Wednesday, May 13, 2009
Nobel Laureate: Richard Ernst
The Nobel Prize in Chemistry 1991.
"for his contributions to the development of the methodology of high resolution nuclear magnetic resonance (NMR) spectroscopy"
Richard R. Ernst (1933 - ) won the Nobel Prize in Chemistry for important contributions to the technology of nuclear magnetic resonance (NMR) as a tool to understanding the three-dimensional structure of molecules. The press release describes his work in some detail.
THEME:
Nobel Laureates
Revolutionary developments make a spectroscopic technique indispensable for chemistry
The 1991 Nobel Prize in Chemistry has been awarded to Professor Richard R. Ernst of the ETH, Zurich, for important methodological developments within nuclear magnetic resonance (NMR) spectroscopy. NMR spectroscopy has during the last twenty years developed into perhaps the most important instrumental measuring technique within chemistry. This has occurred because of a dramatic increase in both the sensitivity and the resolution of the instruments, two areas in which Ernst has contributed more than anybody else.
NMR spectroscopy is today used within practically all branches of chemistry, at universities as well as industrial laboratories. The method has its most important applications as a tool for the determination of molecular structure in solution. It can today be applied to a wide variety of chemical systems, from small molecules (e.g. drugs) to proteins and nucleic acids. Further, chemists use NMR to study interactions between different molecules (e.g. enzyme - substrate, soap - water), to investigate molecular motion, to get information on the rate of chemical reactions and for many other problems. The NMR technique is today also important in related sciences, such as physics, biology and medicine.
Background
The first successful NMR experiments were reported in 1945, by two independent groups in the USA (Bloch and co-workers at Stanford and Purcell with his group at Harvard). Their discovery was awarded a Nobel Prize in Physics in 1952. The NMR phenomenon can be explained in the following way. When matter is placed in a magnetic field, some of the atomic nuclei (e.g. nuclei of hydrogen atoms, called protons) behave like microscopic compass needles. These tiny compass needles (called nuclear spins) can, according to the laws of quantum mechanics, orient themselves with respect to the magnetic field in only a few ways. These orientations are characterized by different energy levels. The nuclear spins can be forced to jump between levels if the sample is exposed to radio waves of exactly specified frequency. The frequency is varied during the course of the experiment and, when it exactly matches the characteristic frequency of the nuclei (the resonance frequency), an electric signal is induced in the detector. The strength of the signal is plotted as a function of frequency in a diagram called the NMR spectrum. Around 1950, it was discovered that nuclear resonance frequencies depended not only on the nature of the atomic nuclei, but also on their chemical environment. The possibility of using NMR as a tool for chemical analysis soon became obvious and was mentioned by, among others, Professor Purcell in his 1952 Nobel lecture. A fundamental difficulty in the early days was the relatively low sensitivity of the NMR method.A major breakthrough occurred in 1966 when Ernst (together with Weston A. Anderson, USA) discovered that the sensitivity of NMR spectra could be increased dramatically if the slow radiofrequency sweep that the sample was exposed to was replaced by short and intense radiofrequency pulses. The signal was then measured as a function of time after the pulse. The next pulse and signal acquisition were started after a few seconds, and the signals after each pulse were summed in a computer. The NMR signal measured as a function of time is not amenable to a simple interpretation (see Figure la). It is however possible to analyze what resonance frequencies are present in such a signal - and to convert it to an NMR spectrum - by a mathematical operation (Fourier transformation, FT) performed rapidly in the computer. The result of the Fourier transformation of Figure la is shown in Figure lb.
This discovery is the basis of modern NMR spectroscopy. The ten-fold, and sometimes hundred-fold, increase in sensitivity has made it possible to study small amounts of material as well as chemically interesting isotopes of low natural occurrence, e.g. carbon- 13. The enormous potential of the new technique - called FT NMR - quickly became obvious to NMR spectroscopists. The chemical research community got access to it in the early seventies through commercial FT NMR instruments. Nowadays, practically no other types of NMR spectrometer are manufactured.
By the end of the sixties, NMR spectroscopists had begun to use new magnet designs, based on superconducting materials, and the quality of spectra - expressed both in terms of sensitivity and resolution - improved quickly during the seventies. Consequently, more complex systems could be studied and more sophishcated questions answered. To move to very large molecules, macromolecules, another breakthrough was necessary, and this again carried the signature of Ernst. Inspired by a lecture of Jean Jeener, Belgium, at a summer school at the beginning of the seventies, Ernst and co-workers showed in 1975-76 how "two-dimensional" (2D) NMR experiments could be performed and demonstrated that 2D FT NMR opened entirely new possibilities for chemical research.
This 2D methods functions in the following way. Nuclear spins in a magnetic field are now subjected to sequences of radio-frequency pulses rather than to single pulses. The time course of the experiment is divided into four intervals. During the "preparation period", the equilibrium of the nuclear spin system is distorted by one or several pulses. This non-equilibrium is allowed to evolve for a certain time (the "evolution period"), after which the next series of pulses (the "mixing period") leads to the "detection period". Here the NMR signal is detected as a function of time in the same way as in ordinary, one-dimensional FT NMR. After this, one moves to the next preparation period and repeats the experiment with different evolution period. The change in the evolution period causes the signal measured during the detection period to change. One might say that the history of spins during the evolution period becomes encoded in the variation of the signal measured during the detection period. This gives a two-dimensional table with signal intensity as a function of both the point in time during the detection period and the length of the evolution period. Finally, the Fourier transformation is performed twice - with respect to both these time parameters - to obtain a two-dimensional frequency spectrum in the form of a map of the dependence of the signal intensity on two frequency parameters (denoted f1 and f2 in Figure 2).Introduction of the second frequency dimension allows the spectral information to attain much higher resolution - like looking at the skyline of a mountain range and then looking at the whole range from an aircraft above. Depending on the design of the preparation and the mixing periods, one obtains a variety of 2D NMR experiments. Some are used to spread the information over two dimensions rather than one (separation of interactions) while others are designed to find which nuclei have some form of contact with each other (correlation of signals).
In the mid-seventies, Ernst also proposed a method of obtaining NMR-tomographic images which became one of the most common (the NMR tomography method as such was earlier realized by Lauterbur in the USA, Mansfield in England and others).
Since the mid-seventies, Ernst and co-workers have continuously and decisively contributed to the development of NMR spectroscopy, and in particular its two-, and more recently three- and multi-dimensional varieties. Applications of his methods were soon to come. For example, it has become possible over the past ten years to use NMR to determine the three-dimensional structure of organic and inorganic compounds as well as proteins and other biological macromolecules in solution with an accuracy comparable to what can be attained in crystals using X-ray diffraction. Interactions between biological molecules and other substances (metal ions, water, drugs) have also been studied in detail. Other important chemical applications are identification of chemical species (where NMR spectra act as the fingerprint of a molecule), studies of rates of certain chemical reactions and of molecular motions in the liquid state. In the border area between chemistry and biology, NMR is being used to study how metabolic processes are influenced by drugs, ischaemia etc. Ernst's own work often falls in the border area between chemistry and physics and can, if one so wishes, be treated as extremely elegant experimental verification of the correctness of quantum mechanics.
[Photo Credit: Science Festival]
The images of the Nobel Prize medals are registered trademarks of the Nobel Foundation (© The Nobel Foundation). They are used here, with permission, for educational purposes only.
Nobel Laureate: Harald zur Hausen
The Nobel Prize in Physiology or Medicine 2008
"for his discovery of human papilloma viruses causing cervical cancer"
Harald zur Hausen (1936 - ) won the Noble Prize in 2008 for discovering that a virus, human papilloma virus, causes cervical cancer. He also won a Gairdner Award in 2008.Zur Hausen's discovery led eventually to the development of an HPV vaccine. Gardasil is the best known of the two vaccines on the market. Most doctors recommend that young girls be vaccinated.
Here's the 2008 press release on Zur Hausen.
THEME:
Nobel Laureates
Discovery of human papilloma virus causing cervical cancer
Against the prevailing view during the 1970s, Harald zur Hausen postulated a role for human papilloma virus (HPV) in cervical cancer. He assumed that the tumour cells, if they contained an oncogenic virus, should harbour viral DNA integrated into their genomes. The HPV genes promoting cell proliferation should therefore be detectable by specifically searching tumour cells for such viral DNA. Harald zur Hausen pursued this idea for over 10 years by searching for different HPV types, a search made difficult by the fact that only parts of the viral DNA were integrated into the host genome. He found novel HPV-DNA in cervix cancer biopsies, and thus discovered the new, tumourigenic HPV16 type in 1983. In 1984, he cloned HPV16 and 18 from patients with cervical cancer. The HPV types 16 and 18 were consistently found in about 70% of cervical cancer biopsies throughout the world.
Importance of the HPV discovery
The global public health burden attributable to human papilloma viruses is considerable. More than 5% of all cancers worldwide are caused by persistent infection with this virus. Infection by the human papilloma virus is the most common sexually transmitted agent, afflicting 50-80% of the population. Of the more than 100 HPV types known, about 40 infect the genital tract, and 15 of these put women at high risk for cervical cancer. In addition, HPV is found in some vulval, penile, oral and other cancers. Human papilloma virus can be detected in 99.7% of women with histologically confirmed cervical cancer, affecting some 500,000 women per year.
Harald zur Hausen demonstrated novel properties of HPV that have led to an understanding of mechanisms for papilloma virus-induced carcinogenesis and the predisposing factors for viral persistence and cellular transformation. He made HPV16 and 18 available to the scientific community. Vaccines were ultimately developed that provide ≥95 % protection from infection by the high risk HPV16 and 18 types. The vaccines may also reduce the need for surgery and the global burden of cervical cancer.
[Photo Credit: IBMLive]
The images of the Nobel Prize medals are registered trademarks of the Nobel Foundation (© The Nobel Foundation). They are used here, with permission, for educational purposes only.
New York: American Museum of Natural History
Guess who I saw in the American Museum of Natural History in New York? No, I'm not thinking of a family of stuffed elephants or a giant blue whale. I'm not even thinking of the butterflies in the butterfly conservatory. The people who I'm thinking about are much more exciting.
My friend and I visited the evolution display. It was really excellent. The dioramas and descriptions described a no-holds-barred version of evolution complete with supporting evidence from fossils, DNA sequences, and biogeography. The statements were factual (mostly) and scientific. No dumbing down and no pulling punches.
I remarked to my friend that this was unusual and I would be surprised if there weren't some "disclaimers" at the end of the display.
Sure enough, just before reaching the end we saw some familiar faces. There were Ken Miller, Francis Collins, and Genie Scott in full length videos explaining why evolution and religion are compatible. I waited to see if PZ Myers or Richard Dawkins would put in an appearance—no such luck. We didn't even see Neil deGrasee Tyson in the video in spite of the fact he's the director of the Hayden Planetarium at the museum. Niles Eldredge famous evolutionary biologist and curator of paleontology at the museum wasn't there either. I wonder why?
Add the American Museum of Natural History to the list of accommodationists. There was no compelling reason to interrupt an otherwise excellent scientific display with a sop to religion.
Britich Columbia Rejects Electoral Reform
In yesterday's election the people of British Columbia were asked to choose between the old first-past-the post electoral system and a new single transferable vote system. The referendum question was ...Which electoral system should British Columbia use to elect members to the provincial Legislative Assembly? The existing electoral system (First-Past-the-Post) or the single transferable vote electoral system (BC-STV) proposed by the Citizen's Assembly on Electoral Reform.Up until the beginning of May, it was widely anticipated that more than 60% would vote for STV, thus ensuring that a fair electoral system would become law in British Columbia.
The actual result was a disaster for electoral reform. Only 39% of the voters favored STV while 61% voted to retain the old unfair first-past-the-post system [Elections BC].
This is a major defeat. It will make it much more difficult to get electoral reform passed in Ontario or any other province. As usual, North Americans are much more conservative than the civilized world.
Is Acupuncture Better than Toothpicks?
Orac is at it again. He describes a pretty good study of the possible effects of acupuncture on lower back pain [Another acupuncture study misinterpreted]. The study showed that patients who got a sham procedure using toothpicks instead of needles reported the same "cure" as those who got two different versions of acupuncture. In other words, acupuncture doesn't work. The scientific evidence is conclusive. Acupuncture is associated with a potent placebo effect but that's all. Patients can't tell the difference between needles and toothpicks. As long as they think they're getting the full-blown acupuncture treatment they'll report an improvement in lower back pain.
Here's the description of the toothpick technique that "cures" back pain.
Simulated acupuncture. We developed a simulated acupuncture technique using a toothpick in a needle guide tube, which was found to be a credible acupuncture treatment by acupuncture-naïve patients with back pain.Simulating insertion involved holding the skin taut around each acupuncture point and placing a standard acupuncture needle guide tube containing a toothpick against the skin. The acupuncturist tapped the toothpick gently, twisting it slightly to simulate an acupuncture needle grabbing the skin, and then quickly withdrew the toothpick and guide tube while keeping his or her fingers against the skin for a few additional seconds to imitate the process of inserting the needle to the proper depth. All acupuncture points were stimulated with toothpicks at 10 minutes (ie, the acupuncturist touched each acupuncture point with the tip of a toothpick without the guide tube and rotated the toothpick clockwise and then counterclockwise less than 30°) and again at 20 minutes just before they were "removed." To simulate withdrawal of the needle, the acupuncturist tightly stretched the skin around each acupuncture point, pressed a cotton ball firmly on the stretched skin, then momentarily touched the skin with a toothpick (without the guide tube) and quickly pulled the toothpick away using the same hand movements as in regular needle withdrawal. The acupuncturists simulated insertion and removal of needles at the 8 acupuncture points used in the standardized treatment.Just about anyone could be trained to do this. Think of how much unnecessary back pain could be eliminated if spouses and friends would just poke each other with toothpicks!
I think I'll ask Ms. Sandwalk to try it next time my back hurts.
Monday's Molecule #121: Winner
UPDATE:The image is a 2D Nuclear magnetic resonance spectrum of cane sugar from the Nobel website. This kid of image can only be produced by mathematically transforming the primary data to create a multidimensional representation. Richard Ernst discovered the Fourier transform method that led to solving three dimensional structures by NMR. He won a Nobel Prize in 1991.
This week's winner is Michael Clarkson of Waltham MA (USA). The dominance of Canadians is coming to an end.
This is a true representation of the structure of a biological molecule but I don't expect you you to guess the molecule. Instead, you have to explain what this image is depicting and how it relates to a Nobel Laureate. There is one Nobel Laureate who is most closely identified with this particular type of image. You have to identify the Nobel Laureate and what the prize was for. Be careful, because I'm looking for the pioneer in this field and not for other Nobel Prize winners who may have come later. Be sure to check the list of previous Nobel Laureates on Sandwalk.
The first person to identify the molecule and the Nobel Laureate wins a free lunch at the Faculty Club. Previous winners are ineligible for one month from the time they first won the prize.
There are seven ineligible candidates for this week's reward: Maria Altshuler of the University of Toronto, Mike Fraser of Toronto, Alex Ling of the University of Toronto, Laura Gerth of the University of Notre Dame, Stefan Tarnawsky of the University of Toronto, Dima Klenchin of the University of Wisconsin, Madison and Adam Santoro of the University of Toronto.
The Canadians are still ahead in the competition between Canadians the rest of the world but Dima and Laura are at least keeping it from being a total rout.
I still have one extra free lunch donated by a previous winner to a deserving undergraduate so I'm going to continue to award an additional free lunch to the first undergraduate student who can accept it. Please indicate in your email message whether you are an undergraduate and whether you can make it for lunch.
THEME:
Nobel Laureates
Send your guess to Sandwalk (sandwalk (at) bioinfo.med.utoronto.ca) and I'll pick the first email message that correctly identifies the molecule and names the Nobel Laureate(s). Note that I'm not going to repeat Nobel Prizes so you might want to check the list of previous Sandwalk postings by clicking on the link in the theme box.
Correct responses will be posted tomorrow.
Tuesday, May 12, 2009
Monday's Molecule #121
This is a true representation of the structure of a biological molecule but I don't expect you you to guess the molecule. Instead, you have to explain what this image is depicting and how it relates to a Nobel Laureate. There is one Nobel Laureate who is most closely identified with this particular type of image. You have to identify the Nobel Laureate and what the prize was for. Be careful, because I'm looking for the pioneer in this field and not for other Nobel Prize winners who may have come later. Be sure to check the list of previous Nobel Laureates on Sandwalk.
The first person to identify the molecule and the Nobel Laureate wins a free lunch at the Faculty Club. Previous winners are ineligible for one month from the time they first won the prize.
There are seven ineligible candidates for this week's reward: Maria Altshuler of the University of Toronto, Mike Fraser of Toronto, Alex Ling of the University of Toronto, Laura Gerth of the University of Notre Dame, Stefan Tarnawsky of the University of Toronto, Dima Klenchin of the University of Wisconsin, Madison and Adam Santoro of the University of Toronto.
The Canadians are still ahead in the competition between Canadians the rest of the world but Dima and Laura are at least keeping it from being a total rout.
I still have one extra free lunch donated by a previous winner to a deserving undergraduate so I'm going to continue to award an additional free lunch to the first undergraduate student who can accept it. Please indicate in your email message whether you are an undergraduate and whether you can make it for lunch.
THEME:
Nobel Laureates
Send your guess to Sandwalk (sandwalk (at) bioinfo.med.utoronto.ca) and I'll pick the first email message that correctly identifies the molecule and names the Nobel Laureate(s). Note that I'm not going to repeat Nobel Prizes so you might want to check the list of previous Sandwalk postings by clicking on the link in the theme box.
Correct responses will be posted tomorrow.
Comments will be blocked for 24 hours.
E.O. Wilson in New York
It was Saturday morning and I was in the offices of the New York Academy of Sciences on the 40th floor of 7 World Trade Center. The view to the East was spectacular. We could see the Brooklyn bridge and the 59th Street bridge with Brooklyn and Queen's in the background.
I love cities, I love the tall buildings and the hustle and bustle of the street life.
E.O. Wilson was about to kick off the opening session of The Two Cultures in the 21st Century. I had never heard him in person so I grabbed a good seat and settled down.
Most of his talk was about imaging the brain, behaviorial psychology, and evolutionary psychology. His main point was that scientists are learning a lot about how the brain works and this brings together the humanities and science. E.O. Wilson favors consilience.
Let me give you one example from his talk to illustrate the concept. Wilson talked about a study that was done to determine the ideal environment for humans. People were asked to identify their favorite scenes and the results were used to derive a composite view of what the ideal human environment would look like.
Wilson illustrated it with a slide taken from the third or fourth floor of the John Deere headquarters in Illinois. The view showed extensive grasslands with some water in the foreground. The trees had large branches that were almost parallel to the ground. Massive abstract sculptures evoked an image of large animals.
According to Wilson, this idealized environment is an ancient memory of the environment where we evolved. Our ancestors lived in caves on a cliff side overlooking a savanna full of large animals. The trees of the savanna have branches that are almost parallel to the ground. We like to have water nearby. This is why the typical modern human prefers that type of environment. Science and beauty come together.
Here's how Wilson describes it in The Creation: An Appeal to Save Life on Earth pp. 66-67.
…Researchers have found that when people of different cultures, including those of North America, Europe, Asia and Africa, are given freedom to select the setting of their homes and work places, they prefer an environment that combines three features. They wish to live on a height looking down and out, to scan a parkland with scattered trees and copses spread before them, closer in appearance to a savanna than either a grassland or a closed forest, and to be near a body of water, such as a lake, river, or sea. Even if all these elements are purely aesthetic and not functional, as in vacation homes, people who have the means will pay a very high price to obtain them.
There is more. Subjects in choice tests prefer their habitation to be a retreat, with a wall, cliff, or something else solid to the rear. They want a view of fruitful terrain in front of the retreat. They like large animals scattered thereabout, either wild or domestic. Finally, they favour trees with low horizontal branches and divided leaves. It is probably not a coincidence that some people, I among them, consider the Japanese Maple the world’s most beautiful tree.
These quirks of human nature do not prove but are at least consistent with the savanna hypothesis of human evolution. Supported by considerable evidence from fossil record, this interpretation holds that human beings today still choose the habitats resembling those in which our species evolved in Africa during millions of years of prehistory.
I realized then and there that I was a strange sort of human. My love of cities must be some kind of aberration. I also realized in an instant that all of my mother's ancestors from the past 2000 years must have been desperately unhappy. They all come from Northern Europe where they lived in clusters of small farms in rolling hills covered in dense forest. The only thing they had going for them was the presence of large animals in the barns. How sad.
[Photo Credit: ©John Deere (John Deere Attractions)]
The Human Genome Sequence Is not Complete
The latest version of the human genome sequence is called Build 36 or GRCh37. Here's an overview from the Genome Reference Consortium.
The large red triangles represent regions where there is a lot of variability so that no single representation of the genome sequence will describe a majority of humans.
The black regions represent parts of the chromosomes that have not been sequenced and assembled into long stretches (contigs) of reliable sequence. Most of the unsequenced regions are at centromeres, or telomeres, or on the Y chromosome. These regions consist of thousands of copies of highly repetitive DNA. It is impossible to assemble these repetitive sequences.
Scientists are urging that more attention be focused on completing the chimpanzee and macaque genome sequences. We have been waiting a long time for the draft sequences of those genomes to be finished. The explosion of data on the human genome can only be realistically evaluated by comparing it to our closest relatives. (For example, are human non-coding RNAs conserved in primates?)
The fact that the human genome is not complete is not a problem. We know what's in the repetitive sequence regions even though we don't know exactly how it is arranged. The effort required to finish of the last bit is probably not as important as getting a final draft of other sequences.
Sandra Porter wonders Why don't we finish the human genome first?.
Jason Rosenhouse Doesn't Understand Pluralists
Jason Rosenhouse has posted some comments on a recent book review by Richard Lewontin. In that book review, Lewontin—who along with Gould is the co-author of the spandrels paper—questions the emphasis on natural selection and the use pf "Darwinism" as a synonym for evolution. Read Lewontin on Darwin to see what Jason thinks of the book review.
I want to focus on a specific question that Jason Rosenhouse asks.
I've never really understood what it is exactly that anti-selectionists are complaining about. If they agree that complex adapations arise as the result of gradual accretion mediated by natural selection, then I fail to see how they are really so different from people like Richard Dawkins or Daniel Dennett (two people often described as being beknighted uber-selectionists). If they do not agree then I would like to hear their proposed alternative mechanism.The original paper by Gould and Lewontin, The Spandrels of San Marco and the Panglossian Paradigm: A Critique of the Adaptationist Programme, explains the problem very well. The authors begin their criticism with ...
We wish to question a deeply engrained habit of thinking among students of evolution. We call it the adaptationist programme, or the Panglossian paradigm. It is rooted in a notion popularized by A.R. Wallace and A. Weismann, (but not, as we shall see, by Darwin) toward the end of the nineteenth century: the near omnipotence of natural selection in forging organic design and fashioning the best among possible worlds. This programme regards natural selection as so powerful and the constraints upon it so few that direct production of adaptation through its operation becomes the primary cause of nearly all organic form, function, and behavior. Constraints upon the pervasive power of natural selection are recognized of course (phyletic inertia primarily among them, although immediate architectural constraints, as discussed in the last section, are rarely acknowledged). But they are usually dismissed as unimportant or else, and more frustratingly, simply acknowledged and then not taken to heart and invoked.The anti-selectionists—I am one—do not question the fact that adaptations are produced by natural selection. What we question is whether everything in evolution is an adaptation. We question those who think that "evolution" and "natural selection" are synonyms. And since "Darwinism" is equivalent to evolution by natural selection we question whether evolution is the same as Darwinism.
We pluralists like to point out that much of evolution is due to random genetic drift. Since Darwin's name is not associated with the theory of evolution by random genetic drift, it is inappropriate to say that all of evolution is Darwinist.
It's not that complicated. It was all explained in the classic spandrels paper published 30 years ago. Complex biological structures may be due entirely to adaptation, or they may be mostly an accident that's arisen by random genetic drift, or they may be due to combinations of drift and selection.
Friday, May 08, 2009
What do protein crystallographers dream of?
"What do protein crystallographers dream of?" is the question asked by Ananyo Bhattacharya in an article published in Nature [Protein structures: Structures of desire]. The structures of many protein complexes have been determined but crystallographers have a list of holy grails that, so far, have eluded them. It's an interesting list and one that I mostly agree with. Can you identify the structure shown here in cartoon form?
One glaring omission is pyruvate dehydrogenase. Lot's of people want to see that structure. Other notable omissions include complex I of the membrane-associated electron transport chain and the protein import complex of the endoplasmic reticulum. Don't protein crystallographers dream of those?
The Biology Textbooks Are Wrong?
The other day I suggested that Casey Luskin was probably just ignorant. Unlike other creationists, he problably isn't a liar. Today I'm not so sure.
What is it with FOX news?
Subscribe to:
Posts
(
Atom
)