until the batter absorbs everything. Add the almond flour, half at a time, mixing very briefly, until combined.

 

Clean the beaters and in a separate bowl, beat egg whites until stiff. Stir 1/4 of egg whites into the cake batter. (don’t beat or whip; stir a little and stir very slowly) Fold in the rest, one quarter at a time, three more times. The batter will be stiff, so it will seem impossible to fold into it, but don’t despair, it will gradually loosen up. Fold each addition of egg whites until absorbed. A little bit of white showing is perfectly okay.

 

 

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Pour the cake batter in your prepared cake pan. Use a spatula to get all the batter into the pan and then to smooth the top of the batter. Arrange (don’t press) the apple halves facedown over the cake batter. If you can only fit 3 or 3 and 1/2 of the apples on top of the batter, that’s fine, no problem. Pour any leftover lemon juice and Splenda, in the bowl, over the apples.

 

Bake 35 to 40 minutes, until a toothpick comes out clean, after inserting in center of cake. When done, remove cake and rest it on a cooling rack for 5 minutes.

 

Cut around the cake to make sure it’s not sticking, at all, and unhinge the sides of the spring-form pan. Let cake cool completely. Then, add your rum or Amaretto with a teaspoon, until all of it is completely absorbed. Follow your own taste with this. For us, we love lots of Amaretto, so I literally soak the apple cake in it, until it can hold no more and starts to leak a bit.

 

This cake can be stored at room temperature for 3 days, after that, store in the fridge.

 

Before serving, if you want the glaze to look glossy, whenever the cake is cool: Warm 1/4 cup honey and a good pinch of sea salt until it liquefies to the point where it makes a thin glaze – this will take less than 30 seconds. Brush honey-salt mixture over cooled cake. Or, forget about a glaze, your choice. None of my photos show the apple cake with a glaze.

 

 

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Apple cake for two. ©Joyce Hays, Target Health Inc.

 

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This Apple cake will melt in your mouth. ©Joyce Hays, Target Health Inc.

 

Have you noticed that sometimes we’re vegan and sometimes paleo? I figure if bears, otters and wolves can be omnivores, so can we humans.

 

We started out this vegan meal with very fresh mozzarella, sweet grape tomatoes and wine. He wanted white (Cloudy Bay, Sauvignon Blanc, New Zealand) and I had red (Hall, Cabernet Sauvignon, Napa Valley).

 

Then came the home made Kale/Quinoa Patties with an avocado topping, mashed garlic-y cauliflower with white truffle oil, and fresh sweet baby green garden peas. If I do say so myself, this entr?e was de-lish!

 

Finally, triumphant, the Apple Cake, literally oozing Amaretto, and was it g-oo-od! With generous dollops of (no-fat) Cool Whip it was truly luscious! Shhhh we had second helpings. J

 

This was a perfect day starting out at the MetOpera with Marriage of Figaro, one of our favorite operas. We love this opera so much, that years ago when we had to miss a performance of Figaro at the Met, and I happened to notice that a production of Figaro was being done at the Santa Fe Opera House, we decided to fly to Santa Fe, in order not to miss this glorious music.

 

That was in 1994 or 95, and that was the beginning of our odyssey of the senses, each August, to beautiful Santa Fe, New Mexico, a (tiny) city overflowing with culture and science; a capitol that looks and feels like a friendly village.

 

Sublime music, like Figaro, really strikes a profound chord in humans. I’m convinced that our five senses (some have six) interact with our intelligence and memory in a way that cannot be duplicated. And this constant interaction is what guides us through life. (Tell that to the robots that are stealing our jobs.)

 

Hope your weekend was as fulfilling as ours has been!

 

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He wanted white and she toasted with red. ©Joyce Hays, Target Health Inc.

 

From Our Table to Yours!

 

Bon Appetit!

 

 

Ebola-A Virus Gets a Czar – Time to Take Politics Out of Medicine

 

Mark L. Horn, MD, MPH, Chief Medical Officer, Target Health Inc.

 

The appointment of an acknowledged competent political operative, sans scientific and medical credentials but with expertise in operations and knowledge of the political landscape, AKA Ebola “Czar“ reinforces the potential for politicization of the emergence of a small but clearly worrisome number of Ebola infections in the United States. As a physician, while it is not hard to see why the decision was taken, I am concerned that appointment, and the response of politicians with no knowledge of science, medicine and basic facts, has the potential to undermine of the primacy of medical and scientific experts– who ideally should be shepherding the nation through this crisis.

 

Trust must be earned, and the management of this potential crisis at the beginning, to be charitable, was disappointing. Yet, despite the obvious missteps, so far the only individuals receiving just praise by various authorities have been two frontline nurses who were almost certainly poorly prepared for the tasks they were assigned, yet unselfishly and bravely did their jobs and contracted a potentially lethal disease. They are, to date, together with the frontline healthcare workers in West Africa, two genuine heroines in this evolving story. Their immediate and vigorous support along with the straightforward recommendations for action from nursing leadership rank among the few unequivocal bright lights in the official responses to this crisis.

 

Many healthcare providers will recall that sometime during their training in medicine and science, they were told “never say always, never say never.“ The obvious point: excessive certainty confers high risk that one will ultimately be proven wrong. With Ebola it didn’t take long. We have discovered yet again that hubris is dangerous, perhaps especially so with an unfamiliar, highly lethal infectious agent.

 

In tragi-comedic sequence, the projections from the authorities that we want and need to trust, have been proven suspect, from reassurances that the virus would unlikely reach us to repeated assurances that should the unexpected happen, our health care system was prepared, capable of stopping any spread to health care workers and the general public. In addition, specific decisions–e.g. authorizing a known exposed individual to board a commercial flight–were taken that in retrospect appear not merely careless, but reckless. Sadly, these errors are not simply medically and scientifically questionable; they challenge common sense and have therefore alarmed the public.

 

While it may have been ideal to eliminate politics from this multivariate equation, rapidly moving events have apparently convinced the Administration that a politically sophisticated manager is needed to take control of a deteriorating situation. The administration and the members of the scientific and medical support teams need to establish (or reestablish) their personal credibility, and the credibility of government and its institutions. They must get ahead of the virus, but not ahead of the facts. Uncertainties, challenges, and deficiencies must be frankly acknowledged, capabilities accurately assessed and not overestimated. Spokespersons must show genuine respect for the public which, despite constant exposure to concerning headlines and rhetoric, has displayed remarkable calm. Provided with reliable information offered by trusted leaders, people are far less likely to panic.

 

It is time for leadership, political, medical and scientific, to step up, acknowledge reality (especially what we don’t know) and implement and communicate proper plans which, importantly, self-evidently err on the side of caution. In short, treat us as adults with much at stake.

 

As I write this, a case of Ebola has been confirmed in our city. The staff at Bellevue Hospital, where I learned medicine, will be caring for this patient. We hope and trust that they are well prepared and wish them, and their patient, the very best outcome.

 

Editor’s note:  Let us continue our American optimism, and “can do“ approach leading to solutions for significant global crisis, like Ebola. Mistakes will be made. We’re on a learning curve. Here in NYC there is no panic. We know we’lll get through this. Our medical system is the best in the world and we believe in it.