Tuesday, November 11, 2008

The DNA Network

The DNA Network

Quotes of interest -- Alu again. [Genomicron]

Posted: 11 Nov 2008 08:39 PM CST

I discussed the early papers involving the discovery of Alu elements in a previous post in the series. Unlike some transposable elements that are capable of autonomous transposition, Alu elements do not encode the requisite enzymes and depend on those of other sequences such as LINE-1 elements. Alu is restricted to primates, and its origin seems to have been a duplication and reverse transcription of a 7SL RNA gene early in primate evolution. One in ten nucleotides in each human genome is part of an Alu sequence, of which there are more than 1 million copies.

The elucidation of the evolutionary origins of Alu elements came some time after their initial discovery in 1979. Initially, it was thought that the 7SL RNA gene was derived from Alu, but the reverse conclusion was given by Ullu and Tschudi (1984) and was discussed further by authors such as Quentin (1992). As noted, the original papers reporting the existence of Alu elements raised the question about their potential functions. However, the later articles arrived right in the middle of the supposed time when non-coding DNA was dismissed as irrelevant. Once again, the actual literature from the period does not support the notion that such a dismissal ever actually occurred.

Ullu and Tschudi (1984) did not discuss possible function explicitly, but they did note that "these 7SL-specific homologies may reflect a strong functional constraint acting on these sequences." In an accompanying article in the same issue of Nature, Brown (1984) was more specific about the significance of the results. He stated,
Ullu and Tschudi suggest that Alu sequences represent defective 7SL RNA molecules that have been reverse-transcribed into DNA and inserted into the genome. An analogous origin has been suggested for alpha-globin pseudogenes in the mouse, and the multiple pseudogenes for small nuclear RNAs in man. Pseudogenes are generally thought not to play an important role in the cell. Perhaps those who have argued that Alu, by its very abundance, must have an important function will recognize that this argument has now lost some of its weight.
Two important things are expressed here. One, the assumption that Alu elements are functional because they are abundant (i.e., an adaptationist expectation that they would have been removed otherwise) was apparently common in the early 1980s. Indeed, that's why the "selfish DNA" idea was proposed (Orgel and Crick 1980; Doolittle and Sapienza 1980). Two, pseudogenes -- defunct coding genes -- were indeed thought to be non-functional, for obvious reasons. These are the sequences to which the term "junk DNA" originally related.

Additional information regarding the origin of Alu sequences was provided by Quentin (1992), who said,
from the beginning, the Alu progenitor sequences could have retained the capacity to interact with cellular components, suggesting that they are functionally important for the host genome. On the other hand, this RNA secondary structure could have some affinity for reverse transcriptases or other components of the retroposition machinery, and its conservation in the monomeric and Alu dimeric sequences could be related to their mobility. Indeed, this structure is first found in the 7SL RNA sequences that are prone to retroposition, and it is also retained by the progenitor sequences of the Bl family in the rodent genomes. Nevertheless, both hypotheses (secondary structure involved in a cellular function or in the reverse transcription) are not mutually exclusive.
Yet, here is a fairly typical introduction from a recent paper about Alu (Hasler and Strub 2006):
Alu elements, as well as other repetitive elements, were at the origin considered as parasites of the genome that had no major effect on its stability and genic expression. They were thought to be 'selfish' or 'junk'DNA (6,7), but nowadays, several lines of evidence show that the presence of repetitive elements and especially of Alu elements, had a great influence on the human genome, in particular on its evolution. These effects were both negative and positive. On one hand, integration into genic regions that caused gene inactivation might often have been deleterious for the organism. On the other hand, because of their extended sequence homology, Alu elements induced a considerable number of non-allelic recombinations that lead to both duplications and deletions of DNA segments, thereby accelerating evolution by several orders of magnitude. Another function frequently attributed to Alu elements is their ability to provide new regulatory elements to neighboring genes. It was, indeed, reported several times that Alu elements became effectors of gene transcription by providing new enhancers, promoters and polyadenylation signals to many genes.


The only authors cited for the "Alu is just junk" are Orgel and Crick (1980) and Orgel et al. (1980). I have discussed these articles before, but will reiterate one statement from each.

Orgel and Crick (1980):

It would be surprising if the host genome did not occasionally find some use for particular selfish DNA sequences, especially if there were many different sequences widely distributed over the chromosomes. One obvious use ... would be for control purposes at one level or another.

Orgel et al. (1980):

In our recent experience most people will agree, after discussion, that ignorant DNA, parasitic DNA, symbiotic DNA (that is, parasitic DNA which has become useful to the organism) and 'dead' DNA of one sort or another are all likely to be present in the chromosomes of higher organisms. Where people differ is in their estimates of the relative amounts. We feel that this can only be decided by experiment.
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Part of the Quotes of interest series.
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References

Brown, A.L. 1984. On the origin of the Alu family of repeated sequences. Nature 312: 106.

Hasler, J. and K. Strub. 2006. Alu elements as regulators of gene expression. Nucl. Acids Res. 34: 5491-5497.

Orgel, L.E. and F.H.C. Crick. 1980. Selfish DNA: the ultimate parasite. Nature 284: 604-607.

Orgel, L.E., F.H.C. Crick, and C. Sapienza. 1980. Selfish DNA. Nature 288: 645-646.

Quentin, Y. 1992. Origin of the Alu family: a family of Alu-like monomers gave birth to the left and right arms of the Alu elements. Nucl. Acids Res. 20: 3397-3401.

Ullu, E. and C. Tschudi. 1984. Alu sequences are processed 7SL RNA genes. Nature 312: 171-172.

Genetically Engineered HTC Touch Diamond Phone [Eye on DNA]

Posted: 11 Nov 2008 08:09 PM CST

Fantastic! A phone “genetically engineered for your thumbs.” I’d like one genetically engineered for my brain, please. :D

htc genetic engineering

Blogging from Bangladesh, Part 1 [Tomorrow's Table]

Posted: 11 Nov 2008 07:23 PM CST



This is the first in a series of 7 posts from Bangladesh and India. Photos will be added soon.

Saturday, 01 November 2008

Bangladesh is a land of rivers. I can see that from my airplane window as we flying into Dhaka. The waters flow into the Bay of Bengal, along seemingly orderly channels. The riverbanks and small low-lying islands are planted to rice.
Upon landing our group (scientists, breeders, writers and photographers) make our way through the crowded parking lot to find our limousine. The cars line up bumper to bumper; the drivers blowing their horns every few seconds to encourage the beggars, mostly young barefooted boys, to move aside. One boy sleeps soundly on the pavement.
One hundred and fifty million people live in Bangladesh, in a geographic area the size of Wisconsin.

After checking into hotel Laurel (certainly nothing like the Mayflower hotel in Washington DC where my husband I stayed last week), we squeeze back into the vehicles and drive to our first meeting at Dhaka University.

Built in 1921 by the British, Dhaka University is the main research and teaching center in the country. The edges of the dirty, worn stairs are hand painted with colorful flowers. I wonder if enthusiastic students did the work on a day where they had some spare time, perhaps during a power outage that are frequent here.

Our host, and the leader of the laboratory, Zeba I. Seraj, introduces us to her 10 students who have waited until late in the day (our plane was delayed for 2 hours) to meet us. We walk through the hallways where the AC whirrs loudly in an attempt to cool the building. Because the outside air moves in through gaps in the wall, it is still hot.



The room where we meet the students is beautiful; every foot of wall is covered with 100-year old wooden cabinets filled with biology books and journals. I imagine that this room is filled with young hardworking students during the day anxious to learn what is before them and perhaps relieved to escape the hot ill-equipped labs for a short while.

Zeba tells us that salinity is a problem for rice farmers here. Not only is the sea water rising, but fresh water supplies are under pressure, not only because farmers are pumping more every year but because Bangladesh is downstream from India, who gets first dibs on the fresh water through a network of dams. The result is that every year the saline lands encroach north, hurting rice yields, a serious problem here where the average Bengali receives 2/3 of their diet from rice. And then there are floods that arrive unpredictably, sometimes wiping out the entire crop.



Zeba and her students are working to develop salt tolerant rice. They have had success in identifying a chromosomal regions from local landraces that confer salt tolerance to the rice. They are now trying to introduce those regions into higher-yielding varieties. They have also had some success with a genetic engineering approach. She shows us a dramatic picture of their newly developed transgenic lines thriving under high salt concentrations that kill the conventional variety. Zeba's group is now testing to see how the transgenic lines yield under normal growing conditions.

Blogging from Bangladesh, Part 2 [Tomorrow's Table]

Posted: 11 Nov 2008 07:22 PM CST





Sunday, November 2

This is the second post in a series describing my trip to Bangladesh and India. For part 1 please see this post.









Our first morning in Bangladesh, we wake to the morning prayer (Bangladesh is largely a Muslim country) and the sound of birds. After breakfast, we drive 7 hours to visit the Bangladesh Rice Research Institute in Rangpur where breeders are field testing four newly developed rice varieties carrying the Submergence tolerance 1 chromosomal region.

Before I get to the results of the field trials, let me first explain why we are here and who we are. I am part of a collaborative group of scientists who developed new rice varieties for Bangladesh and India that can survive flash floods

My contribution to this work began 13 years ago when my colleague and friend Dave Mackill a breeder at IRRI (International Rice Research Institute (IRRI, Philippines) asked if I would clone a gene from a traditional variety found in the Eastern Indian state of Orissa that can survive 2 weeks of submergence. Although rice is typically cultivated in a paddy with the root system flooded, complete submergence of the plant is lethal to most varieties within a matter of days.








Using the rice populations that Dave and his group developed from the submergence tolerant variety, Postdoc Kenong Xu in my lab isolated the submergence tolerance (Sub1) locus, cloned it, sequenced it and identified an ethylene responsive transcription factor called Sub1a that is induced in response to flooding. My laboratory genetically engineering a rice variety with Sub1a and found that the transgenic plants survive 2 weeks underwater. Normally, 3 days of submergence is enough kill any rice variety.

Julia Bailey Serres (Professor, UC Riverside) joined our project in 2001 and has begun to elucidate the molecular mechanisms of action of this gene. Using the sequences we identified, Dave's group used marker assisted breeding (a hybrid of genetic engineering and conventional breeding) to introduce Sub1 into rice varieties that are adapted to the local growing conditions in India and Bangladesh.



This work was initially supported by s NRI Plant Genome Program (1996-1999; Grant 96-35300-3723) to Mackill (PI) and Ronald (coPI) and then by a second NRI Plant Genome Program (2000-2003; Grant 00-35300-3723) to Ronald (PI) and Mackill (coPI). The recent grants from the USDA environmental stress group were awarded to Julia Bailey Serres (PI) and Pam Ronald (collaborator) from 2004-2008.

We are also joined on this trip by scientists, breeders and communication staff from the IRRI, The Bangladesh Rice Research Institute (BRRI) and the Central Rice Research Institute (India). Our traveling team numbers nearly 30 people. This visit wraps up an IRRI project, funded by the German government (BMZ) "From genes to Farmers fields: enhancing and stabilizing productivity of rice in submergence-prone environments".

As biologists who research the nitty gritty of how plants endure the stress of attack from pathogens and sub-optimal growth conditions, Julia and I look forward to seeing firsthand the needs of the people of Bangladesh and hearing how the efforts of researchers at BRRI and IRRI have dramatically increased the amount of rice produced per acre each year.

The results are dramatic-in every genetic background (IR64, Swarna, BR11 and Samba Mashuri) tested, the Sub1 line yielded 2-3 fold more when the field is flooded. The yields were similar in non-flooded conditions. Tomorrow we will visit farmers fields to see how the rice plants behave in the farmers hands.

Weird Fishes and the Origin of Fingers [A Free Man » Science]

Posted: 11 Nov 2008 04:11 PM CST

Getting in the middle of a scientific controversy is more dangerous than you might think. I have fond memories of a conference at which, under the influence of the product of yeast anaerobic sugar metabolim, I watched two well known professors very nearly come to blows over a question regarding the role of chromatin in gene expression. When you throw in a group of pseudo-scientific know nothings, that debate becomes both fiercer and more absurd. Such is the “controversy” around macroevolution - evolution at the species level - it regrettably melds science, religion and politics in a sort of perfect storm of dispute.

Catherine Boisvert knows a little bit about this particular scientific controversy. The Canadian graduate student (studying at Uppsala in Sweden) found herself in the midst of an ridiculous debate when some creationists took, completely out of context, a couple of quotes that she gave in an interview with The Scientist and loudly and ignorantly claimed that they supported their position.

In reality, Boisvert’s recent Nature paper offers irrefutable evidence supporting macroevolution. Boisvert and her colleagues at Uppsala used MicroCT scanning to shed light on an age old evolutionary question: whether digits (fingers and toes) are an evolutionary novelty to tetrapods (four limbed critters like us) or were present in some form in the last common ancestor of tetrapods and our fishy kin.

Recently, Boisvert was kind enough to take a seat on A Free Man’s virtual couch for a chat about evolution, fish and creationism. In a nod to my audience’s diversity, I’ve tried to start the interview out with more general topics and to move into the hard science as we move on.

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AFM: My readers run the gamut from working scientists to lay persons. Can you clearly and concisely explain to the latter class why they should pay attention to your research?

CB: Anybody interested in their origins and how they evolved would be interested in knowing where their fingers come from. The origin of finger precursors in fish is fascinating given the fact that it allowed fish to transform into land animals and later exploit all ecological niches, from land, trees, air and even returning to the seas! The success of land vertebrates is closely tied to the evolution of limbs and fingers and I certainly would not be able to type this, or play violin for that matter, without them!

AFM: I'm interested in Panderichthys as a species. Where would it have fit in the food chain of the late middle Devonian? What kind of species roamed the sea with Panderichthys? What did it eat? What ate it? Paint a picture of Panderichthys' neighbourhood.

CB: Panderichthys was a medium to large predator (1 - 1.5 m in length) living in shallow waters in deltaic systems (so probably a mix of salt and fresh water). It ate other fish, so you could say it was at the top of the food chain and I doubt that it had many, if any predators. At the time, the seas (in terms of vertebrate life) were dominated by lobe-finned fish such as Eusthenopteron and Panderichthys, placoderms (armoured jawed fish) as well as acanthodians. Sharks were beginning their radiation and so were ray-finned fish, which were still relatively rare and very small in the Devonian. There were of course an abundance of invertebrates at the time and insects were beginning their foray onto land, only preceded by plants.

AFM: It's been proposed that the driving pressure to diversify limbs came from demands of feeding and locomotion in the Ordovician and Silurian seas (Shubin, et al. 1997). Do you agree with this assessment? What were the challenges faced by paleozoic fish?

CB: It is obvious that feeding and locomotion are main drivers of evolution since they are so closely related to survival. What Shubin and co-authors refer to in their 1997 article pertains to the diversity of fin forms observed in vertebrates in the Ordovician and Silurian seas and how much "experimentation" there was. As agnathans (jawless vertebrates) are being outcompeted by gnathostomes (jawed vertebrates) in the Silurian, the body plan of vertebrates stabilizes at two sets of paired fins (pectoral and pelvic) (the body plans of gnathostomes). The challenges of moving to feed and of moving to avoid predators are no different in gnathostomes than they were in agnathans and are therefore some of the challenges faced by Paleozoic fish.

AFM: Your paper has pretty much put the nail in the coffin of the hypothesis that gained some credence in the 1990's that fingers and toes are an evolutionary novelty. What was that hypothesis based on? And for those who haven't read your paper, can you briefly outline how your finding rejects that hypothesis.

CB: The hypothesis was based on the comparison of developmental data from Zebrafish and mice. Zebrafish lack the second phase of expression of the gene Hoxd13 which is responsible for the formation of digits in mice. This led Denis Duboule's team to hypothesize that digits were novelty in tetrapods (four footed vertebrates like amphibians, reptiles, birds and mammals). This was supported at the time by the fact that the pectoral fins of the fossil fish Panderichthys, then the closest fish to tetrapods, had been described as being composed of large plates at the end of the fin. This pointed to the fact that this fossil did not have any elements that could be identified as precursors of fingers. Our new analysis of Panderichthys performed by CT-scan showed that this was an artefact of preparation. Panderichthys has small elements at the end of its pectoral fins that we interpret as fingers precursors.

AFM: Macroevolution isn't my strong suit and as a geneticist I'm often swayed by developmental genetic data. Is there any molecular work that has been done that supports your hypothesis?

CB: Indeed, there is. It is in combination with new fossil data (from Tiktaalik and Gogonasus for example) as well as developmental genetic data from skarks, the basal actinopterygian (ray finned fish such as zebrafish and salmon), Polyodon (paddlefish, a close relative of the sturgeon) and the sarcopterygian (lobe finned fish who gave rise to all amphibians, reptiles, birds and mammals) Neoceratodus (the Australian lungfish) that we are able to confidently homologize the distal radials to fingers. Several studies have been conducted in the past few years about the expression of Hoxd13 in those species and, in all of them, a second, late phase of expression is present. Zebrafish, being a derived ray finned fish, has a very reduced fin. It lacks the metapterygium, from which the entire fin of lobe finned fish is derived. It is therefore understandable that by loosing this part of the fin, genetic expression associated with it would be lost as well. Sharks and paddlefish have a more primitive fin retaining all parts and therefore show Hoxd13 expression in their fins where the metapterygium develops. In the Australian lungfish as well as all tetrapods, only the metapterygium is retained and the late phase of Hoxd13 is expressed where distal radials, or in the case of tetrapods, fingers, develop.

AFM: As you're no doubt aware, creationism in the mantle of "Intelligent Design" is creeping back into schools in the U.S., Britain and many other parts of the world. What could a secondary school teacher take from your research into their classroom to serve as a counterpoint to the pseudo-science of ID?

Our work shows how similar the fins of Panderichthys are to that of Tiktaalik, Eusthenopteron and the arms of Acanthostega while being slightly different. These similarities and how they differ can only be explained by shared ancestry and evolution. Paleontologists have hypothesised a long time ago that Panderichthys was more closely related to tetrapods than Eusthenopteron was and by examining the fossil and finding that its fins are intermediate in morphology between Eusthenopteron and Acanthostega for example, it proves the predictive nature of evolution.

AFM: The creationist Discovery Institute has pounced on some of the statements in your paper regarding sample quality as evidence that scientists are trying to backpedal on previous hypotheses regarding digit development and evolution. Can you clarify your statements regarding sample quality of Tiktaalik and Panderichthys?

CB: As you know, the "Discovery" Institute tactic is not to go to the primary literature in order to understand it but rather to use quotations from secondary, even tertiary sources, reorganise or use them out of context opportunistically to their own convenience. In this case, they used an article where the journalists unfortunately misunderstood me. Tiktaalik's material is in fact exquisite, it is very well preserved, basically uncrushed and can be prepared out to be examined in three dimensions. I never said the quality was poor. I have simply explained that the morphology of the fin of Panderichthys is more tetrapod-like than that of Tiktaalik, which has nothing to do with the quality of the material.

AFM: Specifically regarding the sample quality of Panderichthys, how does CT scanning permit the type of analysis that you presented in the Nature paper?

CB: The material of Panderichthys is of high quality but it is material that is extremely difficult to prepare and manipulate because it is so fragile and preserved in clay. Previous analyses of the fin was based on prepared material but when I visited the institution in Moscow where the specimens were housed, I noticed that it was incompletely prepared, producing the results published in the 1990's. It is almost impossible to prepare this material without destroying the underlying fin endoskeleton and I do not think many palaeontologists would have dared preparing this precious specimen. Our analysis was based on the CT-scanning of another specimen, housed in Estonia. This technique permitted us to visualise the endoskeleton, the scale covering as well as the shoulder girdle without destroying anything. We then produced three-dimensional models that can be rotated and manipulated to understand the morphology.

AFM: What's next for you? I see that you've joined us Down Under. What have you got going on in Australia?

CB: I was indeed in Australia when you joined me. I was continuing developmental studies on the Australian lungfish, provided by Jean Joss' laboratory at Macquarie University. I am interested in understanding how the pelvic girdle transformed during the fish tetrapod transition and, in addition to my fossil work, I am studying the development of that structure in the Australian lungfish and salamanders. I will be finishing my PhD soon, here in Sweden and will return to Australia for a post-doc in developmental genetics.

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Man, they don’t mess around in Uppsala. Catherine has two first author Nature papers to her name and is still working toward her Ph.D.! Thanks to Catherine for taking a time out from a clearly strenuous Ph.D. project to talk about her work today.

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Image Credits:

One Small Step

Devonian sea

Fins to fingers

Catherine Boisvert

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Radiohead helped to break the Big 4’s iron grip on musical sales last year by making their new album, “In Rainbows” on the net as a “pay what you will” release. It was a risky experiment, but one that worked out well, netting the band about $9 million (USD). This figures dwarfs the sales of their previous studio records and hopefully will encourage more artists to cut out the middle man. “In Rainbows” is the band’s best record since “Kid A” and if you like this track, support blogger-friendly artists by buying the whole record.

This posting includes an audio/video/photo media file: Download Now

Why Is Healthcare So Expensive? [ScienceRoll]

Posted: 11 Nov 2008 02:30 PM CST


You definitely know the video series of Commoncraft (… in plain English). Now here is a new piece about the healthcare system.

      

Dr. Baird on Judge David Young [DNA Testing Blog]

Posted: 11 Nov 2008 12:45 PM CST

Dr. Michael Baird, DDC’s laboratory director, appears in several episodes of the Judge David Young Show this season. DDC has performed DNA testing for the show since 2007, but this is the first year that they have arranged for Dr. Baird to deliver the test results over streaming video into the courtroom.

100 years of genetic research and science journalists are still confused [The Daily Transcript]

Posted: 11 Nov 2008 10:57 AM CST

If you missed it, today's NY Times Science section has been dedicated to "The Gene" a concept invented 99 years ago by Wilhelm Johanssen.

Overall, the articles were very good, however as a scientist who wants to explain basic concepts of molecular biology to the masses, I have a few problems.

First, there is a misplacement of emphasis on how information flows from DNA to phenotype. The idea that the articles try to convey is that in the old model went along theses lines: DNA contains genes, each is copied into RNAs that are then translated into a certain type of protein ... and then presto the end result is a fully formed organism. Now apparently the new model is that the DNA encodes more than genes, it has all sorts of weird stuff mostly noncoding-RNAs, and that there is mass confusion in the biomedical sciences. There is also this epigenetics (as in DNA methylation and histone modification) our simple ideas have to be thrown out the window.

To this I say, WOT?

First of all there hasn't been a clear paradigm shift in the biomedical sciences. In fact our view has essentially remained unchanged since the 1970s. DNA encodes three different types of information.

Read the rest of this post... | Read the comments on this post...

Blogging from Bangladesh [Tomorrow's Table]

Posted: 11 Nov 2008 03:23 AM CST

The posts this week will be from Bangladesh and India where I will travel to look at the results of our Sub1- rice varieties in farmers fields.

Top 10 Genomics News from news.thinkgene.com - Week of 3 Nov 08 [Think Gene]

Posted: 10 Nov 2008 10:44 PM CST

Friendfeed and Twitter [Think Gene]

Posted: 10 Nov 2008 10:08 PM CST

Thinkgene is now available on Friendfeed and Twitter. Check us out!

http://friendfeed.com/thinkgene

http://twitter.com/thinkgene

HIV’s disguises no match for ‘bionic assassins’ [Think Gene]

Posted: 10 Nov 2008 10:04 PM CST

Josh: This is a really neat idea. I’m guessing they would take CD8 cells from the patient, modify them, perhaps grow them in culture, and re-introduce them? I don’t think this is really going to be that practical in reality, and would probably be more expensive that taking anti-retrovirals.

HIV is a master of disguise, able to rapidly change its identity and hide undetected in infected cells. But now, in a long-standing collaborative research effort partially-funded by the Wellcome Trust, scientists from Oxford-based Adaptimmune Limited, in partnership with the Universities of Cardiff and Pennsylvania have engineered immune cells to act as “bionic assassins” that see through HIV’s many disguises.

The findings of the study, published online today in the journal Nature Medicine, may have important implications for developing new treatments for HIV and slowing – or even preventing – the onset of AIDS. Over 33 million people were estimated to be living with HIV worldwide in 2007. Although anti-retroviral drugs have been successful in delaying the onset of AIDS for several years, the drugs are expensive, have serious side effects and must be taken for life. No vaccine or cure yet exists and drug resistance is increasingly becoming a problem.

When viruses enter our bodies, they hijack the machinery of host cells in order to replicate and spread infection. When our body’s cells are infected with a virus they expose small parts of the virus on their surface, offering a “molecular fingerprint” called an epitope for killer T-cells from the immune system to identify. This triggers an immune response, eliminating the virus and any cells involved in its production.

As with other viruses, HIV enters the body and replicates itself rapidly. However, it also has the ability to mutate quickly, swiftly disguising its fingerprints to allow it to hide from killer T-cells.

“When the body mounts a new killer T-cell response to HIV, the virus can alter the molecular fingerprint that these cells are searching for in just a few days,” explains Professor Andy Sewell from Cardiff University, co-lead author of the study and long-term collaborator with Adaptimmune. “It’s impossible to track and destroy something that can disguise itself so readily. As soon as we saw over a decade ago how quickly the virus can evade the immune system we knew there would never be a conventional vaccine for HIV.”

Now, Professor Sewell and colleagues from Adaptimmune Ltd and the University of Pennsylvania School of Medicine have engineered and tested a killer T-cell receptor that is able to recognise all of the different disguises that HIV is known to have used to evade detection. The researchers attached this receptor to the killer T-cells to create genetically engineered “bionic assassins” able to destroy HIV-infected cells in culture.

“The T-cell receptor is nature’s way of scanning and removing infected cells – it is uniquely designed for the job but probably fails in HIV because of the tremendous capability of the virus to mutate,” says Dr Bent Jakobsen, co-lead author and Chief Scientific Officer at Adaptimmune Ltd, the company which owns the technology. “Now we have managed to engineer a receptor that is able to detect HIV’s key fingerprints and is able to clear HIV infection in the laboratory. If we can translate those results in the clinic, we could at last have a very powerful therapy on our hands.”

The researchers believe that HIV’s chameleon-like ability may still prevent the virus from being completely flushed out of the body. It could mutate and change its fingerprint further, hiding behind these new disguises and evading detection. However, each time the virus is forced to mutate to avoid detection by killer T-cells, it appears to become less powerful.

“In the face of our engineered assassin cells, the virus will either die or be forced to change its disguises again, weakening itself along the way,” says Professor Sewell. “We’d prefer the first option but I suspect we’ll see the latter. Even if we do only cripple the virus, this will still be a good outcome as it is likely to become a much slower target and be easier to pick off. Forcing the virus to a weaker state would likely reduce its capacity to transmit within the population and may help slow or even prevent the onset of AIDS in individuals.”

Pending regulatory approval, Professor Carl June and Dr James Riley from the University of Pennsylvania in Philadelphia will shortly begin clinical trials using the engineered killer T-cells.

“We hope to begin testing the treatment on patients with advanced HIV infection next year,” says Professor June. “If the therapy in that group proves successful, we will treat patients with early stage well-controlled HIV infection. The goal of these studies is to establish whether the engineered killer T cells are safe, and to identify a range of doses of the cells that can be safely administered.”

“The AIDS virus evades human immunity in all it infects,” says Professor Rodney Phillips, from the University of Oxford, where the collaborative research effort first began in 2003. “Until now no-one has been able to clear the virus naturally. Immune cells modified in the laboratory in this way provide a test as to whether we can enhance the natural response in a useful and safe way to clear infected cells. If successful the technology could be applied to other infectious agents.”

The researchers are now exploring using engineered receptors on killer T-cells as a way of improving immune responses to cancer.

Source: Wellcome Trust

Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor. Angel Varela-Rohena, Peter E Molloy, Steven M Dunn, Yi Li, Megan M Suhoski, Richard G Carroll, Anita Milicic, Tara Mahon, Deborah H Sutton, Bruno Laugel, Ruth Moysey, Brian J Cameron, Annelise Vuidepot, Marco A Purbhoo, David K Cole, Rodney E Phillips, Carl H June, Bent K Jakobsen, Andrew K Sewell & James L Riley. Nature Medicine. 09 November 2008; | doi:10.1038/nm.1779

Jim Watson Wins 'Double Helix Medal For Scientific Research' - Why? [adaptivecomplexity's blog]

Posted: 10 Nov 2008 09:57 PM CST

Craig Venter and James Watson have won this year's Cold Spring Harbor 'Double Helix Medal For Scientific Research'. Venter deserves it, but what's the deal with Watson? He hasn't done much for science research recently except tarnish its image by insulting black people and calling everyone else boring.

Hasn't the guy won enough medals for a career that stalled scientifically decades ago? What's even stranger is that this award is completely incestuous, coming from the lab that Watson directed for years. It's like the Catholic Church giving the Pope an award for community service.

read more

Challenge to Michael Nierenberg, Medical Director of Navigenics [Think Gene]

Posted: 10 Nov 2008 09:15 PM CST

Michael Nierenberg, Medical Director of Navigenics comments on “Absence of "High Penetrance" in SNP Genomic Services” regarding my statement “existing SNP genomic services just aren't that useful.” (comment appended below)

Rather than entertain an “ongoing discussion” about “preferences” and confidence, this debate about Navigenic’s efficacy can be immediately resolved with a simple concrete response to the following challenge:

Dr. Nierenberg, as a physician, what action would you almost certainly prescribe given a Navigenics test result which you would almost certainly not prescribe without that information?

Assume no bound on cost. Please remember that you must also defend why you would almost certainly not prescribe the given action without the genomic information if cost were no issue. For example, any non-invasive screening test would be a bad example because one could reasonably prescribe the test to all cost-insensitive patients without genomic testing.

Additionally, you may respond with an economic argument. As of 2008, state an approximate dollar amount savings for what healthcare spending and by what savings mechanism (e.g. insurance reimbursement, state provider). State as an expected net present value savings per average American greater than the cost of the net present value cost of a Navigenics test ($2500 + $250 each year for life). If you respond with an economic argument, you must respond with a falsifiable savings hypothesis specific enough to be tested by real patients.

Please respond within one month, though sooner would be better considering Navigenics has been for sale to consumers for several months as a cost-insensitive service for improved healthcare efficacy, and I thus hope Navigenics has a long list of excellent responses to this efficacy challenge already prepared.

To be fair, I will meet this challenge immediately for BRCA testing.

Cost-Insensitive Efficacy Challenge: BRCA

Test: BRCA 1&2 genomic test by Myriad
Physician Advocate
: Dr. Barbara Ward, surgical oncologist at Yale-New Haven
Action: prophylactic bilateral mastectomy (the removal of both breasts before evidence of cancer)
Positive Clinical Precedence: Jessica Queller. In fact, she wrote a book about it which she discusses at Helix: Jessica Queller and “Pretty is What Changes” [audio]
Physician Testimonial:

Dr. Barbara Ward: “In terms of managing hereditary [breast cancer], I have to say as surgeon, I believe very much in prophylactic surgery. I look forward to the day that we’ll look back and say ‘can you actually believe that we did mastectomies for [BRCA] gene carriers?’ but at this point in time it is the best that we can offer.” Source at Helix [audio]

Why Action is not prescribed without genomic information: Action is removing a woman’s healthy breasts
Other relevant qualified action: testing for family, oophorectomy, fertility counseling
Cost-insensitive efficacy if administered to entire population: reduced suffering and fatality due to breast and ovarian cancer

I am unable to make an additional economic argument that meets my challenge criteria.

Thank you for your comment, Dr. Nierenberg, and we anticipate your response. I understand you and your team at Navigenics are genomic enthusiasts, but Navigenics markets itself as a genomic test held to a high medical standards of efficacy that other genomic tests are not. I and others simply are yet unconvinced regarding that advertised usefulness. Please help better inform us.

Appendix

Dr. Michael Nierenberg’s original comment [source]:

Mr. Andrew Yates offers the following comment in Absence of “High Penetrance” in SNP Genomic Services about espousing the uselessness of genetic testing by companies such as Navigenics:

“The reality is that except for a few enthusiasts (like anyone in the DNA Network, including myself), existing SNP genomic services just aren’t that useful. It’s not useful to know that one has a 7% lifetime risk rather than a 5%. I need to know risks of about 40% and higher.”

In response to Mr. Andrew Yates I offer the following information about lifetime risk assessments offered by Navigenics (http://www.navigenics.com).

On the Navigenics HealthCompass six conditions have a lifetime risk potential that exceeds 35% (Five conditions exceed 40%). Since some conditions are less common in the population, it is useful to also consider relative risk, as opposed to absolute risk.

Half of all 23 conditions reported have a relative risk (compared to the average genetic risk in the general population) greater than 2; seven conditions, greater than 3; and three conditions greater than 4. For comparison, this level of relative risk is in line with other well-accepted, commonly used risk factors such as positive family history and environmental risk factors (high lipids, age at menopause etc.)

I hope this clarifies things for Mr. Yates who can now feel better about being an enthusiast.

I would also ask Mr. Yates to reconsider his statement about why Navigenics is not doing BRCA testing. Patent considerations aside, it is of import only in about 5% of breast cancer cases (those with “extreme” positive family histories and early age of onset). The contribution of BRCA1/2 mutations in sporadic breast cancers has not been determined conclusively. Our preference is truly to offer a test that is applicable to the majority of individuals. We are cognizant that in a minority of people BRCA testing is important and have addressed this issue on our web site in several places. We realize that no test is complete in and of itself; otherwise people would have heart surgery based only on a treadmill. So, I would ask Mr. Yates to please give us credit for more than trying to get around patent considerations. We are enthusiasts as well.

Nature Network Pub Night with a theme - "what science would be like if unconstrained by reality" [The Daily Transcript]

Posted: 10 Nov 2008 04:43 PM CST

After a hiatus, Nature has relaunch its Pub Nights, but this time there's a twist. Here's the email that I just got from my good fiend Anna Kushnir:

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New concern about plastic containers [The Navigator - Navigenics Blog]

Posted: 10 Nov 2008 04:02 PM CST

Michael Nierenberg, M.D.

imageThere's been much ado lately about bisphenol-A, a chemical used in the packaging of some foods and drinks – and found in the bodies of 93 percent of Americans.

While some scientists insist it is impossible to say that BPA is safe, others say there isn't enough evidence yet to conclude that it's unsafe.

Among the research studies raising eyebrows – and concerns that consumers may be better off avoiding the substance: a large study published in September, the first to link BPA to heart disease and type 2 diabetes in humans.

Researchers found that the 25 percent of the adult population with the highest BPA levels were more than twice as likely to have heart disease or diabetes as the 25 percent with the lowest BPA levels. High BPA levels were also linked to liver enzyme abnormalities.

“Our study has revealed, for the first time, an association between raised BPA loads and two common diseases in adults," said David Melzer, one of the study's authors, in a written statement. "At the moment we can't be absolutely sure that BPA is the direct cause of the extra cases of heart disease and diabetes: if it is, some cases of these serious conditions could be prevented by reducing BPA exposure."

A Good Weekend [The Daily Transcript]

Posted: 10 Nov 2008 03:29 PM CST

This weekend a group of postdocs and grad students got together for a spontaneous celebration.

Yes, the economy is in the tank, job prospects for even us academics are looking worse, but over the past week we've all felt a sense of relief. To quote a cliché that has never felt more true, the nightmare is over. Perhaps now we could once again cherish what makes America so special for all of us. So there we were, Americans, Canadians, Germans, Portuguese, Chinese, and Japanese having a great time. We toasted to Obama and kissed an anti-American administration goodbye. You might be wondering, who are you guys to call Bush, his cronies and the greed-industrial complex anti-American?

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DNA in the Plot [Genome Blog]

Posted: 10 Nov 2008 02:00 PM CST


My Biopunk partner hasn’t written about these ones yet, but on Sunday, I ended up watching a series of movies on TV with DNA in the plot. First up, the B-movie Sumuru. I channel surfed into this one and would have gone right out except the discussion of DNA caught my attention. What I gathered was that these two guys from earth pick a planet full of women to help the human DNA line survive. I think they were suggesting some kind of founder effect into the future. I wondered if in fact they were not suggesting more a Genghis Khan effect. I never found out as before the movie was resolved my doorbell rang and by the time I got back to my TV, Star Trek: Insurrection was on. What!!! Now we have regenerative radiation having a positive effect on the DNA to prevent ageing. Wow!!!

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