Advertisements
Feeds:
Posts
Comments

Archive for the ‘Discovery process’ Category


Twitter, Google, LinkedIn Enter in the Curation Foray: What’s Up With That?

 

Reporter: Stephen J. Williams, Ph.D.

Recently Twitter has announced a new feature which they hope to use to increase engagement on their platform. Originally dubbed Project Lightning and now called Moments, this feature involves many human curators which aggregate and curate tweets surrounding individual live events(which used to be under #Live).

As Madhu Muthukumar (@justmadhu), Twitter’s Product Manager, published a blog post describing Moments said:

“Every day, people share hundreds of millions of tweets. Among them are things you can’t experience anywhere but on Twitter: conversations between world leaders and celebrities, citizens reporting events as they happen, cultural memes, live commentary on the night’s big game, and many more,” the blog post noted. “We know finding these only-on-Twitter moments can be a challenge, especially if you haven’t followed certain accounts. But it doesn’t have to be.”

Please see more about Moments on his blog here.

Moments is a new tab on Twitter’s mobile and desktop home screens where the company will curate trending topics as they’re unfolding in real-time — from citizen-reported news to cultural memes to sports events and more. Moments will fall into five total categories, including “Today,” “News,” “Sports,” “Entertainment” and “Fun.” (Source: Fox)

Now It’s Google’s Turn

 

As Dana Blankenhorn wrote in his article Twitter, Google Try It Buzzfeed’s Way With Curation

in SeekingAlpha

What’s a challenge for Google is a direct threat to Twitter’s existence.

For all the talk about what doesn’t work in journalism, curation works. Following the news, collecting it and commenting, and encouraging discussion, is the “secret sauce” for companies like Buzzfeed, Vox, Vice and The Huffington Post, which often wind up getting more traffic from a story at, say The New York Times (NYSE:NYT), than the Times does as a result.

Curation is, in some ways, a throwback to the pre-Internet era. It’s done by people. (At least I think I’m a people.) So as odd as it is for Twitter (NYSE:TWTR) to announce it will curate live events it’s even odder to see Google (NASDAQ:GOOG) (NASDAQ:GOOGL) doing it in a project called YouTube Newswire.

Buzzfeed, Google’s content curation platform, made for desktop as well as a mobile app, allows sharing of curated news, viral videos.

The feel for both Twitter and Google’s content curation will be like a newspaper, with an army of human content curators determining what is the trendiest news to read or videos to watch.

BuzzFeed articles, or at least, the headlines can easily be mined from any social network but reading the whole article still requires that you open the link within the app or outside using a mobile web browser. Loading takes some time–a few seconds longer. Try browsing the BuzzFeed feed on the app and you’ll notice the obvious difference.

However it was earlier this summer in a Forbes article Why Apple, Snapchat and Twitter are betting on human editors, but Facebook and Google aren’t that Apple, Snapchat and Twitter as well as LinkedIn Pulse and Instragram were going to use human editors and curators while Facebook and Google were going to rely on their powerful algorithms. Google (now Alphabet) CEO Eric Schmidt has even called Apple’s human curated playlists “elitist” although Google Play has human curated playlists.

Maybe Google is responding to views on its Google News like this review in VentureBeat:

Google News: Less focused on social signals than textual ones, Google News uses its analytic tools to group together related stories and highlight the biggest ones. Unlike Techmeme, it’s entirely driven by algorithms, and that means it often makes weird choices. I’ve heard that Google uses social sharing signals from Google+ to help determine which stories appear on Google News, but have never heard definitive confirmation of that — and now that Google+ is all but dead, it’s mostly moot. I find Google News an unsatisfying home page, but it is a good place to search for news once you’ve found it.

Now WordPress Too!

 

WordPress also has announced its curation plugin called Curation Traffic.

According to WordPress

You Own the Platform, You Benefit from the Traffic

“The Curation Traffic™ System is a complete WordPress based content curation solution. Giving you all the tools and strategies you need to put content curation into action.

It is push-button simple and seamlessly integrates with any WordPress site or blog.

With Curation Traffic™, curating your first post is as easy as clicking “Curate” and the same post that may originally only been sent to Facebook or Twitter is now sent to your own site that you control, you benefit from, and still goes across all of your social sites.”

The theory the more you share on your platform the more engagement the better marketing experience. And with all the WordPress users out there they have already an army of human curators.

So That’s Great For News But What About Science and Medicine?

 

The news and trendy topics such as fashion and music are common in most people’s experiences. However more technical areas of science, medicine, engineering are not in most people’s domain so aggregation of content needs a process of peer review to sort basically “the fact from fiction”. On social media this is extremely important as sensational stories of breakthroughs can spread virally without proper vetting and even influence patient decisions about their own personal care.

Expertise Depends on Experience

In steps the human experience. On this site (www.pharmaceuticalintelligence.com) we attempt to do just this. A consortium of M.D.s, Ph.D. and other medical professionals spend their own time to aggregate not only topics of interest but curate on specific topics to add some more insight from acceptable sources over the web.

In Power of Analogy: Curation in Music, Music Critique as a Curation and Curation of Medical Research Findings – A Comparison; Dr. Larry Berstein compares a museum or music curator to curation of scientific findings and literature and draws similar conclusions from each: that a curation can be a tool to gain new insights previously unseen an observer. A way of stepping back to see a different picture, hear a different song.

 

For instance, using a Twitter platform, we curate #live meeting notes and tweets from meeting attendees (please see links below and links within) to give a live conference coverage

https://pharmaceuticalintelligence.com/press-coverage/

and curation and analysis give rise not only to meeting engagement butunique insights into presentations.

 

In addition, the use of a WordPress platform allows easy sharing among many different social platforms including Twitter, Google+, LinkedIn, Pinterest etc.

Hopefully, this will catch on to the big powers of Twitter, Google and Facebook to realize there exists armies of niche curation communities which they can draw on for expert curation in the biosciences.

Other posts on this site on Curation and include

 

Inevitability of Curation: Scientific Publishing moves to embrace Open Data, Libraries and Researchers are trying to keep up

The Methodology of Curation for Scientific Research Findings

Scientific Curation Fostering Expert Networks and Open Innovation: Lessons from Clive Thompson and others

The growing importance of content curation

Data Curation is for Big Data what Data Integration is for Small Data

Stem Cells and Cardiac Repair: Content Curation & Scientific Reporting

Cardiovascular Diseases and Pharmacological Therapy: Curations

Power of Analogy: Curation in Music, Music Critique as a Curation and Curation of Medical Research Findings – A Comparison

 

 

 

 

 

 

 

Advertisements

Read Full Post »


Mature cells can be reprogrammed to become pluripotent – John Gurdon and Shinya Yamanaka

Larry H. Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Innovation

Series E: 2; 7.1

In 1962, John B. Gurdon successfully cloned frogs. He took the nucleus of an adult frog cell – the part of the cell that holds the DNA – and put it into a frog egg cell. The egg was able to develop into a normal tadpole. These experiments showed that an adult, specialised cell still had the information needed to form a new tadpole. The same technique was later used to produce the famous cloned sheep, Dolly.

In 2006, Shinya Yamanaka’s work again took the scientific community by surprise and changed the way researchers think about how cells develop.Yamanaka showed that adult, fully specialised mouse cells could be reprogrammed to become cells that behave like embryonic stem cells – so-called induced pluripotent stem cells, which can develop into all types of cells in the body.

Gurdon and Yamanaka’s work is celebrated and explained in the award-winning documentary, Stem Cell Revolutions, by Clare Blackburn and Amy Hardie. The short clip above is taken from the film and links Gurdon and Yamanaka’s work (click the red button on the image above to watch the clip). Amy Hardie, who directed the film, commented: “So many scientists have said that Shinya Yamanaka has overturned our understanding of basic developmental biology. And he has – with the discovery of iPS cells. What Shinya Yamanaka himself points out and we were able to show in our film, Stem Cell Revolutions, is the lineage from John Gurdon who cloned frogs in Cambridge. Shinya’s groundbreaking discovery would not have been possible without Gurdon’s pioneering work.

Proc Natl Acad Sci U S A. 2013 Apr 9; 110(15): 5740–5741.

Published online 2013 Mar 28. doi:  10.1073/pnas.1221823110

Sir John Bertrand Gurdon, FRS, FMedSci (born 2 October 1933), is an English developmental biologist. He is best known for his pioneering research in nuclear transplantation[2][3][4] and cloning.[1][5][6][7] He was awarded the Lasker Award in 2009. In 2012, he and Shinya Yamanaka were awarded the Nobel Prize for Physiology or Medicine for the discovery that mature cells can be converted to stem cells.[8]

The Nobel Prize in Physiology or Medicine 2012
Sir John B. Gurdon, Shinya Yamanaka

ohn Bertrand Gurdon (JBG), born 2 October 1933, was brought up in a comfortable home by his parents (fig.1) on the Surrey/Hampshire border in a village, Frensham in South England, endowed with a large amount of National Trust heathland and ponds. His mother, Marjorie Byass, was from an East Yorkshire farming family. Brought up on a farm, and educated in that region, she became a physical training teacher working for some time in an American private school. When her son and daughter (Caroline, who trained as a nurse) had been raised, she gave much time to the regional administration of the “Women’s Institute,” a voluntary organisation for educating women.

His father, William Gurdon, was from a longstanding Suffolk family whose ancestors go back to 1199 (fig. 2; Muskett, 1900; Cunnington, 2008); with the family motto “virtus viget in arduis” [virtue flourishes in adversity].

Paternal lineage of JBG.

Many of them had distinguished careers in government and as regional administrators, including Sir Adam Gurdon [Muskett, 1900]. JBG’s ancestors lived in a stately home, Assington Hall, in West Suffolk (fig. 3).

His grandfather had to leave the family home through lack of money to maintain it, due to repeal of the Corn Laws (1846) so that tenant farmers could no longer pay their rent, because of foreign imports. Assington Hall was requisitioned by the army during World War II, and was burnt down in a supposedly accidental fire in 1957. The remaining part of the house was partly restored and part of the original home, including its minarets, is still present in Assington. One of JBG’s ancestors married again after his first wife died and the outcome of a second marriage yielded a distinguished lawyer who accepted the hereditary title of Baron Cranworth. JBG’s father left school at the age of 16 and took a position in a rice broking firm in Burma. He was an early volunteer in the First World War and was decorated with the Distinguished Conduct Medal (DCM) before being commissioned to an officer rank. After that he led a career in banking in Assam and East India. He retired, in his forties, and in retirement, he gave much time to the transcribing of professional textbooks (especially legal) into Braille for the blind as voluntary work.

World War II started in 1939 when JBG was aged six. It was a time of austerity. Limited rations of food were managed by his mother, and the garden was used to raise chickens. He did not see luxuries like a banana or an orange until well after the end of the war. At the age of eight he was sent to a local private school, Frensham Heights. In an intelligence test at that age, he was asked to draw an orange. He started drawing the stalk by which the orange would hang from a tree, reasoning that an orange would not exist in space. The teacher tore up the piece of paper and reported to his parents that he was mentally subnormal and would need special teaching. The teacher meant to say, draw a circle. He was moved to another private school in the village, namely Edgeborough, where he thrived. At that age he had an intense interest in plants and insects. In most of his spare time he collected butterflies and moths and raised their caterpillars.

At the age of 13, he started school at Eton as a boarder. He found life there intensely uncomfortable, because senior boys acted as despots, administering punishments for trivial misdemeanours. As a means of survival, he took up squash, and as a result of hard work rather than ability, he became eventually the school captain in this sport. While at school he continued his interest in Lepidoptera, raising large numbers of moths from their larval stage.

Gurdon attended Edgeborough and then Eton College, where he ranked last out of the 250 boys in his year group at biology, and was in the bottom set in every other science subject. A schoolmaster wrote a report stating “I believe he has ideas about becoming a scientist; on his present showing this is quite ridiculous.”[9] Gurdon explains it is the only document he ever framed; Gurdon also told a reporter “When you have problems like an experiment doesn’t work, which often happens, it’s nice to remind yourself that perhaps after all you are not so good at this job and the schoolmaster may have been right.”[10]

It was during his first term of being taught Science at the school, at the age of 15, that he received a totally damning report from the Biology master (fig. 4). This report resulted from JBG being placed in the bottom position of the lowest form in a group of 250 students of the same age. The report, sent to his housemaster, resulted in him being taken off any further study of Science of any kind at the school. For the rest of his school days, for the next three years, he was given no Science teaching and was placed in a class which studied Ancient Greek, Latin and a modern language, a course intended for those judged to be unsuited for studying any subject in depth.

Eton school report for JBG from Biology master, 1949.

 

Entrance to University was a problem: having sat the Entrance examination in Latin and Greek, the Admissions tutor at Christ Church Oxford University told JBG that he would be accepted for Entrance on condition that he did not plan to study the subject in which he took the Entrance (Classics). Later the Admissions tutor admitted that he had under-filled the college and had his mind on other things; he was Hugh Trevor-Roper, later Lord Dacre, and author of The Last Days of Hitler. In due course it emerged that JBG’s acceptance for Christ Church involved a complicated arrangement between JBG’s uncle, at that time a Fellow of Christ Church, JBG’s school housemaster and a friend of his uncle, Sir John Masterman, who was Master of Worcester College, Oxford and in charge of the wartime Enigma operation at Bletchley, agreeing to accept the housemaster’s son. Such a manoeuvre, and admission to Oxford on those terms, could never happen now. At that time, 1952, it was not very easy to fill a college with paying students. Before entering University, JBG had to take a year off to learn elementary Biology with a private tutor, generously funded by his parents who had already paid several years of Eton fees. He was told that he could formally enter the Department of Zoology course at Oxford if he passed the elementary exams in Physics, Chemistry and Biology in a preliminary year. He survived this and started the course in Zoology at Oxford in 1953. The course was extremely oldfashioned, by today’s standards. A major part of the teaching involved learning Palaeontology, and the names of skeletal parts of dinosaurs. JBG later became a personal friend of Sir Alister Hardy, the Head of that department, through his Oxford aunt (see later).

As the Zoology course came to an end, JBG enquired about the possibility of doing a PhD in Entomology, in accord with his continuing interest in insects. While still a student, he had got permission to go to Oxford University’s nature reserve, namely Wytham Woods, with his butterfly net. No butterflies were to be seen, but he caught the only moving thing, which was a kind of fly. He used the taxonomic reference works to try to identify this “fly.” Having realised that the fly was a Hymenopteron, he was still unable to identify it. He therefore went to the Natural History Museum in London for help. They pronounced that it was in fact a species of sawfly new to Britain. This must have been intensely irritating to the Professor of Entomology, whose main research project was to identify animals and plants in Wytham Woods. JBG was later rejected for PhD work in Entomology. This was a great blessing because the work he would have done in Entomology was not well regarded and had very little, if any, analytical component to it. By his immense good fortune, he was invited to do a PhD with the Oxford University lecturer who taught Developmental Biology, Dr Michael Fischberg.

Fischberg was born in St Petersburg, Russia, in 1919. He was educated in Switzerland and was a PhD student of E. Hadorn. Hadorn in turn was a student of F. Baltzer, who was a student of H. Spemann, himself a student of T. Boveri. This German-Swiss lineage of eminent Developmental Biologists turns out to be the background of a great many of the successful Developmental Biologists of the mid-1950s. Most of those that did not have this background can trace their own training back to R. G. Harrison (1870–1959) of the USA, who pioneered cell culture. Having finished his PhD with Hadorn, Fischberg took a position in the Institute of Animal Genetics under Waddington in Edinburgh, from where he accepted his appointment in the Oxford Zoology department, headed by Professor Sir Alister Hardy, an eminent marine biologist [Royal Society memoirs].

Starting his PhD work in 1956, Fischberg suggested to JBG that he should try to carry out somatic cell nuclear transfer in Xenopus, a procedure for this having been recently published by Briggs and King (1952). The advisability and technical problems that arose at this point are described in the accompanying papers (Gurdon 2013 a,b). Once these technical obstacles had been overcome, largely as a result of good luck, JBG’s work proceeded extraordinarily fast; strongly motivated by early success, he became an intensely hard worker. By the end of his PhD he had succeeded in obtaining normal development of intestinal epithelium cell nuclei transplanted to enucleated eggs of Xenopus. When these tadpoles had eventually reached sexual maturity, he was able to publish a paper entitled “Fertile intestine nuclei.”This was the first decisive evidence that all cells of the body contain the same complete set of genes. This answered a long-standing and important question in the field of Developmental Biology. However it also showed very clearly, as was commented on in JBG’s papers at the time, the remarkable ability of eggs to reprogram somatic cell nuclei back to an embryonic state. Eventually this phenomenon attracted increasingly large interest, and led to the idea of cell replacement using accessible adult cells, such as skin. A key future discovery was that of Martin Evans (Nobel Prize, 2006) that a permanently proliferating embryonic stem cell line could be established from mouse embryos. Under appropriate conditions these cells could be caused to differentiate into all different cell types. The combination of somatic cell nuclear transfer and the derivation of embryonic stem cells in mammals made it realistic to think of cell replacement for human diseases. A huge boost for this idea was later provided by Takahashi and Yamanaka (2006), with their discovery that the overexpression of certain transcription factors can also yield embryonic stem cells from adult somatic tissue. The accompanying Nobel lecture provides more detail of the later scientific part of JBG’s career.

A visit by the Nobel Laureate George Beadle to the Fischberg Group in the Oxford Zoology department in 1960 led to an offer from the California Institute of Technology (CalTech) (previous chairman George Beadle) for JBG to do postdoctoral work there. Fischberg very wisely advised JBG to accept the CalTech offer of postdoctoral work rather than offers from other nuclear transplant labs. Stimulated by his mother’s adventurous spirit, JBG decided to buy a secondhand Chevrolet in New York and drive across the USA to California, using the famous Route 66 (now replaced). He gave lectures as he travelled across the USA and stopped at laboratories of Briggs and King, Alexander Brink (paramutation) etc. He had hoped to become a post-doctoral student of R. Dulbecco at CalTech (Nobel Prize), but the chairman of that department advised against this because JBG had no training in virology. Therefore JBG did his postdoctoral work with Robert Edgar on Bacteriophage Genetics. JBG found he had no aptitude at all for Phage Genetics and decided to return to Britain after one year at CalTech. Nevertheless, that year at CalTech was extremely formative because it provided some acquaintance with Molecular Biology, which had so far entirely escaped his training. During that year he met Sturtevant, a student of Morgan, who pioneered the whole field of Drosophila Genetics. He also got to know Ed Lewis (future Nobel Laureate). Thanks to James Ebert (director of the Department of Embryology, Carnegie Institute of Washington, in Baltimore) JBG visited various labs in the USA at the end of his post-doctoral period and met Donald Brown in Baltimore on that visit. Meantime, the success of the nuclear transfer work in Oxford had led to Michael Fischberg being offered a head of department professorship in Geneva, Switzerland. JBG was offered the teaching position in Oxford vacated by M. Fischberg. JBG returned from California to England via Japan and many other countries over a two-month period. One month of that time he spent in Japan and met Tokindo Okada and made other friends in Japan, including M. Furusawa and subsequently Koichiro Shiokawa.

While doing graduate and postdoctoral work in Oxford, JBG made other contacts and friendships. His mother’s sister lived in Oxford, and he spent much time at her house and visiting famous gardens, fostering a lifelong interest in plants. Through that connection he met Miriam Rothschild, and became a lifelong friend of hers (Van Emden and Gurdon, 2006). This friendship contained, through Miriam Rothschild’s generosity, ski mountaineering holidays based in her house in Wengen. JBG had achieved the British ski club’s Gold standard ski medal, again through relentless practice rather than any natural ability. Also, in accord with his interest in the open air and dogged determination, he became a reasonably accomplished ice figure skater.

Nobel Lecture by Sir John B. Gurdon (42 minutes)

Sir John B. Gurdon delivered his Nobel Lecture on 7 December 2012 at Karolinska Institutet in Stockholm. He was introduced by Professor Urban Lendahl, Chairman of the Nobel Committee for Physiology or Medicine.
Credits: Sveriges Television AB (production)

Copyright © Nobel Media AB 2012

The Nobel Prize in Physiology or Medicine 2012    Lecture (pdf)

Nuclear transfer

In 1958, Gurdon, then at the University of Oxford, successfully cloned a frog using intact nuclei from the somatic cells of a Xenopus tadpole.[14][15] This work was an important extension of work of Briggs and King in 1952 on transplanting nuclei from embryonic blastula cells[16] and the successful induction of polyploidy in fish Stickleback, Gasterosteus aculatus, in 1956 by Har Swarup reported in Nature.[17] However, he could not yet conclusively show that the transplanted nuclei derived from a fully differentiated cell. This was finally shown in 1975 by a group working at the Basel Institute for Immunology in Switzerland.[18] They transplanted a nucleus from an antibody-producing lymphocyte (proof that it was fully differentiated) into an enucleated egg and obtained living tadpoles.

Gurdon’s experiments captured the attention of the scientific community and the tools and techniques he developed for nuclear transfer are still used today. The term clone[19] (from the ancient Greek word κλών (klōn, “twig”)) had already been in use since the beginning of the 20th century in reference to plants. In 1963 the British biologist J. B. S. Haldane, in describing Gurdon’s results, became one of the first to use the word “clone” in reference to animals.

Messenger RNA expression

Gurdon and colleagues also pioneered the use of Xenopus (genus of highly aquatic frog) eggs and oocytes to translate microinjected messenger RNA molecules,[20] a technique which has been widely used to identify the proteins encoded and to study their function.

Recent research

Gurdon’s recent research has focused on analysing intercellular signalling factors involved in cell differentiation, and on elucidating the mechanisms involved in reprogramming the nucleus in transplantation experiments, including the role of histone variants,[21][22] and demethylation of the transplanted DNA.[23]

Reprogramming of Mature Cells

Our lives begin when a fertilized egg divides and forms new cells that, in turn, also divide. These cells are identical in the beginning, but become increasingly varied over time. As a result of this process, our cells become specialized for their location in the body – perhaps in a nerve, a muscle, or a kidney. It was long thought that a mature or specialized cell could not return to an immature state, but this has been proven incorrect.

In 1962, John Gurdon removed the nucleus of a fertilized egg cell from a frog and replaced it with the nucleus of a mature cell taken from a tadpole’s intestine. This modified egg cell grew into a new frog, proving that the mature cell still contained the genetic information needed to form all types of cells. In 2006, Shinya Yamanaka succeeded in identifying a small number of genes within the genome of mice that proved decisive in this process. When activated, skin cells from mice could be reprogrammed to immature stem cells, which, in turn, can grow into all types of cells within the body. In the long-term, these discoveries may lead to new medical treatments.

Shinya Yamanaka

A winding road to pluripotency

http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/yamanaka-lecture.pdf

http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/ypdfamanaka-lecture_slides.

Nobel Lecture

46 min.
by Shinya Yamanaka Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
INTRODUC TION John Gurdon received recognition for his landmark achievement in 1962, which provided the first experimental evidence of reprogramming by the transplantation of amphibian somatic cell nuclei into enucleated oocytes [1]. This breakthrough in technology introduced a new paradigm; that each nucleus of a differentiated cell retains a complete set of blueprints for the whole body, while oocytes possess a certain potential for reprogramming. Inspired by this paradigm shift and subsequent research achievements, we identified four transcription factors that could induce pluripotency in somatic cells by their forced expression and successfully consolidated effective reprogramming methods in mouse cells in 2006 [2] and in human cells in 2007 [3]. The established reprogrammed cells were named “induced pluripotent stem (iPS) cells.” I would like to provide an overview focusing on the experimental background of the generation of iPS cells, and the future perspectives regarding iPS cell research, which has been developing rapidly.

Figure 1. My first experiment as a graduate student. Intravenous injection of a vasoactive molecule platelet activating factor (PAF) caused a transient decrease in blood pressure in dogs (upper panel). We hypothesized that this hypotension would be blocked by pretreatment with a thromboxane A2 inhibitor (lower left panel). Unexpectedly, we observed a profound hypotension (lower right panel).

In 1989, however, my life took a new turn from clinical medicine in orthopedic surgery to basic science research for two reasons. First, I found that I was not a very talented surgeon. Second, I saw many patients suffering from intractable diseases and injuries, which even highly talented surgeons and physicians were not able to cure. For example, I had encountered patients suffering from spinal cord injuries, amyotrophic lateral sclerosis and osteosarcomas. Furthermore, I lost my father due to liver cirrhosis during my residency. Basic medical research is the only way to find cures for these patients. For these reasons, I decided to go back to school. I became a Ph.D. student at Osaka City University Medical School in April of 1989.

Among the many departments at the school, I applied to the Department of Pharmacology, directed by Dr. Kenjiro Yamamoto.  Dr. Ikemoto repeatedly told me that we should not perform research that simply reproduced somebody else’s re-sults. Rather, we should do something unique and new. During my training as a scientist, I was very fortunate to have two types of teachers: namely, great men-tors and unexpected results from my experiments.
My direct mentor at the graduate school was Dr. Katsuyuki Miura. In my first few months as a Ph.D. student, Dr. Miura told me to read as many manuscripts as possible and propose new projects. I felt like I was given a blank canvas and told that I could draw whatever I wanted. This mentorship was very different from what I had experienced during my residency. At the hospital, I’d had little freedom, and had to follow instructions from senior physicians and textbooks. I thought “wow, I like this system!” Another thing that Dr. Miura often told me was that we were competing worldwide. Whatever project you chose, you will compete with other scientists throughout the world, mostly in the U.S. or Europe, on the same or similar projects. This was again very different from my experience at the hospital, where I was competing only with other residents at the same hospital. The idea of “worldwide” competition had never entered my mind when I was working at the hospital. For all of these reasons, I found that basic research was a more suitable career, based on my interests and temperament.
In the summer of 1989, I was still struggling to find my project. Dr. Miura proposed a simpler project to begin my research studies. He suggested that I examine the role of a vasoactive molecule, platelet activating factor (PAF), in dogs to study the regulation of blood pressure (Fig. 1). Because it was known that the intravenous injection of PAF into dogs caused a transient decrease in blood pressure (transient hypotension), Dr. Miura hypothesized that this decrease in blood pressure would be mediated by another vasoactive molecule, thromboxane A2. If that hypothesis was correct, then pretreatment with a thromboxane A2 inhibitor should block the PAF-induced transient decrease in blood pressure. My first experiment, where I treated dogs with an inhibitor of thromboxane A2, was performed based on his hypothesis, and I had expected no decrease in the blood pressure in the pretreated dogs. It should have been a simple experiment suitable for a beginner. However, the result was totally unexpected. In the beginning, the thromboxane A2 inhibitor did not seem to be effective, with subsequent PAF treatment inducing the normal transient decrease in the blood pressure. Surprisingly, however, a few minutes after the treatment, a profound and prolonged decrease in blood pressure was observed, which we had never observed following treatment with PAF alone (Fig. 1). I got so excited! I ran into Dr. Miura’s office to report this result excitedly. Although the result did not support his hypothesis, Dr. Miura responded with excitement, too, and encouraged me to explore the finding further. I spent another two years uncovering the mechanism responsible for this unexpected result [4, 5]. I was extremely lucky to obtain this kind of unexpected result in my very first experiment as a graduate student.

A scandal involving Japanese stem-cell research took a surprising turn Monday when the nation’s most revered researcher in the field, Nobel Prize laureate Shinya Yamanaka, apologized for what he described as poor record-keeping.

The apology came after months of soul-searching in Japan over research ethics. A researcher at the prestigious Riken institute, Haruko Obokata, apologized earlier this month after admitting errors in a paper in the journal Nature that described a possible new method of creating stem cells.

Last week, the head of the Riken panel investigating Dr. Obokata had to resign from the panel after admitting that a paper he co-authored used some of the same improper methods of cutting and pasting images that he had criticized in Dr. Obokata’s work.

On Monday evening, Dr. Yamanaka, a professor at Kyoto University, spoke at a news conference after questions arose about an image in a 2000 paper on which he was the lead author. In the paper, Dr. Yamanaka, then at Nara University, described a protein that played a role in turning embryo cells into cells specific to a part of the body.

The university said it conducted an investigation after Dr. Yamanaka informed administrators about allegations he discovered online that an image in the paper was doctored.

 

Read Full Post »


Lonely Receptors: RXR – Jensen, Chambon, and Evans

Larry H. Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Intelligence

Series E. 2; 7.2

 

Nuclear receptors provoke RNA production in response to steroid hormones

Albert Lasker Basic Medical Research Award

Pierre Chambon, Ronald Evans and Elwood Jensen

For the discovery of the superfamily of nuclear hormone receptors and elucidation of a unifying mechanism that regulates embryonic development and diverse metabolic pathways.

Hormones control a vast array of biological processes, including embryonic development, growth rate, and body weight. Scientists had known since the early 1900s that tiny hormone doses dramatically alter physiology, but they had no idea that these signaling molecules did so by prodding genes. The 1950s, when Jensen began his work, was the great era of enzymology. Conventional wisdom held that estradiol—the female sex hormone that instigates growth of immature reproductive tissue such as the uterus—entered the cell and underwent a series of chemical reactions that produced a particular compound as a byproduct. This compound—NADPH—is essential for many enzymes’ operations but its small quantities normally limit their productivity. A spike in NADPH concentrations would stimulate growth or other activities by unleashing the enzymes, the reasoning went.

In 1956, Jensen (at the University of Chicago) decided to scrutinize what happened to estradiol within its target tissues, but he had a problem: The hormone is physiologically active in minute quantities, so he needed an extremely sensitive way to track it. He devised an apparatus that tagged it with tritium—a radioactive form of hydrogen—at an efficiency level that had not previously been achieved. This innovation allowed him to detect a trillionth of a gram of estradiol.

When he injected this radioactive substance into immature rats, he noticed that most tissues—skeletal muscle, kidneys and liver, for example—started expelling it within 15 minutes. In contrast, tissues known to respond to the hormone—those of the reproductive tract—held onto it tightly. Furthermore, the hormone showed up in the nuclei of cells, where genes reside. Something there was apparently grabbing the estradiol.

Jensen subsequently showed that his radioactive hormone remained chemically unchanged once inside the cell. Estrogen did not act by being metabolized and producing NADPH, but presumably by performing some job in the nucleus. Subsequent work by Jensen and Jack Gorski established that estradiol converts a protein in the cytoplasm, its receptor, into a form that can migrate to the nucleus, embrace DNA, and turn on specific genes.

From 1962 to 1980, molecular endocrinologists built on Jensen’s work to discover the receptors for the other major steroid hormones—testosterone, progesterone, glucocorticoids, aldosterone, and the steroid-like vitamin D. In addition to Jensen and Gorski, many scientists—notably Bert O’Malley, Jan-Ake Gustafsson, Keith Yamamoto, and the late Gordon Tompkins—made crucial observations during the early days of steroid receptor research.

Clinical Applications of Estrogen-Receptor Detection

Clinicians knew that removing the ovaries or adrenal glands of women with breast cancer would stop tumor growth in one out of three patients, but the molecular basis for this phenomenon was mysterious. Jensen showed that breast cancers with low estrogen-receptor content do not respond to surgical treatment. Receptor status could therefore indicate who would benefit from the procedure and who should skip an unnecessary operation. In the mid-1970s, Jensen and his colleague Craig Jordan found that women with cancers that contain large amounts of estrogen receptor are also likely to benefit from tamoxifen, an anti-estrogen compound that mimics the effect of removing the ovaries or adrenal glands. The other patients—those with small numbers of receptors—could immediately move on to chemotherapy that might combat their disease rather than waiting months to find out that the tumors were growing despite tamoxifen treatment. By 1980, Jensen’s test had become a standard part of care for breast cancer patients.

In the meantime, Jensen set about generating antibodies that bound the receptor—a tool that provided a more reliable way to measure receptor quantities in excised breast tumor specimens. His work has transformed the treatment of breast cancer patients and saves or prolongs more than 100,000 lives annually.

Long-Lost Relatives

By the early 1980s, interest in molecular endocrinology had shifted toward the rapidly developing area of gene control. Chambon and Evans had long wondered how genes turn on and off, and recognized nuclear hormone signaling as the best system for studying regulated gene transcription. They wanted to know exactly how nuclear receptors provoke RNA production in response to steroid hormones. To manipulate and analyze the receptors, they would need to isolate the genes for them.

By late 1985 and early 1986, Evans (at the Salk Institute in La Jolla) and Chambon (at the Institute of Genetics and Molecular and Cellular Biology in Strasbourg, France) had pieced together the glucocorticoid and estrogen receptor genes, respectively. They noticed that the sequences resembled that of v-erbA, a miscreant viral protein that fosters uncontrolled cell growth. This observation raised the possibility that v-erbA and its well-behaved cellular counterpart, c-erbA, would also bind DNA and control gene activity in response to some chemical activator, or ligand. In 1986, Evans and Björn Vennström simultaneously reported that c-erbA was a thyroid hormone receptor that was related to the steroid hormone receptors, thus uniting the fields of thyroid and steroid biology.

Chambon and Evans set to work deconstructing the glucocorticoid and estrogen receptors. By creating mutations at different spots and probing which activities the resulting proteins lost, they dissected the receptor into three domains: one bound hormone, one bound DNA, and one activated target genes. The structure of each domain strongly resembled the analogous one in the other receptor.

Chambon and Evans wanted to match other members of the growing receptor gene family with their chemical triggers. Because the DNA- and ligand-binding regions functioned independently, it was possible to hook the DNA-binding domain of, say, the glucocorticoid receptor to the ligand-binding domain of another receptor whose ligand was unknown. The ligand for that receptor would then activate a glucocorticoid-responsive test gene.

Evans would use this method to identify ligands for several novel members of the nuclear receptor family, and both he and Chambon exploited it to discover a physiologically crucial receptor. In the late 1970s, scientists had suggested that the physiologically active derivative of vitamin A, retinoic acid, could exert its effects by binding to a nuclear receptor. This nutrient is essential from fertilization through adulthood, and researchers were eager to understand its activities on a molecular level. During embryonic development, deficiency of retinoic acid impairs formation of most organs, and the compound can hinder cancer cell proliferation. So Chambon set out to find a receptor that responded to retinoic acid. He isolated a member of the nuclear receptor gene family whose production increased in breast cancer cells that slowed their growth upon exposure to the chemical. Simultaneously, Evans identified the same protein. He tested whether more than a dozen compounds activated an unknown receptor and one passed: retinoic acid.

Remarkably, in 1986, the two scientists had independently—and unbeknownst to each other—identified the same retinoic acid receptor, a molecule of tremendous significance. The discovery of this molecule provided an entry point for detailing vitamin A biology.

Rx for Lonely Receptors: RXR

The list of presumptive nuclear receptors was growing quickly as scientists realized that the common DNA sequences provided a handle with which to grab these molecules from the genome. Because their chemical activators weren’t known, they were called “orphan” receptors, and researchers were keen on “adopting” them to ligands. Some of these ligands, they reasoned, would represent previously unknown classes of gene activators. The test system that Chambon and Evans used to match up retinoic acid with its receptor, in which they stitched an unknown ligand-binding domain to a DNA-binding domain for a receptor with known target sequences, could be harnessed to accomplish this task.

Evans had identified some potential nuclear receptors from fruit flies. He decided to pursue a human orphan receptor that closely resembled one of these receptor genes, reasoning that a protein that functioned in both flies and mammals was likely to perform an important job.

This receptor responded to retinoic acid in intact cells but did not bind it in the test tube, so Evans called it the Retinoid X Receptor (RXR), thinking that its ligand was some retinoic acid derivative. In cells, enzymes convert retinoic acid to metabolites and it seemed possible that one of these compounds was RXR’s ligand. In 1992, Evans’s group and one at Hoffmann-La Roche discovered that 9-cis-retinoic acid, a stereoisomer of retinoic acid, could activate RXR, identifying the first new receptor ligand in 25 years. This finding launched the orphan receptor field because it provided strong evidence that the strategy could unearth previously unknown ligands.

In the meantime, Chambon had found that the purified retinoic acid receptor, in contrast to the estrogen receptor, did not bind efficiently to its target DNA. Other nuclear receptors, too, needed help grasping genes. In the test tube, the retinoic acid, thyroid hormone, and vitamin D3 receptors could attach well to their target DNA only when supplemented with cellular material, which presumably contained some crucial substance. Chambon and Michael Rosenfeld independently purified a single protein that performed this feat, and it turned out to be none other than RXR. This ability of RXR to pair with other receptors—forming so-called heterodimers—would turn out to be key for switching on many orphan receptors. These heterodimeric couplings yield large numbers of distinct gene-controlling entities.

Chambon revealed the power of mixing and matching in these molecular duos through his thorough and extensive genetic manipulations in mice. He has shown that vitamin A exerts its wide-ranging effects on organ development in the embryo through the action of eight different forms of the retinoic acid receptor and six different forms of RXR, interacting with each other in a multitude of combinations.

Clinical Applications of the Superfamily Work

The concept of RXR as a promiscuous heterodimeric partner for certain nuclear receptors led to the unexpected identification of a number of clinically relevant receptors. These proteins include the peroxisome proliferator-activated receptor (PPAR), which stimulates fat-cell maturation and sits at the center of Type 2 diabetes and a number of lipid-related disorders; the liver X receptors (LXRs) and bile acid receptor (FXR), which help manage cholesterol homeostasis; and the steroid and xenobiotic receptor (PXR), which turns on enzymes that dispose of chemicals that need to be detoxified, such as drugs.

Because the nuclear receptors wield such physiological power, they have provided excellent targets for disease treatment. The anti-diabetes compounds glitazones, for example, work by stimulating PPAR, and the clinically used lipid-lowering medications called fibrates work by binding a closely related receptor, PPAR. Retinoic acid therapy has dramatically altered the prognosis of people with acute promyelocytic leukemia by triggering specialization of the immature white blood cells that accumulate in these individuals. The three-dimensional structure of nuclear receptors with and without their ligands, which Chambon and his colleagues first solved, promises to accelerate drug discovery in the whole field.

Nuclear hormone receptors have touched on human health in other ways as well. Genetic perturbations in the genes for these proteins cause a variety of illnesses. For example, certain forms of rickets arise from mutations in the vitamin D receptor and several disorders of male sexual differentiation stem from defects in the androgen receptor.

The discoveries of Jensen, Chambon, and Evans revealed an unimagined superfamily of proteins. At the start of this work almost 50 years ago, no one would have anticipated that steroids, thyroid hormone, retinoids, vitamin D, fatty acids, bile acids, and many lipid-based drugs transmit their signal through similar pathways. Four dozen human nuclear receptors are now known, and scientists are working out the roles of these proteins in normal and aberrant physiology. These discoveries have revolutionized the fields of endocrinology and metabolism, and pointed toward new tactics for drug discovery.

by Evelyn Strauss, Ph.D.

 

The 2004 Lasker Award for Basic Medical Research will be presented to Elwood Jensen, Ph.D., the Charles B. Huggins Distinguished Service Professor Emeritus in the Ben May Institute for Cancer Research at the University of Chicago, one of three scientists whose discoveries “revolutionized the fields of endocrinology and metabolism,” according to the award citation. Jensen’s work had a rapid, direct and lasting impact on treatment and prevention of breast cancer.

The Lasker Awards are the nation’s most distinguished honor for outstanding contributions to basic and clinical medical research. Often called “America’s Nobels,” the Lasker Award has been awarded to 68 scientists who subsequently went on to receive the Nobel Prize, including 15 in the last 10 years.

Jensen will share the basic medical research award with two colleagues, Pierre Chambon, of the Institute of Genetics and Molecular and Cellular Biology (Strasbourg, France), and Ronald M. Evans of the Salk Institute for Biological Studies (La Jolla, California) and the Howard Hughes Medical Institute.

They were selected for their discovery of the “superfamily of nuclear hormone receptors and the elucidation of a unifying mechanism that regulates embryonic development and diverse metabolic pathways.” The implications of this research for understanding human disease and accelerating drug discovery “have been profound and hold much promise for the future,” notes the announcement from the Lasker Foundation.

Jensen is being honored for his pioneering research on how steroid hormones, such as estrogen, exert their influence. His discoveries explained how these hormones work, which has led to the development of drugs that can enhance or inhibit the process.

Hormones control a vast array of biological processes, including embryonic development, growth rate and body weight. Before Jensen, however, the way which hormones cause these effects was “a complete mystery,” recalled Gene DeSombre, Ph.D., professor emeritus at the University of Chicago, who worked with Jensen in the Ben May Institute as a post-doctoral fellow and then as a colleague.

In the 1950s, biochemists thought a hormone entered a cell, where a series of oxidation and reductions reactions with the estrogen provided needed energy for the growth stimulation and other specific actions shown by estrogens.

From the late 1950s to the 1970s Jensen entirely overturned that notion. Working with estrogen, he proved that hormones do not undergo chemical change. Instead, they bind to a receptor protein within the cell. This hormone-receptor complex then travels to the cell nucleus, where it regulates gene expression.

At the time, this idea was heresy. “That really got him into some hot water,” recalled DeSombre. “Jensen struggled quite a lot,” echoes Shutsung Liao, Ph.D., another Ben May colleague, who subsequently found a similar system for testosterone action. But for Jensen, just getting into hot water was a struggle. When he first presented preliminary data at a 1958 meeting in Vienna, only five people attended, three of whom were the other speakers. More than 1,000 attended a simultaneous symposium on the metabolic processing of estrogen.

In the next 20 years, Jensen convinced his colleagues by publishing a series of major and highly original discoveries in four related areas of hormone research:

  • Jensen discovered the estrogen receptor, the first receptor found for any hormone. In 1958, using a radioactive marker, he showed that only the tissues that respond to estrogen, such as those of the female reproductive tract, were able to concentrate injected estrogen from the blood. This specific uptake suggested that these cells must contain binding proteins, which he called “estrogen receptors.”
  • In 1967, Jensen and Jack Gorski of the University of Wisconsin showed that these putative receptors were macromolecules that could be extracted from these tissues. With this method, Jensen showed that when estrogen bound to this receptor, the compound then migrated to the nucleus where it bound avidly and activated specific genes, stimulating new RNA synthesis.
  • By 1968, Jensen had devised a reliable test for the presence of estrogen receptors in breast cancer cells. It had been known for decades that about one-third of premenopausal women who had advanced breast cancer would respond to estrogen blockade brought about by removing their ovaries, the source of estrogen, but there was no way to predict which women would respond. In 1971, Jensen showed that women with receptor-rich breast cancers often have remissions following removal of the sources of estrogen, but cancers that contain few or no estrogen receptors do not respond to estrogen-blocking therapy.
  • By 1977, Jensen and Geoffrey Greene, Ph.D., also in the University of Chicago’s Ben May Institute, had developed monoclonal antibodies directed against estrogen receptors, which enabled then to quickly and accurately detect and count estrogen receptors in breast and other tumors. By 1980, this test had become a standard part of care for breast cancer patients

This work “transformed the treatment of breast cancer patients,” notes the Lasker Foundation, “and saves or prolongs more than a 100,000 lives annually.”

”Jensen’s revolutionary discovery of estrogen receptors is beyond doubt one of the major achievements in biochemical endocrinology of our time,” said DeSombre. “His work is hallmarked by great technical ingenuity and conceptual novelty. His promulgation of simple yet profound ideas concerning the role of receptors in estrogen action have been of the greatest importance for research on the basic and clinical physiology not only of estrogens but also of all other categories of steroid hormones.”

By the early 1970s, Jensen was searching for chemical, rather than surgical, ways to shield estrogen-dependent tumors from circulating hormones. He and colleague Craig Jordan (then at the Worcester Foundation for Experimental Biology in Massachusetts) subsequently found that women with cancers that contain large amounts of estrogen receptor are also likely to benefit from tamoxifen, a compound that blocks some of the effects of estrogen. Patients with few or no receptors could immediately move on to chemotherapy rather than waiting months to find out that the tumors were growing despite tamoxifen treatment.

Following Jensen’s lead, researchers soon found that the receptors for the other major steroid hormones, such as testosterone, progesterone, and cortisone, worked essentially the same way.

In 1986, Pierre Chambon and Ronald Evans separately but simultaneously discovered that the steroid hormone receptors were merely the tip of the iceberg of what would turn out to be a large family of structurally related nuclear receptors, now known to consist of 48 members. Evans and Chambon unearthed a number of these receptors, which revealed new regulatory systems that control the body’s response to essential nutrients (such as Vitamin A), fat-soluble signaling molecules (such as fatty acids and bile acids), and drugs (such as the glitazones used to treat Type 2 diabetes and retinoic acid for certain forms of acute leukemia).

These three individuals “created the field of nuclear hormone receptor research, which now occupies a large area of biological and medical investigation,” said Dr. Joseph L. Goldstein, chairman of the international jury of researchers that selects recipients of the Lasker Awards, and recipient of the Lasker Award for Basic Medical Research and the Nobel Prize in Medicine in 1985.

They revealed the “unexpected and unifying mechanism by which many signaling molecules regulate a plethora of key physiological pathways that operate from embryonic development through adulthood. They discovered a family of proteins that allows chemicals as diverse as steroid hormones, Vitamin A, and thyroid hormone to perform in the body.”

Jensen, known for concluding his lectures in verse, neatly summed up what his extraordinary series of discoveries might mean to a woman who has been diagnosed with breast cancer:

“A lady with growth neoplastic
Thought surgical ablation too drastic.
She preferred that her ill
Could be cured with a pill,
Which today is no longer fantastic.”

JBC THEMATIC MINIREVIEW SERIES 2011

Nuclear Receptors in Biology and Diseases

Thematic Minireview Series on Nuclear Receptors in Biology and Diseases

Sohaib Khan and Jerry B Lingrel

Although a connection between breast cancer and the ovary was made by Sir George Beatson in 1896 and estrogen was purified in 1920, it remained puzzling as to how the hormone exerted its biological effects. In the late 1950s, when Elwood Jensen delved into this problem by asking, essentially, “What does tissue do with this hormone?” little did he know that his quest would lead to the establishment of the nuclear receptor field. The late 1950s was the era of intermediary metabolism and enzymology, when steroid hormones were considered likely substrates in the formation of metabolites that functioned as cofactors in an essential metabolic pathway. The biological responses to estrogens and other steroids were thought to be mediated by enzymes. Against this background and prevailing dogma, Jensen and colleagues defined the biochemical mechanisms by which steroid hormones exert their effects. While working at the University of Chicago’s Ben May Institute for Cancer Research, they synthesized tritium-labeled estradiol and concurrently developed a new method to measure its uptake in biological material. These tools enabled them to determine the biochemical fate of physiological amounts of hormone. They discovered that the reproductive tissues of the immature rat contain characteristic hormone-binding components with which estradiol reacts to induce uterine growth without itself being chemically changed. From the close correlation between the inhibition of binding and inhibition of growth response, Jensen established that the binding substances were receptors. Thus, we saw the birth of the first member of the nuclear receptor family (known as the estrogen receptor). These findings stimulated the search for other physiological receptors, and the pioneering works by Pierre Chambon, Ronald Evans, Jan-Åke Gustafsson, Bert W. O’Malley, and Keith Yamamoto led to the discoveries of the glucocorticoid receptor (GR),2 progesterone receptor, retinoic acid receptor, and orphan receptors. In a rather short span of time, the nuclear receptor family has grown into a 49-member-strong “superfamily.” This is a family whose members, functioning as sequence-specific transcription factors, have defined the many intricacies of the mechanism of transcription. These ligand-dependent transcription factors generally possess similar “domain organizations,” of which the DNA-binding domain and the ligand-binding domain are critical in amplifying the hormonal signals via the receptor target genes. The nuclear receptor family is divided into four groups: (i) Group 1 is composed of steroid hormone receptors that control target gene transcription by binding as homodimers to response element (RE) palindromes; (ii) in Group 2, the nuclear receptors heterodimerize with retinoid X receptor and generally bind to direct repeat REs; (iii) Group 3 consists of those orphan receptors that function as homodimers and bind to direct repeat REs; and (iv) orphan receptors in Group 4 function as monomers and bind to single REs.

Since the early demonstration by Jack Gorski and Jensen that the estrogen receptor (ER) activates transcription, the nuclear receptor field has come a long way. In addition to the first cloning of the polymerase II transcription factors (GR and ER cDNAs), of note is the discovery of steroid receptor coactivators (SRCs), a truly major piece of the transcriptional jigsaw puzzle, described by the laboratories of O’Malley and Myles Brown. The induction of coactivators and corepressors in the transcriptional machinery has expanded tremendously our understanding of this complex process. We now know that ligand binding to the respective receptors triggers a fascinating chain of events, including the translocation of the receptors to the nucleus, ligand-induced changes in the receptor conformations, receptor dimerization, interaction with the target gene promoter elements, recruitment of coactivators (or corepressors), chromatin remodeling, and subsequent interaction with the polymerase II complex to initiate transcription.

By virtue of their abilities to regulate a myriad of human developmental and physiological functions (reproduction, development, metabolism), nuclear receptors have been implicated in a wide range of diseases, such as cancer, diabetes, obesity, etc. Not surprisingly, drug companies are spending billions of dollars to develop medicines for cancer and metabolic disorders that involve nuclear receptors. More than 50 years after the discovery of the ER, the scientific community owes Jensen and other founding members of the nuclear receptor family much gratitude, for they have taken us through a remarkable expedition filled with eureka moments to understand how hormones and other ligands function!

This thematic minireview series will cover a range of topics in the nuclear receptor field. The minireviews include the current studies of identifying subtypes of the GR. Different receptors arise from alternative mRNA splicing and from the use of different promoter start sites and post-translational modifications, such as phosphorylation. The series covers the physiological roles of the different GRs. The field of orphan nuclear receptors and the search for possible ligands also are reviewed. One minireview concentrates largely on the following nuclear receptors: peroxisome proliferator-activated receptor (PPAR) α, PPARγ, Rev-erbα, and retinoic acid receptor-related orphan receptor α. ERα was the first identified and has been studied the most, whereas ERβ has not been studied in the same detail. ERβ is very important, and one of the minireviews provides a summary of the new biological functions that are being ascribed to it. Also, the development of small molecule inhibitors for the ER will be considered. An important aspect of nuclear receptor function is how these receptors function in transcription. The role of transcriptional coactivators in nuclear receptor gene regulation will be reviewed as well as how signal amplification and interaction are involved in transcription regulation by steroids. The SRC/p160 family of coregulators includes SRC-1, SRC-2, and SRC-3, and the latter has been shown to act as an oncogene, particularly in breast cancer. Molecular analysis of its role in breast cancer progression and metastasis will be the focus of one of the minireviews. In addition, interactions of nuclear receptors with the genome will be reviewed, as will the role of the homeodomain protein HoxB13 in specifying the cellular response to androgens. Mining nuclear receptor cistromes and how nuclear receptors reset metabolism also will be considered. The association of nuclear receptors (e.g. PPARδ) with physiological functions, such as circadian rhythm and muscle functions, will also be addressed. Finally, the role of nuclear receptors in disease using the retinoid X receptor α/β knock-out and transgenic mouse model skin syndromes and asthma will be reviewed. These are diverse and important topics that are critical in understanding the regulation of nuclear receptors and the biological roles they play in normal function and disease.

The Nuclear Receptor Superfamily: A Rosetta Stone for Physiology

Ronald M. Evans
Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037
Molecular Endocrinology 19(6):1429–143   http://dx.doi.org:/10.1210/me.2005-0046

In the December 1985 issue of Nature, we described the cloning of the first nuclear receptor cDNA encoding the human glucocorticoid receptor (GR) (1). In the 20 yr since that event, our field has witnessed a quantum leap by the subsequent discovery and functional elaboration of the nuclear receptor superfamily (2)—a family whose history is linked to the evolution of the entire animal kingdom and whose actions, by decoding the genome, span the vast diversity of biological functions from development to physiology, pathology, and treatment. A messenger is an envoy or courier charged with transmitting a communication or message. In one sense, the cloning of that first messenger (the GR) represented the completion of a prediction that began with Elwood Jensen’s characterization of the first steroid receptor protein (3) and continued with the pioneering work of others in the steroid receptor field (including Gorski, O’Malley, Gustafsson, and Yamamoto). Yet, like the discovery of the Rosetta stone in 1799, the revelation of the GR sequence heralded a completely unpredictable demarcation in the field, helping to solve mysteries unearthed nearly 100 yr ago as well as opening a portal to the future. The beginnings of the adventure lie in disciplines such as medicine and nutrition, which gave rise to the emergent field of endocrinology in the first half of the last century. The purification of chemical messengers ultimately known as hormones from organs and vitamins from foods spurred the study of these compounds and their physiologic effects on the body. At about the same time, the field of molecular biology was emerging from the disciplines of chemistry, physics, and their application to biological problems such as the structure of DNA and the molecular events surrounding its replication and transcription. It would not be until the late 1960s and 1970s that endocrinology and molecular biology would begin to intersect as the link between receptors and transcriptional control were being laid down. During this time, the work of Jensen (4) and Gorski (5) identified a high-affinity estrogen receptor (ER) that suggested an action in the nucleus. Gordon Tomkins and his associates (J. Baxter, G. Ringold, E. B. Thompson, H. Samuels, H. Bourne, and others) were one of the most creative forces studying glucocorticoid action (6). Concurrent work by O’Malley, Gustafsson, and Yamamoto provided further, important evidence supporting a link between steroid receptor action and transcription (see accompanying perspective articles in this issue of Molecular Endocrinology). But whereas the steroid hormone field continued to evolve in this direction, it is of interest to note that the mechanism of action of thyroid hormone and retinoids remained clouded and controversial until the eventual cloning of their receptors in the late 1980s. Likewise, no one had foreseen the possibility that other lipophilic molecules (like oxysterols, bile acids, and fatty acids) would also function through a similar mechanism, or that other steroid receptor-like proteins existed that would play an important role in transcriptional regulation of so many diverse pathways. Thus, the GR isolation in 1985 led to the concept of a hidden superfamily of receptors that in a very real way provided the needed molecular code to unravel the puzzle of physiologic homeostasis.

Unconventional Gene-Ology

The study of RNA tumor viruses was ascendant, and the concept that they evolved by pirating key signaling pathways greatly influenced my future studies. With this training, I went on to work with Jim Darnell at the Rockefeller University on adenovirus transcription, a model brought to the lab by Lennart Philipson. At the time, adenovirus was one of the best tools to study programmed gene expression in an animal cell. My sole focus was to localize the elusive major late promoter, which provided my first Nature paper (7). Ed Ziff, a newly hired assistant professor from Cambridge, brought innovative unpublished DNA and RNA sequencing techniques that, after much technical angst, allowed us to sequence the major late promoter and derive the structure of the first eukaryotic polymerase II promoter (8). This thrilling result convinced me that the problem of gene control could be solved at the molecular level. Our next goal, which I shared with Michael Harpold in the Darnell lab, was to translate the concepts developed around adenovirus into cellular systems. My model was to analyze the glucocorticoid and thyroid hormone regulation of the GH gene. Under the strict federal guidelines for newly approved recombinant DNA research, we cloned the GH cDNA in 1977 and the first genomic clones in 1978 (9) after I moved on to The Salk Institute. However, to fully address the hormone signaling problem, I realized that it would be necessary to clone the GR and thyroid hormone receptors (TRs), which began in earnest in 1981. Up until that time, the purification and cloning of any polymerase II transcription factor had eluded researchers because of their low abundance. Four years later, the GR would be the first transcription factor for a defined response element to be cloned, sequenced, and functionally identified.

A Rock and A Hard Place

A key question was whether the GR protein encoded by the receptor was sufficient, when expressed in a heterologous cell, to convey the hormonal message. Before the publication, a new postdoc, Vincent Giguere, began tinkering with the isolated GR, trying to address this question. The rate of development of any field is limited by the existing techniques and depends on the development of new ones. Vincent devised a revolutionary technique—the cotransfection assay that required two plasmids to be taken up in the same cell, the expression vector to be transcribed, the encoded protein to be functional and an inducible promoter linked to a chloramphenicol acetyltransferase reporter in the nucleus ready to flicker on (10, 12). With so many variables and unknowns, I was stunned and expressionless when it worked the very first time. Cotransfection was an easy, fast, and quantitative technique. It would become (and still remains) the dominant assay to characterize receptor function. It would also become the mainstay for drug discovery in the pharmaceutical industry. The development of this technique proved a great advantage because existing technology involved creating stable cell lines, a tedious process prone to integration artifacts that ultimately could not match the explosive pace of the field. Indeed, within 4 months Stan and Vincent had fully characterized 27 insertional mutants delineating the DBD, LBD, and two activation domains (12). The route to understanding the signaling mechanism now had a solid structural foundation. A serendipitous gift to my retroviral origins was the homology of the GR sequence to the v-erbA oncogene product of the avian erythroblastosis virus genome (13). With this discovery, erbA advanced to a candidate nuclear transcription factor potentially involved in a signal transduction pathway. Thus, while Stan concentrated on the GR, Cary began to delve into the erbA discovery. Within months of the GR publication, the human c-erbA gene was in hand (14). Unbeknownst to us, Bjorn Vennstrom, one of the first to characterize the avian erythroblastosis virus genome, had also isolated c-erbA and was searching for a function. Based on the low homology of the LBD region to the GR and ER, both groups deduced that the imaginary erbA ligand would be nonsteroidal.

The work of our two groups (15, 16), published in December of 1986, broadened the principles of the signal transduction pathway by demonstrating that thyroid and steroid hormone receptor signaling had a common evolutionary origin and provided an entree to understand how mutations within a receptor could activate it to an oncogene. Although we did not know it at the time, this work would also lead us to the concept of the corepressor. In the meantime, my student, Catherine Thompson, zeroed in on an erb-A-related gene and soon identified a second TR expressed at high levels in the central nervous system (17). Thus came into existence the and forms of the TR. Jeff Arriza, the third graduate student in the lab, purified a genomic fragment that had weakly hybridized to the GR resulting in the isolation of the human mineralocorticoid receptor (MR) (18). MR proved to have an at least 10-fold higher affinity for glucocorticoids than the GR itself and was further distinguished by its ability to bind and be activated by aldosterone. This enabled the development of GR- and MR-selective drugs such as the recent MR antagonist eplerenone. Thus, in a 2-yr time span our lab had progressed on three distinct, albeit related, receptor systems, and in doing so molecular biology and endocrinology were irrevocably linked. The field of molecular endocrinology (and coincidentally the eponymous journal) was born.

Ligands From Stone

I have often been asked how we could handle so many divergent systems. Indeed, from a medical perspective, these systems seem widely unrelated. Studies of ER, progesterone receptor, and androgen receptor (AR) fall under reproductive physiology, vitamin D under bone and mineral metabolism, with vitamin A part of nutritional science. Medical fields are naturally idiosyncratic because of the specialized knowledge required to conduct experiments. With my training as a molecular biologist, physiology was the complex output of genes and thus control of gene expression was the overriding problem. This conceptual approach had a great unifying effect because all receptors transduce their signaling through the gene. As an “outsider,” my goal was to exploit multiple receptor systems to seek general principles. This philosophical approach afforded us a freedom to redefine the signaling problem from the nucleus outward and thus even poorly characterized, even unknown, physiologic systems fell into the crosshairs of our molecular gun.

Vincent, while screening a testes Fig. 1. Models of Nuclear Receptor Structure Top, Original hand-shaped wire model (circa 1992) of the nuclear receptor DBD. Bottom, Schematic representation of the GR DBD. Conserved residues in zinc fingers, P-box and D-box are indicated isolated what would become the vitamin A or retinoic acid receptor (RAR) (19). Initially, Vincent thought he had isolated the AR, although this later proved not to be the case. By that stage, the lab had perfected a new technique—the domain swap—by which the GR DBD could be introduced into any receptor and confers on the chimeric protein the ability to activate a mouse mammary tumor virus reporter. This clever technique, independently developed in the Chambon lab, would prove to be essential. Effectively, the domain swap would enable us to screen for ligands without any knowledge of their physiologic function. Activation of a target gene was all that was needed! By creating this GR chimera, Vincent was able to screen the new receptor against a ligand cocktail including androgens, steroids, thyroid hormone, cholesterol, and the vitamin A metabolite retinoic acid. From the first assay, it was clear that he had isolated a high-affinity selective RAR that had no response to any other test ligand. Thus, without knowing any true direct target gene for retinoic acid, we were nonetheless able to isolate and characterize its receptor. Remarkably, Martin Petkovich in the Chambon lab isolated the same gene. Once again, this is an example where a new technique offered an entirely new approach to a problem. Both papers were published in the December 1987 issue of Nature (19, 20). With the combination of steroids, thyroid hormones, and vitamin A, the three elemental components of the nuclear receptor superfamily were in hand. By the time the RAR papers were published, Vincent with Na Yang, had already isolated two estrogen-related receptors termed ERR1 and 2 that would represent the first true orphan receptors in the evolving superfamily (21). A third receptor (ERR3) would be isolated 10 yr later (22). The three ERRs are distinguished by their ability to activate through ER response elements, but required no ligand. However, of potential major medical relevance, estrogen antagonists such as 4-hydroxy-tamoxifen silences ERR constitutive activity (23). The superfamily was growing exponentially, transforming into a new field, driven by a new breed of exceptional students and fellows attracted by the mechanics of transcription and its emerging link to physiology. For example, the RAR and TR offered an unprecedented look at understanding the action of vitamin A as a morphogen and the role of thyroxin in setting the basal metabolic rate of the body. We were a relatively small group, and our decision to work on multiple different receptor systems created a unique environment. Because there was so little overlap between projects, postdocs and students readily discussed all results, exchanged reagents and freely collaborated, resulting in a tremendous acceleration of progress. The high level of camaraderie was powered by the joie de vivre of the exciting discoveries and the ability of our family of students and postdocs to each adopt their own receptors. We all felt we were in a golden age and even more was to come.

In 1989, Jan Sap in Vennstrom’s group and Klaus Damm in our group demonstrated that the TR becomes oncogenic by mutation in the LBD (24, 25). Although we expected ligand-independent activation, it was clearly a constituitive repressor becoming the first example of a dominant-negative oncogene. The concept of the dominant-negative oncogene had been proposed one year earlier by Ira Herskowitz (26). This discovery changed our thinking on hormone action, and repression soon would be shown to be a common feature of receptor antagonists. David Mangelsdorf, who had arrived in the lab the year before was captivated by the glow of weakly hybridizing DNA bands and, in 1989, had amassed his own collection of orphan receptors, among which was the future retinoid X receptor (RXR) (27). In search for biological activity, a candidate ligand was found in lipid extracts from outdated human blood. However, the key test came from demonstrating that addition of all-trans retinoic acid to cultured cells would lead to its rapid metabolism coupled with the release of an inducing activity for RXR, which we termed retinoid X. David and his benchmate, Rich Heyman, began working on the chemistry of this inducer along with Gregor Eichele and Christine Thaller, then at Baylor College of Medicine (Houston, TX). This work led to the identification of 9-cis retinoic acid by our lab and a group at Hoffman LaRoche (Nutley, NJ) (28, 29). Like the retinal molecule in rhodopsin, 9-cis-retinoic acid represents the exploitation of retinoid isomerization by nature to control a key signaling pathway. More importantly, in the 39 yr since the discovery of aldosterone in 1953, this revelation would reawaken and reinvent the single most defining but dormant tool of endocrinology—ligand discovery. Indeed, the discovery that new receptors could lead to new ligands opened up an entirely new avenue of research. Like the puzzle of the structure of the benzene ring, which was solved in 1890 when Fredrick Kekule dreamed of a snake biting its own tail, the physiologic head of the “endocrine snake” and the molecular biology tail had come full circle. The era of reverse endocrinology was now upon us.

Response Elements: Deciphering The Scripts

One problem in addressing the downstream effects of our newly discovered receptors was that their response elements and target genes were by definition unknown. Kaz Umesono delved into this mystery and would produce a paradigm shift that would both solve the problem and further unify the field. With the view that the DBD functioned as a molecular receptor for its cognate hormone response element, meticulous mutational studies revealed two key DBD sequences, termed the P-box and D-box, that controlled the process (30).

The D-box was shown to direct dimerization, a feature previously thought to be unique to the LBD. One perplexing point was that the P-boxes of the nonsteroidal receptors were conserved, leading to the improbable prediction that many different receptors would recognize the same target sequence. By manual compilation and comparison of all known response elements, Kaz proposed a core hexamer— AGGTCA—as the prototypic common target sequence. By requiring the half-site to be an obligate hexamer an underlying pattern—the direct repeat—emerged. In the direct repeat paradigm, we proposed that half-site spacing, not sequence difference, was the key ingredient to distinguishing the response elements. The metric was referred to as the 3-4-5 rule (31). According to the rule, direct repeats of AGGTCA spaced by three nucleotides, would be a vitamin D response element (DR-3), the same repeat spaced by four nucleotides a thyroid hormone response element (DR-4), and the same repeat spaced by five nucleotides a vitamin A response element (DR-5). Eventually, all steps from 0–5 on the DR ladder would be filled (Fig. 2). The validity of this paradigm was ensured by a crystal structure solved in collaboration with Paul Sigler’s group at Yale (32). Indeed, of the remaining 40 nonsteroidal receptors, all but three can be demonstrated to have a preferred binding site within some component of the direct repeat ladder. Exceptions include SHP and DAX, which lack DBDs, and farnesoid X receptor (FXR) that binds to the ecdysone response element as a palindrome with zero spacing. Kaz’s insight, by drawing commonality from diversity, came to solve a problem that impacted on virtually every receptor. Remarkably, each new receptor in the superfamily could immediately be assigned a place on the ladder. The ladder also provided a simple means to conduct a ligand screening assay in absence of any knowledge of an endogenous target gene. Kaz’s ladder was a turbo charge for the field. The next major advance in the field was the discovery of the RXR heterodimer. Although we knew that retinoid and thyroid receptors required a nuclear competence factor for DNA binding, its identity was unknown. We tested RXR, but our initial experiments were flawed. Of the first four papers describing the discovery, that from Chambon’s lab was most elegant because they simply purified an activity to homogeneity to find RXR (33)! Rosenfeld was first to publish, and Ozato, Pfahl and Kliewer all concurred (34–37). Tony Oro and Pang Yao in our lab soon published that the ecdysone receptor functions as a heterodimer with ultraspiracle, the insect homolog of RXR (38, 39), revealing that the ancient origins of the heterodimer which arose before the divergence of vertebrates and invertebrates.

Reverse Endocrinology: Decoding Physiology

The orphan receptors would transform our view of endocrine physiology with unexpected links to toxicology, nutrition, cholesterol, and triglyceride metabolism as well as to a myriad of diseases including atherosclerosis, diabetes, and cancer. The three RXR isoforms formed the core with 14 heterodimer partners including the vitamin D receptor (VDR), TR/, and RAR//. The initial adopters of orphan receptors included Giguere, Mangelsdorf, Weinberger, Bruce Blumberg, Steve Kliewer, and Barry Forman. Barry unlocked the first secret to for peroxisome proliferator-activated receptor (PPAR) by identifying prostaglandin J2 (PGJ2) as a high-affinity ligand (40). The second step, in collaboration with Peter Tontonoz in Bruce Spiegleman’s lab, revealed that PGJ2 was adipogenic in cell lines and perhaps more importantly that the synthetic antidiabetic drug Troglitazone was a potent PPAR agonist (41). Similar work was conducted and published by Kliewer, who had now moved to Glaxo (42). By acquiring a ligand, a physiologic response, and a drug, PPAR was suddenly transported to the center of a physiologic cyclone that would spin into its own specialty field. Since 1995, more than 1000 papers (see PubMed) have been published on PPAR and its natural and synthetic ligands. This early work illuminated the molecular strategy of reverse endocrinology and the emerging importance of the orphan receptors in human disease and drug discovery. Cary returned to the lab for a sabbatical and, with Barry, demonstrated that FXR was responsive to farnesoids and other molecules in the mevalonate pathway. The findings by Mangelsdorf that liver X receptors (LXRs) bound oxysterols (43) and by Kliewer, Mangelsdorf, and Forman that FXR is a bile acid receptor (44–46) provided a whole new conceptual approach to cholesterol and triglyceride homeostasis. The steroid and xenobiotic receptors (SXR)/pregnane X receptor (PXR) (47–49) and the constituitive androstane receptor (CAR) (50) respond to xenobiotics to activate genes for P450 Fig. 2. Examples of Receptor Heterodimer Combinations that Fill the Direct Repeat (DR) Response Element Ladder from DR1 to DR5 Evans enzymes, conjugation and transport systems that detoxify drugs, foreign chemicals, and endogenous steroids. RXR and its associated heterodimeric partners quickly established a new branch of physiology, shedding its dependence on endocrine glands and allowing the body to decode signals from environmental toxins, dietary nutrients, and common metabolites of intermediary metabolism.

Continued…

ROCK OF AGES

The human body is, after all a living machine, a complex device that consumes and uses energy to sustain itself, defend against predators, and ultimately reproduce. One might reasonably ask, “If the superfamily acts through a common molecular template, can the family as a whole be viewed as a functional entity?” In other words, is there yet some overarching principle that we have yet to grasp. . . and might this imaginary principle lie at the heart of systems physiology? Simply stated, what led to the evolution of integrated physiology as the functional output of the superfamily? One obvious speculation is survival. To survive, all organisms must be able to acquire, absorb, distribute, store, and use energy. The receptors are exquisitely evolved to manage fuel—everything from dietary and endogenous fats (PPARs), cholesterol (LXR, FXR), sugar mobilization (GR), salt (MR), and calcium (VDR) balance and maintenance of basal metabolic rate (TR). Because only a fraction of the material we voluntarily place in our bodies is nutritional, the xenobiotic receptors (PXR, CAR) are specialized to defend against the innumerable toxins in our environment. Survival also means reproduction, which is controlled by the gonadal steroid receptors (progesterone receptor, ER, AR). However, fertility is dependent on nutritional status, indicating the presumptive communication between these two branches of the family. The third key component managed by the nuclear receptor family is inflammation. During viral, bacterial, or fungal infection, the inflammatory response defends the body while suppressing appetite, conserving fuel, and encouraging sleep (associated with cytokine release). However, if needed, even an ill body is capable of defending itself by releasing adrenal steroids, mobilizing massive amounts of fuel, and transiently suppressing inflammation. In fact, clinically, (with the exception of hormone replacement) glucocorticoids are only used as antiinflammatory agents. Other receptors including the RARs, LXRs, PPAR and , and vitamin D receptor protect against inflammation. Thus, nature evolved within the structure of the receptor the combined ability to manage energy and inflammation, indicating the important duality between these two systems. In aggregate, this commonality between distinct physiologic branches suggests that the superfamily might be approached as an intact functional dynamic entity.

Historically, endocrinologists and geneticists rarely saw eye to eye. As I have indicated in this perspective article, the disciplines have now become united in a new subject—transcriptional physiology. With this in mind, we might expect the existence of larger organizational principles that establish how the various evolutionary branches of the superfamily integrate to form whole body physiology. The existence of molecular rules governing the function and evolution of a megagenetic entity like the nuclear receptor superfamily, if correct, may be useful in understanding complex human disease and provide a conceptual basis to create more effective pharmacology. With so much accomplished in the last 20 yr (see Fig. 3), there are glimpses of clarity—enough to see the enormity and wonder of the problem and enough to know there is still a long and challenging voyage ahead. But who knows, the next breakthrough may only be a stone’s throw away.

http://press.endocrine.org/doi/pdf/10.1210/me.2005-0046

 

Pierre Chambon MD

Recipient of the Canada Gairdner International Award, 2010
“For the elucidation of fundamental mechanisms of transcription in animal cells and to the discovery of the nuclear receptor superfamily.”

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch-Graffenstaden, France

Dr. Pierre Chambon is Honorary Professor at the College de France (Paris), and Emeritus Professor at the Faculté de Médecine of the Strasbourg University. He was the Founder and former Director of the IGBMC, and also the Founder and former Director of the Institut Clinique de la Souris (ICS/MCI), in Strasbourg.

Dr. Pierre Chambon is a world expert in the fields of gene structure, and transcriptional control of gene expression. During the last 25 years his studies on the structure and function of nuclear receptors has changed our concept of signal transduction and endocrinology. By cloning the estrogen and progesterone receptors, and discovering the retinoic acid receptor family, he markedly contributed to the discovery of the superfamily of nuclear receptors and to the elucidation of their universal mechanism of action that links transcription, physiology and pathology. Through extensive site-directed mutagenesis and genetic studies in the mouse, Pierre Chambon has unveiled the paramount importance of nuclear receptor signaling in embryonic development and homeostasis at the adult stage. The discoveries of Pierre Chambon have revolutionized the fields of development, endocrinology and metabolism, and their disorders, pointing to new tactics for drug discovery, and finding important applications in biotechnology and modern medicine.

These scientific achievements are logically inscribed in an uninterrupted series of discoveries made by Pierre Chambon over the last 45 years in the field of transcriptional control of gene expression in higher eukaryotes: discovery of PolyADPribose (1963), discovery of multiple RNA polymerases differently sensitive to a-amanitin (1969), contribution to elucidation of chromatin structure: the Nucleosome (1974), discovery of animal split genes (1977), discovery of enhancer elements (1981), discovery of multiple promoter elements and their cognate factors (1980-1993).

Pierre Chambon has received numerous international awards, including the 2004 Lasker Basic Medical Research Award for the discovery of the superfamily of nuclear hormone receptors and the elucidation of a unifying mechanism that regulates embryonic development and diverse metabolic pathways. He is a member of the French Académie des Sciences, and also a Foreign Member of the National Academy of Sciences (USA) and of the Royal Swedish Academy of Sciences. Pierre Chambon serves on a number of editorial boards, including Cell, and Molecular Cell. Pierre Chambon is author of more than 900 publications. He has been ranked fourth among most prominent life scientists for the 1983-2002 period.

An Interview with Pierre Chambon
2004 Albert Lasker Basic Medical Research Award
http://www.laskerfoundation.org/media/v_chambon.htm

Pierre Chambon, MD

​Honorary Professor at the Collège-de-France and Professor of Molecular Biology and Genetics, Institute for Advanced Study, University of Strasbourg; Group Leader, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch-Graffenstaden, Strasburg, France

A pioneer in the fields of gene structure and transcriptional control of gene expression, Dr. Chambon has fundamentally changed our understanding of signal transduction, which has led to revolutionary new tactics for drug discovery. His work elucidated how molecules that promote gene transcription are organized and regulated in eukaryotic organisms and, independently of Dr. Ronald Evans, he discovered in 1987 the retinoid receptor families, which led to the discovery and characterization of the superfamily of nuclear hormone receptors, including steroid and retinoid receptors.

Dr. Chambon’s previous research led to the discovery of PolyADPribose, multiple RNA polymerases differentially sensitive to α-amaniti, and has markedly contributed to the elucidation of the nucleosome and chromatin structure, as well as to the discovery of animal split genes, DNA sequences called enhancer elements, and multiple promoter elements and their cognate factors. These discoveries have greatly enhanced understanding of embryonic development and cell differentiation. To further studies of various nuclear receptors, Dr. Chambon has developed a method that allows in the mouse the generation of somatic mutations of any gene, at any time, and in any specific cell type, a tool valuable in generating mouse models of cancer.

In 1994, Dr. Chambon took on the role of founding a major research institute in France. As the first director of IGBMC, he built the institute to encompass hundreds of top researchers and multiple research programs funded by public agencies and private industry. In 2002, he founded and was the first director of the Institut Clinique de la Souris in Strasbourg. In these positions, he has succeeded in supporting and influencing a generation of scientists.

Career Highlights

​2010  Canada Gairdner International Award

2004  Albert Lasker Basic Medical Research Award

2003  Alfred P. Sloan, Jr., Prize, General Motors Cancer Foundation

1999  Louisa Gross Horwitz Prize, Columbia University

1998  Robert A. Welch Award in Chemistry

1991  Prix Louis-Jeantet de médecine, Fondation Louis-Jeantet

1990  Sir Hans Krebs Medal, Federation of European Biochemical Societies

1988  King Faisal International Prize for Science, King Faisal Foundation

1987  Harvey Prize, Technicon-Israel Institute of Technology

more…

 

Minireviews In This Series:

Thematic Minireview Series on Nuclear Receptors in Biology and Diseases

Sohaib Khan and Jerry B Lingrel

Steroid Receptor Coactivator (SRC) Family: Masters of Systems Biology

Brian York and Bert W. O’Malley

Estrogen Signaling via Estrogen Receptor β

Chunyan Zhao, Karin Dahlman-Wright, and Jan-Åke Gustafsson

Small Molecule Inhibitors as Probes for Estrogen and Androgen Receptor Action

David J. Shapiro, Chengjian Mao, and Milu T Cherian

Cellular Processing of the Glucocorticoid Receptor Gene and Protein: New Mechanisms for Generating Tissue Specific Actions of Glucocorticoids

Robert H Oakley and John A Cidlowski

Endogenous Ligands for Nuclear Receptors: Digging Deeper

Michael Schupp and Mitchell A. Lazar

 

 

 

Read Full Post »


The Neurogenetics of Language – Patricia Kuhl

Larry H. Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Innovation

Series E. 2; 5.7

 

2015 George A. Miller Award

In neuroimaging studies using structural (diffusion weighted magnetic resonance imaging or DW-MRI) and functional (magnetoencephalography or MEG) imaging, my laboratory has produced data on the neural connectivity that underlies language processing, as well as electrophysiological measures of language functioning during various levels of language processing (e.g., phonemic, lexical, or sentential). Taken early in development, electrophysiological measures or “biomarkers” have been shown to predict future language performance in neurotypical children as well as children with autism spectrum disorders (ASD). Work in my laboratory is now combining these neuroimaging approaches with genetic sequencing, allowing us to understand the genetic contributions to language learning.

http://www.ted.com/talks/patricia_kuhl_the_linguistic_genius_of_babies%3Flanguage%3Den

http://www.youtube.com/watch%3Fv%3DG2XBIkHW954

http://www.youtube.com/watch%3Fv%3DM-ymanHajN8

Patricia Kuhl shares astonishing findings about how babies learn one language over another — by listening to the humans around them

Kuhl Constructs: How Babies Form Foundations for Language

MAY 3, 2013

by Sarah Andrews Roehrich, M.S., CCC-SLP

Years ago, I was captivated by an adorable baby on the front cover of a book, The Scientist in the Crib: What Early Learning Tells Us About the Mind, written by a trio of research scientists including Alison Gopknik, PhDAndrew Meltzoff, PhD, and Patricia Kuhl, PhD.

At the time, I was simply interested in how babies learn about their worlds, how they conduct experiments, and how this learning could impact early brain development.  I did not realize the extent to which interactions with family, caretakers, society, and culture could shape the direction of a young child’s future.

Now, as a speech-language pathologist in Early Intervention in Massachusetts, more cognizant of the myriad of factors that shape a child’s cognitive, social-emotional, language, and literacy development, I have been absolutely delighted to discover more of the work of Dr. Kuhl, a distinguished speech-and-language pathologist at The University of Washington.  So, last spring, when I read that Dr. Kuhl was going to present “Babies’ Language Skills” as one part of a 2-part seminar series sponsored by the Mind, Brain, and Behavior Annual Distinguished Lecture Series at Harvard University1, I was thrilled to have the opportunity to attend. Below are some highlights from that experience and the questions it has since sparked for me:

Lip ‘Reading’ Babies
According to a study by Dr. Patricia Kuhl and Dr. Andrew Meltzoff, “Bimodal Perception of Speech in Infancy” (Science, 1982), cited in the 2005 Seattle Times article, “Infant Science: How do Babies Learn to Talk?” by Paula Bock, Drs. Patricia Kuhl and Andrew Meltzoff showed that babies as young as 18 weeks of age could listen to “Ah ah ah” or “Ee ee ee” vowel sounds and gaze at the correct, corresponding lip shape on a video monitor.
This image from Kuhl’s 2011 TED talk shows how a baby is trained to turn his head in response to a change in such vowel sounds, and is immediately rewarded by watching a black box light up while a panda bear inside pounds a drum.  Images provided courtesy of Dr. Patricia Kuhl’s Lab at the University of Washington.

Who is Dr. Patricia Kuhl and how has her work re-shaped our knowledge about how babies learn language?

Dr. Kuhl, who is co-director of the Institute for Learning and Brain Sciences at The University of Washington, has been internationally recognized for her research on early language and brain development, and for her studies on how young children learn.  In her most recent research experiments, she’s been using magnetoencephalography (MEG)–a relatively new neuroscience technology that measures magnetic fields generated by the activity of brain cells–to investigate how, where, and with what frequency babies from around the world process speech sounds in the brain when they are listening to adults speak in their native and non-native languages.

A 6-month-old baby sits in a magnetoencephalography machine, which maps brain activity, while listening to various languages in earphones and playing with a toy. Image originally printed in “Brain Mechanisms in Early Language Acquisition” (Neuron review, Cell Press, 2010) and provided courtesy of Dr. Patricia Kuhl’s Lab at the University of Washington.

Not only does Kuhl’s research point us in the direction of how babies learn to process phonemes, the sound units upon which many languages are built, but it is part of a larger body of studies looking at infants across languages and cultures that has revolutionized our understanding of language development over the last half of the 20th century—leading to, as Kuhl puts it, “a new view of language acquisition, that accounts for both the initial state of linguistic knowledge in infants, and infants’ extraordinary ability to learn simply by listening to their native language.”2

What is neuroplasticity and how does it underlie child development?

Babies are born with 100 billion neurons, about the same as the number of stars in the Milky Way.3 In The Whole Brain Child,Daniel Siegel, MD and Tina Payne Bryson, PhD explain that when we undergo an experience, these brain cells respond through changes in patterns of electrical activity—in other words, they “fire” electrical signals called “action potentials.”4

In a child’s first years of life, the brain exhibits extraordinary neuroplasticity, refining its circuits in response to environmental experiences. Synapses—the sites of communication between neurons—are built, strengthened, weakened and pruned away as needed. Two short videos from the Center on the Developing Child at Harvard, “Experiences Build Brain Architecture” and “Serve and Return Interaction Shapes Brain Circuitry”, nicely depict how some of this early brain development happens.5

Since brain circuits organize and reorganize themselves in response to an infant’s interactions with his or her environment, exposing babies to a variety of positive experiences (such as talking, cuddling, reading, singing, and playing in different environments) not only helps tune babies in to the language of their culture, but it also builds a foundation for developing the attention, cognition, memory, social-emotional, language and literacy, and sensory and motor skills that will help them reach their potential later on.

When and how do babies become “language-bound” listeners?

In her 2011 TED talk, “The Linguistic Genius of Babies,” Dr. Kuhl discusses how babies under 8 months of age from different cultures can detect sounds in any language from around the world, but adults cannot do this. 6   So when exactly do babies go from being “citizens of the world”, as Kuhl puts it, to becoming “language-bound” listeners, specifically focused on the language of their culture?”

Between 8-10 months of age, when babies are trying to master the sounds used in their native language, they enter a critical period for sound development.1  Kuhl explains that in one set of experiments, she compared a group of babies in America learning to differentiate the sounds “/Ra/” and “/La/,” with a group of babies in Japan.  Between 6-8 months, the babies in both cultures recognized these sounds with the same frequency.  However, by 10-12 months, after multiple training sessions, the babies in Seattle, Washington, were much better at detecting the “/Ra/-/La/” shift than were the Japanese babies.

Kuhl explains these results by suggesting that babies “take statistics” on how frequently they hear sounds in their native and non-native languages.  Because “/Ra/” and “/La/” occur more frequently in the English language, the American babies recognized these sounds far more frequently in their native language than the Japanese babies.  Kuhl believes that the results in this study indicate a shift in brain development, during which babies from each culture are preparing for their own languages and becoming “language-bound” listeners.

In what ways are nurturing interactions with caregivers more valuable to babies’ early language development than interfacing with technology?

If parents, caretakers, and other children can help mold babies’ language development simply by talking to them, it is tempting to ask whether young babies can learn language by listening to the radio, watching television, or playing on their parents’ mobile devices. I mean, what could be more engaging than the brightly-colored screens of the latest and greatest smart phones, iPads, iPods, and computers? They’re perfect for entertaining babies.  In fact, some babies and toddlers can operate their parents’ devices before even having learned how to talk.

However, based on her research, Kuhl states that young babies cannot learn language from television and it is necessary for babies to have lots of face-to-face interaction to learn how to talk.1  In one interesting study, Kuhl’s team exposed 9 month old American babies to Mandarin in various forms–in person interactions with native Mandarin speakers vs. audiovisual or audio recordings of these speakers–and then looked at the impact of this exposure on the babies’ ability to make Mandarin phonetic contrasts (not found in English) at 10-12 months of age. Strikingly, twelve laboratory visits featuring in person interactions with the native Mandarin speakers were sufficient to teach the American babies how to distinguish the Mandarin sounds as well as Taiwanese babies of the same age. However, the same number of lab visits featuring the audiovisual or audio recordings made no impact. American babies exposed to Mandarin through these technologies performed the same as a control group of American babies exposed to native English speakers during their lab visits.

This diagram depicts the results of a Kuhl study on American infants exposed to Mandarin in various forms–in person interactions with native speakers versus television or audio recordings of these speakers. As the top blue triangle shows, the American infants exposed in person to native Mandarin speakers performed just as well on a Mandarin phoneme distinction task as age-matched Taiwanese counterparts. However, those American infants exposed to television or audio recordings of the Mandarin speakers performed the same as a control group of American babies exposed to native English speakers during their lab visits. Diagram displayed in Kuhl’s TED TAlk 6, provided courtesy of Dr. Patricia Kuhl’s Lab at the University of Washington.

Kuhl believes that this is primarily because a baby’s interactions with others engages the social brain, a critical element for helping children learn to communicate in their native and non-native languages. 6  In other words, learning language is not simply a technical skill that can be learned by listening to a recording or watching a show on a screen.  Instead, it is a special gift that is handed down from one generation to the next.

Language is learned through talking, singing, storytelling, reading, and many other nurturing experiences shared between caretaker and child.  Babies are naturally curious; they watch every movement and listen to every sound they hear around them.  When parents talk, babies look up and watch their mouth movements with intense wonder.  Parents respond in turn, speaking in “motherese,” a special variant of language designed to bathe babies in the sound patterns and speech sounds of their native language. Motherese helps babies hear the “edges” of sound, the very thing that is difficult for babies who exhibit symptoms of dyslexia and auditory processing issues later on.

Over time, by listening to and engaging with the speakers around them, babies build sound maps which set the stage for them to be able to say words and learn to read later on.  In fact, based on years of research, Kuhl has discovered that babies’ abilities to discriminate phonemes at 7 months-old is a predictor of future reading skills for that child at age 5.7

I believe that educating families about brain development, nurturing interactions, and the benefits and limits of technology is absolutely critical to helping families focus on what is most important in developing their children’s communication skills.  I also believe that Kuhl’s work is invaluable in this regard.  Not only has it focused my attention on how babies form foundations for language, but it has illuminated my understanding of how caretaker-child interactions help set the stage for babies to become language-bound learners.

Sources

(1) Kuhl, P. (April 3, 2012.) Talk on “Babies’ Language Skills.” Mind, Brain, and Behavior Annual Distinguished Lecture Series, Harvard University.

(2) Kuhl, P. (2000). “A New View of Language Acquisition.” This paper was presented at the National Academy of Sciences colloquium “Auditory Neuroscience: Development, Transduction, and Integration,” held May 19–21, 2000, at the Arnold and Mabel Beckman Center in Irvine, CA. Published by the National Academy of Sciences.

(3) Bock, P. (2005.)  “The Baby Brain.  Infant Science: How do Babies Learn to Talk?” Pacific Northwest: The Seattle Times Magazine.

(4) Siegel, D., Bryson, T. (2011.)  The Whole-Brain Child: 12 Revolutionary Strategies to Nurture Your Child’s Developing Mind. New York, NY:  Delacorte Press, a division of Random House, Inc.

(5) Center on the Developing Child at Harvard University. “Experiences Build Brain Architecture” and “Serve and Return Interaction Shapes Brain Circuitry” videos, two parts in the three-part series, “Three Core Concepts in Early Development.

http://developingchild.harvard.edu/resources/multimedia/videos

(6) Kuhl, P.  (February 18, 2011.) “The Linguistic Genius of Babies,” video talk on TED.com, a TEDxRainier event.

www.ted.com/talks/patricia_kuhl_the_linguistic_genius_of_babies.html

(7) Lerer, J. (2012.) “Professor Discusses Babies’ Language Skills.”  The Harvard Crimson.

 

Andrew Meltzoff & Patricia Kuhl: Joint attention to mind

Sarah DeWeerdt  11 Feb 2013

Power couple: In addition to a dizzying array of peer-reviewed publications, Andrew Meltzoff and Patricia Kuhl have written a popular book on brain development, given TED talks and lobbied political leaders.

Andrew Meltzoff shares many things with his wife — research dollars, authorship, a keen interest in the young brain — but he does not keep his wife’s schedule.

“It’s one of the agreements we have,” he says, laying out the rule with a twinkle in his eye that conveys both the delights and the complications of working with one’s spouse.

Meltzoff, professor of psychology at the University of Washington in Seattle, and his wife, speech and hearing sciences professor Patricia Kuhl, are co-directors of the university’s Institute for Learning and Brain Sciences, which focuses on the development of the brain and mind during the first five years of life.

Between them, they have shown that learning is a fundamentally social process, and that babies begin this social learning when they are just weeks or even days old.

You could say the couple is attached at the cerebral cortex, but not at the hip: They take equal roles in running the institute, but they each have their own daily rhythms and distinct, if overlapping, scientific interests.

Kuhl studies how infants “crack the language code,” as she puts it — how they figure out sounds and meanings and eventually learn to produce speech. Meltzoff’s work focuses on social building blocks such as imitation and joint attention, or a shared focus on an object or activity. Meltzoff says these basic behaviors help children develop theory of mind, a sophisticated awareness and understanding of others’ thoughts and feelings.

All of these abilities are impaired in children with autism. Most of the couple’s studies have focused on typically developing infants, because, they say, it’s essential to understand typical development in order to appreciate the irregularities in autism.

Both also study autism, which can in turn help explain typical development.

In addition to a dizzying array of peer-reviewed publications, the duo have written a popular book on developmental psychiatry, The Scientist in the Crib, and promote their ideas through TED talks and by lobbying political leaders.

Geraldine Dawson, chief science officer of the autism science and advocacy organization Autism Speaks and a longtime collaborator, calls Meltzoff and Kuhl “the dynamic duo.” “They’re sort of bigger-than-life type people, who fill the room when they walk into it,” she says.

Making a match:

Meltzoff and Kuhl’s story began with a scientific twist on a standard rom-com meet cute.

It was the early 1980s, and Kuhl, who had recently joined the faculty at the University of Washington, wanted to understand how infants hear and see vowels. But she was having trouble designing an effective experiment.

“I kept running into Andy’s office,” which was near hers, to talk it through, Kuhl recalls.

Meltzoff had done some research on how babies integrate what they see with what they touch, a process called cross-modal matching1. Soon he and Kuhl realized that they could adapt his experimental design to her question, and decided to collaborate.

They showed babies two video screens, each featuring a person mouthing a different vowel sound – “ahhh” or “eeee.” A speaker placed between the two screens played one of those two vowel sounds.

They found that babies as young as 18 to 20 weeks look longer at the face that matches the sound they hear, integrating faces with voices2.

But that wasn’t the only significant result from those experiments.

“Speaking only for myself, I will say I became very interested in the very attractive, smart blonde that I was collaborating with,” Meltzoff says. “Criticizing each other’s scientific writing at the same time the relationship was building was… interesting.”

And effective: Their paper appeared in Science in 1982, and the couple married three years later.

Listening to Meltzoff tell that story, it’s easy to understand why some colleagues say he is funny but they can’t quite explain why. His humor is subtle and wry. More obvious is his passion, not just for science, but for working out the theory underlying empirical results. Even his wife describes his personality as “cerebral.”

“He just has this laser vision for homing in on what is the heart of the issue,” says Rechele Brooks, research assistant professor of psychiatry and behavioral sciences at the University of Washington, who collaborates with Meltzoff on studies of gaze.

For example, in one of his earliest papers, Meltzoff wanted to investigate how babies learn to imitate. He found that infants just 12 to 21 days old can imitate both facial expressions and hand gestures, much earlier than previously thought3.

“It really turned the scientific community on its head,” Brooks says.

Early insights:

Face to face: Meltzoff and Kuhl are developing a method to simultaneously record the brain activity of two people as they interact.

Meltzoff continued to study infants, tracing back the components of theory of mind to their earliest developmental source. That sparked the interest of Dawson, who had gotten to know Meltzoff as a student at the University of Washington in the 1970s, and became the first director of the university’s autism center in 1996.

Meltzoff and Dawson together applied his techniques to study young, often nonverbal, children with autism. In one study, they found that children with autism have more trouble imitating others than do either typically developing children or those with Down syndrome4.

In another study, they found that children with autism are less interested in social sounds such as clapping or hearing their name called than are their typically developing peers5.  They also found that how children with autism imitate and play with toys when they are 3 or 4 years old predicts their communication skills two years later6.

Most previous studies of autism had focused on older children, Dawson says, and this work helped paint a picture of the disorder earlier in childhood.

Kuhl began her career with studies showing that monkeys7 and even chinchillas8 can distinguish the difference between speech sounds, or phonemes, such as “ba” and “pa,” just as human infants can.

“The bottom line was that animals were sharing this aspect of perception,” Kuhl says.

So why are people so much better than animals at learning language? Kuhl has been trying to answer that question ever since, first through behavioral studies and then by measuring brain activity using imaging techniques.

Kuhl is soft-spoken, but a listener wants to lean in to catch every word. Scientists who have worked with her describe her as poised and perfectly put together, a master of gentle yet effective diplomacy.

“She has her sort of magnetic power to pull people together,” says Yang Zhang, associate professor of speech-language-hearing sciences at the University of Minnesota in Rochester, who was a graduate student and postdoctoral researcher in Kuhl’s lab beginning in the late 1990s.

Listen and learn:

At one point, Kuhl turned her considerable powers of persuasion on a famously smooth negotiator, then-President Bill Clinton.

Kuhl had shown that newborns hear virtually all speech sounds, but by 6 months of age they lose the ability to distinguish sounds that aren’t part of their native language9.

At the White House Conference on Early Childhood Development and Learning in 1997, she described how infants learn by listening, long before they can speak.

Clinton, ever the policy wonk, asked her how much babies need to hear in order to learn. Kuhl said she didn’t know — but if Clinton gave her the funds, she would find out. “Even the president could see that research on the effects of language input on the young brain had impact on society,” she says.

Kuhl used the funds Clinton gave her to design a study in which 9-month-old babies in the U.S. received 12 short Mandarin Chinese ‘lessons.’ The babies quickly learned to distinguish speech sounds in the second language, her team found — but only if the speaker was live, not in a video10.

Those results contributed to Kuhl’s ‘social gating’ hypothesis, which holds that social interaction is necessary for picking up on the sounds and patterns of language. “We’re saying that social interaction is a kind of gate to an interest in learning, the kind that humans are completely masters of,” she says.

Her results also suggest that the language problems in children with autism may be the result of their social deficits.

“Children with autism will have a very difficult time acquiring language if language requires the social gate to be open,” she says.

Over the years, Kuhl and Meltzoff have had largely independent research programs, but her recent focus on the social roots of language dovetails with his long-time focus on social interaction.

These days, they are trying to develop ‘face-to-face neuroscience,’ which involves simultaneously recording brain activity from two people as they interact with each other.

This approach would allow researchers to observe, for example, what happens in an infant’s brain when she hears her mother’s voice, and what happens in the mother’s brain as she sees her infant respond to her. “It’s going to be very special to do,” Meltzoff says enthusiastically, even though the effort is more directly related to Kuhl’s work than to his own.

It’s clear that this fervor for each other’s work goes both ways.

“That’s one of the great things about being married to a scientist,” Meltzoff says. “When you come home and think, ‘God, I really nailed this methodologically,’ your wife, instead of yawning, leans forward and says, ‘You did? Tell me about the method, that’s so exciting.’”

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Meltzoff A.N. and R.W. Borton Nature 282, 403-404 (1979) PubMed

2: Kuhl P.K. and A.N. Meltzoff Science 218, 1138-1141 (1982) PubMed

3: Meltzoff A.N. and M.K. Moore Science 198, 75-78 (1977) PubMed

4: Dawson G. et al. Child Dev. 69, 1276-1285 (1998) PubMed

5: Dawson G. et al. J. Autism Dev. Disord. 28, 479-485 (1998) PubMed

6: Toth K. et al. J. Autism Dev. Disord. 36, 993-1005 (2006) PubMed

7: Kuhl P.K. and D.M. Padden Percept. Psychophys. 32, 542-550 (1982) PubMed

8: Kuhl P.K. and J.D. Miller Science 190, 69-72 (1975) PubMed

9: Kuhl P.K. et al. Science 255, 606-608 (1992) PubMed

10: Kuhl P.K. et al. Proc. Natl. Acad. Sci. U.S.A. 100, 9096-9101 (2003) PubMed

 

 

Using genetic data in cognitive neuroscience: from growing pains to genuine insights

Adam E. Green, Marcus R. Munafò, Colin G. DeYoung, John A. Fossella, Jin Fan & Jeremy R. Gray
Nature Reviews Neuroscience 2008 Sep; 9, 710-720
http://dx.doi.org:/10.1038/nrn2461

Research that combines genetic and cognitive neuroscience data aims to elucidate the mechanisms that underlie human behaviour and experience by way of ‘intermediate phenotypes’: variations in brain function. Using neuroimaging and other methods, this approach is poised to make the transition from health-focused investigations to inquiries into cognitive, affective and social functions, including ones that do not readily lend themselves to animal models. The growing pains of this emerging field are evident, yet there are also reasons for a measured optimism.

NSF – Cognitive Neuroscience Award

The cross-disciplinary integration and exploitation of new techniques in cognitive neuroscience has generated a rapid growth in significant scientific advances. Research topics have included sensory processes (including olfaction, thirst, multi-sensory integration), higher perceptual processes (for faces, music, etc.), higher cognitive functions (e.g., decision-making, reasoning, mathematics, mental imagery, awareness), language (e.g., syntax, multi-lingualism, discourse), sleep, affect, social processes, learning, memory, attention, motor, and executive functions. Cognitive neuroscientists further clarify their findings by examining developmental and transformational aspects of such phenomena across the span of life, from infancy to late adulthood, and through time.

New frontiers in cognitive neuroscience research have emerged from investigations that integrate data from a variety of techniques. One very useful technique has been neuroimaging, including positron emission tomography (PET), functional magnetic resonance imaging (fMRI), magnetoencephalography (MEG), optical imaging (near infrared spectroscopy or NIRS), anatomical MRI, and diffusion tensor imaging (DTI). A second class of techniques includes physiological recording such as subdural and deep brain electrode recording, electroencephalography (EEG), event-related electrical potentials (ERPs), and galvanic skin responses (GSRs). In addition, stimulation methods have been employed, including transcranial magnetic stimulation (TMS), subdural and deep brain electrode stimulation, and drug stimulation. A fourth approach involves cognitive and behavioral methods, such as lesion-deficit neuropsychology and experimental psychology. Other techniques have included genetic analysis, molecular modeling, and computational modeling. The foregoing variety of methods is used with individuals in healthy, neurological, psychiatric, and cognitively-impaired conditions. The data from such varied sources can be further clarified by comparison with invasive neurophysiological recordings in non-human primates and other mammals.

Findings from cognitive neuroscience can elucidate functional brain organization, such as the operations performed by a particular brain area and the system of distributed, discrete neural areas supporting a specific cognitive, perceptual, motor, or affective operation or representation. Moreover, these findings can reveal the effect on brain organization of individual differences (including genetic variation), plasticity, and recovery of function following damage to the nervous system.

Read Full Post »

Metabolic Genomics and Pharmaceutics, Vol. 1 of BioMed Series D available on Amazon Kindle


Metabolic Genomics and Pharmaceutics, Vol. 1 of BioMed Series D available on Amazon Kindle

Reporter: Stephen S Williams, PhD

 

Leaders in Pharmaceutical Business Intelligence would like to announce the First volume of their BioMedical E-Book Series D:

Metabolic Genomics & Pharmaceutics, Vol. I

SACHS FLYER 2014 Metabolomics SeriesDindividualred-page2

which is now available on Amazon Kindle at

http://www.amazon.com/dp/B012BB0ZF0.

This e-Book is a comprehensive review of recent Original Research on  METABOLOMICS and related opportunities for Targeted Therapy written by Experts, Authors, Writers. This is the first volume of the Series D: e-Books on BioMedicine – Metabolomics, Immunology, Infectious Diseases.  It is written for comprehension at the third year medical student level, or as a reference for licensing board exams, but it is also written for the education of a first time baccalaureate degree reader in the biological sciences.  Hopefully, it can be read with great interest by the undergraduate student who is undecided in the choice of a career. The results of Original Research are gaining value added for the e-Reader by the Methodology of Curation. The e-Book’s articles have been published on the Open Access Online Scientific Journal, since April 2012.  All new articles on this subject, will continue to be incorporated, as published with periodical updates.

We invite e-Readers to write an Article Reviews on Amazon for this e-Book on Amazon.

All forthcoming BioMed e-Book Titles can be viewed at:

https://pharmaceuticalintelligence.com/biomed-e-books/

Leaders in Pharmaceutical Business Intelligence, launched in April 2012 an Open Access Online Scientific Journal is a scientific, medical and business multi expert authoring environment in several domains of  life sciences, pharmaceutical, healthcare & medicine industries. The venture operates as an online scientific intellectual exchange at their website http://pharmaceuticalintelligence.com and for curation and reporting on frontiers in biomedical, biological sciences, healthcare economics, pharmacology, pharmaceuticals & medicine. In addition the venture publishes a Medical E-book Series available on Amazon’s Kindle platform.

Analyzing and sharing the vast and rapidly expanding volume of scientific knowledge has never been so crucial to innovation in the medical field. WE are addressing need of overcoming this scientific information overload by:

  • delivering curation and summary interpretations of latest findings and innovations on an open-access, Web 2.0 platform with future goals of providing primarily concept-driven search in the near future
  • providing a social platform for scientists and clinicians to enter into discussion using social media
  • compiling recent discoveries and issues in yearly-updated Medical E-book Series on Amazon’s mobile Kindle platform

This curation offers better organization and visibility to the critical information useful for the next innovations in academic, clinical, and industrial research by providing these hybrid networks.

Table of Contents for Metabolic Genomics & Pharmaceutics, Vol. I

Chapter 1: Metabolic Pathways

Chapter 2: Lipid Metabolism

Chapter 3: Cell Signaling

Chapter 4: Protein Synthesis and Degradation

Chapter 5: Sub-cellular Structure

Chapter 6: Proteomics

Chapter 7: Metabolomics

Chapter 8:  Impairments in Pathological States: Endocrine Disorders; Stress

                   Hypermetabolism and Cancer

Chapter 9: Genomic Expression in Health and Disease 

 

Summary 

Epilogue

 

 

Read Full Post »

Cancer Biology and Genomics for Disease Diagnosis (Vol. I) Now Available for Amazon Kindle


Cancer Biology and Genomics for Disease Diagnosis (Vol. I) Now Available for Amazon Kindle

Reporter: Stephen J Williams, PhD

Leaders in Pharmaceutical Business Intelligence would like to announce the First volume of their BioMedical E-Book Series C: e-Books on Cancer & Oncology

Volume One: Cancer Biology and Genomics for Disease Diagnosis

CancerandOncologyseriesCcoverwhich is now available on Amazon Kindle at                          http://www.amazon.com/dp/B013RVYR2K.

This e-Book is a comprehensive review of recent Original Research on Cancer & Genomics including related opportunities for Targeted Therapy written by Experts, Authors, Writers. This ebook highlights some of the recent trends and discoveries in cancer research and cancer treatment, with particular attention how new technological and informatics advancements have ushered in paradigm shifts in how we think about, diagnose, and treat cancer. The results of Original Research are gaining value added for the e-Reader by the Methodology of Curation. The e-Book’s articles have been published on the Open Access Online Scientific Journal, since April 2012.  All new articles on this subject, will continue to be incorporated, as published with periodical updates.

We invite e-Readers to write an Article Reviews on Amazon for this e-Book on Amazon. All forthcoming BioMed e-Book Titles can be viewed at:

https://pharmaceuticalintelligence.com/biomed-e-books/

Leaders in Pharmaceutical Business Intelligence, launched in April 2012 an Open Access Online Scientific Journal is a scientific, medical and business multi expert authoring environment in several domains of  life sciences, pharmaceutical, healthcare & medicine industries. The venture operates as an online scientific intellectual exchange at their website http://pharmaceuticalintelligence.com and for curation and reporting on frontiers in biomedical, biological sciences, healthcare economics, pharmacology, pharmaceuticals & medicine. In addition the venture publishes a Medical E-book Series available on Amazon’s Kindle platform.

Analyzing and sharing the vast and rapidly expanding volume of scientific knowledge has never been so crucial to innovation in the medical field. WE are addressing need of overcoming this scientific information overload by:

  • delivering curation and summary interpretations of latest findings and innovations
  • on an open-access, Web 2.0 platform with future goals of providing primarily concept-driven search in the near future
  • providing a social platform for scientists and clinicians to enter into discussion using social media
  • compiling recent discoveries and issues in yearly-updated Medical E-book Series on Amazon’s mobile Kindle platform

This curation offers better organization and visibility to the critical information useful for the next innovations in academic, clinical, and industrial research by providing these hybrid networks.

Table of Contents for Cancer Biology and Genomics for Disease Diagnosis

Preface

Introduction  The evolution of cancer therapy and cancer research: How we got here?

Part I. Historical Perspective of Cancer Demographics, Etiology, and Progress in Research

Chapter 1:  The Occurrence of Cancer in World Populations

Chapter 2.  Rapid Scientific Advances Changes Our View on How Cancer Forms

Chapter 3:  A Genetic Basis and Genetic Complexity of Cancer Emerge

Chapter 4: How Epigenetic and Metabolic Factors Affect Tumor Growth

Chapter 5: Advances in Breast and Gastrointestinal Cancer Research Supports Hope for Cure

Part II. Advent of Translational Medicine, “omics”, and Personalized Medicine Ushers in New Paradigms in Cancer Treatment and Advances in Drug Development

Chapter 6:  Treatment Strategies

Chapter 7:  Personalized Medicine and Targeted Therapy

Part III.Translational Medicine, Genomics, and New Technologies Converge to Improve Early Detection

Chapter 8:  Diagnosis                                     

Chapter 9:  Detection

Chapter 10:  Biomarkers

Chapter 11:  Imaging In Cancer

Chapter 12: Nanotechnology Imparts New Advances in Cancer Treatment, Detection, &  Imaging                                 

Epilogue by Larry H. Bernstein, MD, FACP: Envisioning New Insights in Cancer Translational Biology

 

Read Full Post »


Treatment of Lymphomas [2.4.4C]

Larry H. Bernstein, MD, FCAP, Author, Curator, Editor

http://pharmaceuticalinnovation.com/2015/8/11/larryhbern/Treatment-of-Lymphomas-[2.4.4C]

 

Lymphoma treatment

Overview

http://www.emedicinehealth.com/lymphoma/page8_em.htm#lymphoma_treatment

The most widely used therapies are combinations of chemotherapyand radiation therapy.

  • Biological therapy, which targets key features of the lymphoma cells, is used in many cases nowadays.

The goal of medical therapy in lymphoma is complete remission. This means that all signs of the disease have disappeared after treatment. Remission is not the same as cure. In remission, one may still have lymphoma cells in the body, but they are undetectable and cause no symptoms.

  • When in remission, the lymphoma may come back. This is called recurrence.
  • The duration of remission depends on the type, stage, and grade of the lymphoma. A remission may last a few months, a few years, or may continue throughout one’s life.
  • Remission that lasts a long time is called durable remission, and this is the goal of therapy.
  • The duration of remission is a good indicator of the aggressiveness of the lymphoma and of the prognosis. A longer remission generally indicates a better prognosis.

Remission can also be partial. This means that the tumor shrinks after treatment to less than half its size before treatment.

The following terms are used to describe the lymphoma’s response to treatment:

  • Improvement: The lymphoma shrinks but is still greater than half its original size.
  • Stable disease: The lymphoma stays the same.
  • Progression: The lymphoma worsens during treatment.
  • Refractory disease: The lymphoma is resistant to treatment.

The following terms to refer to therapy:

  • Induction therapy is designed to induce a remission.
  • If this treatment does not induce a complete remission, new or different therapy will be initiated. This is usually referred to as salvage therapy.
  • Once in remission, one may be given yet another treatment to prevent recurrence. This is called maintenance therapy.

Chemotherapy

Many different types of chemotherapy may be used for Hodgkin lymphoma. The most commonly used combination of drugs in the United States is called ABVD. Another combination of drugs, known as BEACOPP, is now widely used in Europe and is being used more often in the United States. There are other combinations that are less commonly used and not listed here. The drugs that make up these two more common combinations of chemotherapy are listed below.

ABVD: Doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velban, Velsar), and dacarbazine (DTIC-Dome). ABVD chemotherapy is usually given every two weeks for two to eight months.

BEACOPP: Bleomycin, etoposide (Toposar, VePesid), doxorubicin, cyclophosphamide (Cytoxan, Neosar), vincristine (Vincasar PFS, Oncovin), procarbazine (Matulane), and prednisone (multiple brand names). There are several different treatment schedules, but different drugs are usually given every two weeks.

The type of chemotherapy, number of cycles of chemotherapy, and the additional use of radiation therapy are based on the stage of the Hodgkin lymphoma and the type and number of prognostic factors.

Adult Non-Hodgkin Lymphoma Treatment (PDQ®)

http://www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/Patient/page1

Key Points for This Section

Adult non-Hodgkin lymphoma is a disease in which malignant (cancer) cells form in the lymph system.

Because lymph tissue is found throughout the body, adult non-Hodgkin lymphoma can begin in almost any part of the body. Cancer can spread to the liver and many other organs and tissues.

Non-Hodgkin lymphoma in pregnant women is the same as the disease in nonpregnant women of childbearing age. However, treatment is different for pregnant women. This summary includes information on the treatment of non-Hodgkin lymphoma during pregnancy

Non-Hodgkin lymphoma can occur in both adults and children. Treatment for children, however, is different than treatment for adults. (See the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information.)

There are many different types of lymphoma.

Lymphomas are divided into two general types: Hodgkin lymphoma and non-Hodgkin lymphoma. This summary is about the treatment of adult non-Hodgkin lymphoma. For information about other types of lymphoma, see the following PDQ summaries:

Age, gender, and a weakened immune system can affect the risk of adult non-Hodgkin lymphoma.

If cancer is found, the following tests may be done to study the cancer cells:

  • Immunohistochemistry : A test that uses antibodies to check for certain antigens in a sample of tissue. The antibody is usually linked to a radioactive substance or a dye that causes the tissue to light up under a microscope. This type of test may be used to tell the difference between different types of cancer.
  • Cytogenetic analysis : A laboratory test in which cells in a sample of tissue are viewed under a microscope to look for certain changes in the chromosomes.
  • Immunophenotyping : A process used to identify cells, based on the types of antigens ormarkers on the surface of the cell. This process is used to diagnose specific types of leukemia and lymphoma by comparing the cancer cells to normal cells of the immune system.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options depend on the following:

  • The stage of the cancer.
  • The type of non-Hodgkin lymphoma.
  • The amount of lactate dehydrogenase (LDH) in the blood.
  • The amount of beta-2-microglobulin in the blood (for Waldenström macroglobulinemia).
  • The patient’s age and general health.
  • Whether the lymphoma has just been diagnosed or has recurred (come back).

Stages of adult non-Hodgkin lymphoma may include E and S.

Adult non-Hodgkin lymphoma may be described as follows:

E: “E” stands for extranodal and means the cancer is found in an area or organ other than the lymph nodes or has spread to tissues beyond, but near, the major lymphatic areas.

S: “S” stands for spleen and means the cancer is found in the spleen.

Stage I adult non-Hodgkin lymphoma is divided into stage I and stage IE.

  • Stage I: Cancer is found in one lymphatic area (lymph node group, tonsils and nearby tissue, thymus, or spleen).
  • Stage IE: Cancer is found in one organ or area outside the lymph nodes.

Stage II adult non-Hodgkin lymphoma is divided into stage II and stage IIE.

  • Stage II: Cancer is found in two or more lymph node groups either above or below the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen).
  • Stage IIE: Cancer is found in one or more lymph node groups either above or below the diaphragm. Cancer is also found outside the lymph nodes in one organ or area on the same side of the diaphragm as the affected lymph nodes.

Stage III adult non-Hodgkin lymphoma is divided into stage III, stage IIIE, stage IIIS, and stage IIIE+S.

  • Stage III: Cancer is found in lymph node groups above and below the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen).
  • Stage IIIE: Cancer is found in lymph node groups above and below the diaphragm and outside the lymph nodes in a nearby organ or area.
  • Stage IIIS: Cancer is found in lymph node groups above and below the diaphragm, and in the spleen.
  • Stage IIIE+S: Cancer is found in lymph node groups above and below the diaphragm, outside the lymph nodes in a nearby organ or area, and in the spleen.

In stage IV adult non-Hodgkin lymphoma, the cancer:

  • is found throughout one or more organs that are not part of a lymphatic area (lymph node group, tonsils and nearby tissue, thymus, or spleen), and may be in lymph nodes near those organs; or
  • is found in one organ that is not part of a lymphatic area and has spread to organs or lymph nodes far away from that organ; or
  • is found in the liver, bone marrow, cerebrospinal fluid (CSF), or lungs (other than cancer that has spread to the lungs from nearby areas).

Adult non-Hodgkin lymphomas are also described based on how fast they grow and where the affected lymph nodes are in the body.  Indolent & aggressive.

The treatment plan depends mainly on the following:

  • The type of non-Hodgkin’s lymphoma
  • Its stage (where the lymphoma is found)
  • How quickly the cancer is growing
  • The patient’s age
  • Whether the patient has other health problems
  • If there are symptoms present such as fever and night sweats (see above)

Read Full Post »

« Newer Posts - Older Posts »