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In the News, Science

Luminous mouse brain among photomicrography competition winners

Luminous mouse brain among photomicrography competition winners

Entry26382_Ali_Erturk_mouse-brain

Nikon announced the winners of its annual Small World Photomicrography Competition yesterday, and among the group was this stunning image.

The photo was taken by Ali Ertürk, PhD, a researcher at the Institute for Stroke and Dementia Research at Ludwig Maximillian’s University in Munich, Germany. Ertürk and his colleagues’ research is focused on better understanding the “key mechanisms leading to neurodegeneration after acute brain injury.” This image depicts the mouse brain vasculature.

Via Wired Science
Previously: Video of innate immune reaction in the lymph node, Image of the Week: Osteosarcoma cell and Tiny wonders: Small World in Motion competition winners bring microscopic activity to life
Photo by Ali Erturk/Nikon Small World Photomicrography Competition

Research, Science

Nature tracks 100 most-cited scientific papers

Nature tracks 100 most-cited scientific papers

Bound journals on shelves Flickr Taber Andrew BainAfter a researcher painstakingly collects the data, analyzes it, sweats over the manuscript that describes the findings, and finds a journal to publish it, a study that likely took years to conduct finally appears in public. Other researchers will read it and maybe get ideas for further research, and eventually cite the original article when publishing new findings.

The number of citations a paper receives is a way  – though imperfect – of keeping track of its influence in any given scientific field. And so, Nature recently compiled a list of the most-cited papers of all those cataloged in Thomas Reuters’ Web of Science since 1900. The journal ran some nifty graphs related to the list, including a yearly breakdown of the number of citations for each paper.

The top paper, by biochemist Oliver Lowry, MD, PhD, garnered more than 300,000 citations since its publication in 1951. The last one on the list had just a little more than 12,000 citations. Many famous discoveries such as Watson and Crick’s description of DNA’s double helix aren’t on the list, probably because those revolutionary findings quickly become well-known enough and authors didn’t consider citing the work necessary.

The story includes a mention of the work of a Stanford faculty member:

Number 41 on the list is a description of how to apply statistics to phylogenies. In 1984, evolutionary biologist Joe Felsenstein of the University of Washington in Seattle adapted a statistical tool known as the bootstrap to infer the accuracy of different parts of an evolutionary tree. The bootstrap involves resampling data from a set many times over, then using the variation in the resulting estimates to determine the confidence for individual branches. Although the paper was slow to amass citations, it rapidly grew in popularity in the 1990s and 2000s as molecular biologists recognized the need to attach such intervals to their predictions.

Felsenstein says that the concept of the bootstrap, devised in 1979 by Bradley Efron, a statistician at Stanford University in California, was much more fundamental than his work. But applying the method to a biological problem means it is cited by a much larger pool of researchers. His high citation count is also a consequence of how busy he was at the time, he says: he crammed everything into one paper rather than publishing multiple papers on the topic, which might have diluted the number of citations each one received. “I was unable to go off and write four more papers on the same thing,” he says. “I was too swamped to do that, not too principled.”

The article concludes with a description of some of the highlights in the fields of biological techniques, bioinformatics, phylogenetics, statistics, density fuctional theory and crystallography. It’s a nice look at some seminal findings that you won’t likely find in textbooks.

Previously: The benefits and costs for scientists of communicating with the public, Scientists preferentially cite successful studies, new research shows and A new era in scientific discourse? PubMed gets comments
Photo by Taber Andrew Bain

Cancer, Research, Science, Stanford News, Surgery, Technology

New molecular imaging could improve bladder-cancer detection

New molecular imaging could improve bladder-cancer detection

Joseph LiaoThey say a picture is worth a thousand words. For bladder-cancer surgeons, an image can be worth many lives.

That’s because a crucial method for detecting bladder cancer is to produce images that allow surgeons to identify abnormal-looking tissue, a method called cystoscopy. In a study published yesterday in Science Translational Medicine, Stanford researchers developed a new way to image the bladder that they say could detect bladder cancer with more accuracy and sensitivity than the standard methods. As described in our press release:

 The researchers identified a protein known as CD47 as a molecular imaging target to distinguish bladder cancer from benign tissues. In the future, this technique could improve bladder cancer detection, guide more precise cancer surgery and reduce unnecessary biopsies, therefore increasing cancer patients’ quality of life.

Identifying cancerous tumors can be challenging — some bladder cancer treatments cause inflammation, which looks very similar to abnormal, cancerous tissue. The only way to know for sure is to perform a biopsy, which can be stressful for the patient. As co-senior author Joseph Liao, MD, explained:

 Our motivation is to improve optical diagnosis of bladder cancer that can better differentiate cancer from non-cancer, which is exceedingly challenging at times. Molecular imaging offers the possibility of real-time cancer detection at the molecular level during diagnostic cystoscopy and tumor resection.

For their work, the researchers looked for a target that would distinguish cancer cells from benign cells and found it in CD47, a protein on a cell’s surface that cancer cells produce in higher quantities than normal cells. In previous work, co-senior author Irving Weissman, MD, developed a CD47 antibody that binds to the cancer cell’s surface and blocks the signal. They hypothesized it would be a good imaging target. More from our release:

 To test their hypothesis, the researchers added a fluorescent molecule to an antibody that binds to CD47. The modified antibodies were then introduced into intact bladders, which had been surgically removed from patients with invasive bladder cancer. Because they bladders were kept in good condition, the study’s imaging methods mirrored the way an urologist might use with a real patient.

After 30 minutes, they rinsed the bladder, so only the antibodies that bound to the CD47 protein remained. When they shine the tumor was exposed to with fluorescent light, the cancer cells “lit up” whereas normal or inflamed cells did not.

“Our goal through better imaging is to deliver a higher- quality cancer surgery and better cancer outcomes,” Liao told me. “I am very excited about the potential to translate our findings to the clinics in the near future.”

Previously: Healing hands: My experience being treated for bladder cancer, Drug may prevent bladder cancer progression, say Stanford researchers, Cellular culprit identified for invasive bladder cancer, according to Stanford study and Mathematical technique used to identify bladder cancer marker
Photo of Liao by Norbert von der Groeben

Genetics, Pediatrics, Research, Science, Stanford News

Move over CRISPR, there’s a new editor in town: Stanford-devised approach cures hemphilia in mice

Move over CRISPR, there's a new editor in town: Stanford-devised approach cures hemphilia in mice

A lot of attention has been paid lately to the idea of genome editing. This technique allows researchers to precisely modify an animal’s DNA to replace one version of a gene with another, or to add a working copy for a mutated gene. An approach called CRISPR/Cas9 in particular has garnered interest with its ease of use, ability to modify multiple genes, and relatively quick turnaround time when making specific strains of laboratory animals like mice for study.

Now pediatrician and geneticist Mark Kay, MD, PhD, has published  in Nature a new way to conduct genome editing that could give CRISPR a run for its money because it could be both safer and longer-lasting than other methods. As described in our press release:

The approach differs from that of other hailed techniques because it doesn’t require the co-delivery of an enzyme called an endonuclease to clip the recipient’s DNA at specific locations. It also doesn’t rely on the co-insertion of genetic “on” switches called promoters to activate the new gene’s expression.

Inclusion of endonucleases and promoters run the risk of a gamut of adverse effects in the recipient, from cancers if the promoter turns on the wrong gene in the genome to an unwanted immune response geared toward the foreign proteins. The researchers in Kay’s lab, including postdoctoral scholar and study lead author Adi Barzel, PhD, found a way around their use, and showed that it worked to enable mice with hemophilia to produce a missing blood clotting factor:

The technique devised by the researchers uses neither nucleases to cut the DNA nor a promoter to drive expression of the clotting factor gene. Instead, the researchers hitch the expression of the new gene to that of a highly expressed gene in the liver called albumin. The albumin gene makes the albumin protein, which is the most abundant protein in blood. It helps to regulate blood volume and to allow molecules that don’t easily dissolve in water to be transported in the blood.

The researchers used a modified version of a virus commonly used in gene therapy called adeno-associated virus, or AAV. In the modified version, called a viral vector, all viral genes are removed and only the therapeutic genes remain. They also relied on a biological phenomenon known as homologous recombination to insert the clotting factor gene near the albumin gene. By using a special DNA linker between the genes, the researchers were able to ensure that the clotting factor protein was made hand-in-hand with the highly expressed albumin protein.

As Kay, who is also a member of the Stanford Cancer Institute, the Stanford Child Health Research Institute and Stanford Bio X, explained, the integration of the clotting factor gene is key to the successful treatment (other clinical trials involving gene therapy for hemophilia rely on the expression of a free floating, unintegrated gene in the nucleus):

The real issue with AAV is that it’s unclear how long gene expression will last when the gene is not integrated into the genome. Infants and children, who would benefit most from treatment, are still growing, and an unintegrated gene could lose its effectiveness because it’s not copied from cell to cell. Furthermore, it’s not possible to re-administer the treatment because patients develop an immune response to AAV. But with integration we could get lifelong expression without fear of cancers or other DNA damage.

Previously: Gene “editing” could correct a host of genetic disorders, Policing the editor: Stanford scientists devise way to monitor CRISPR effectiveness and Both a doctor and a patient: Stanford physician talks about his hemophilia

Cardiovascular Medicine, Chronic Disease, In the News, Research, Science, Stanford News

How best to treat dialysis patients with heart disease

How best to treat dialysis patients with heart disease

523392_4923732760_zKidney failure patients on dialysis often have other chronic diseases – heart disease topping the list. They’re prescribed an average of 12 pills a day by physicians, according to Stanford nephrologist Tara Chang, MD, and they spend three-to-four hours at a treatment center three times a week connected to an artificial kidney machine.

For Chang, this makes it all the more important that any medication she prescribes for a patient on dialysis is both essential and effective.

The problem is, particularly in the case of treating kidney patients with heart disease, evidence-based treatment guidelines just aren’t available. Kidney doctors are left making best guesses based on guidelines written for the general population.

“Our patients might be different from patients not on dialysis,” said Chang. “Dialysis patients have a lot of heart disease, yet rarely does a cardiology study enroll patients on dialysis, so we just don’t know.”

This was part of the motivation behind Chang’s most recent study examining the use of anti-platelet drugs such as clopidogrel, one of the most commonly prescribed drugs for kidney patients. The researchers looked at the use of anti-platelet medications such as clopidogrel as treatment following stenting procedures to unclog arteries in the heart in 8,458 dialysis patients between 2007 and 2010. The data suggests that longer-duration of drug use may be of benefit to patients on dialysis who get drug-eluding stents but not those who get bare metal stents. Chang told me:

We found that for those who got drug-eluting stents who took the drug for 12 months compared to those who had stopped the drug at some earlier time point, there was a non-statistically significant trend towards lower risks of death and heart attacks. So for this group, following the same guidelines as for the general population may be appropriate. However, we found no indication of benefit with longer duration of anti-platelet drug use for patients on dialysis who got bare metal stents.

About half of the 400,000 patients in the U.S. on dialysis also have coronary artery disease, as referenced in the study. The number of those getting stents inserted to unclog arteries also has increased 50 percent in the past decade, the study states. The results of the study, while not definitive as to exactly how long doctors should prescribe the drug, does stress the need for more clinical research on patients with kidney failure to provide guidance on treatment strategies for heart disease.

“Because our study was not a randomized trial,” said Chang, “we tried to be very measured in how we interpreted the results. What it does point to is the fact that we can’t assume that what works in non-dialysis patients works in dialysis patients. Hopefully our study will help convince researchers to include our dialysis patients in their studies.”

The paper was published this week in the Journal of the American Heart Association.

Previously: Keeping kidney failure patients out of the hospitalStudy shows higher rates of untreated kidney disease among older adults and Study shows daily dialysis may boost patients’ heart function, physical health.
Photo by newslighter

Ebola, In the News, Myths, Science

The slippery slope toward “a dangerous dependence on facts”

The slippery slope toward "a dangerous dependence on facts"

220px-Sputnik_asmThe ever-funny Andy Borowitz has written in The New Yorker about a previously unreported challenge in the fight against Ebola: It might make Americans believe in science. He writes:

In interviews conducted across the nation, leading anti-science activists expressed their concern that the American people, wracked with anxiety over the possible spread of the virus, might desperately look to science to save the day.

“It’s a very human reaction,” said Harland Dorrinson, a prominent anti-science activist from Springfield, Missouri. “If you put them under enough stress, perfectly rational people will panic and start believing in science.”

For someone who left science to become a writer specifically to help explain science to the public, this piece is both funny and also so very not funny at the same time. Almost 20 years after I put down my pipette, Americans are, if anything, less willing to let science guide their health, energy, or environmental decisions than they were back when I started – thus the humor in Borowitz’ piece.

All of this makes me wonder if I could have spared myself several decades of worrying about clever analogies, agonizing about transitions, and racing the clock to make deadlines and done something less stressful with my life. Something fulfilling. Something where at the end of the day, my work would help people live happier, healthier lives rather than producing something people will ignore if it doesn’t fit their ideology.

Matthew Nisbet and Dietram Scheufele have written a number of articles about science communication and its effects on public perception of science. In the American Journal of Botony they write, “Often when the relationship between science and society breaks down, science illiteracy is typically blamed, the absence of quality science coverage is bemoaned, and there is a call put out for ‘more Carl Sagans.’”

In a nutshell, that sums up my career switch. I bemoaned the absence of quality science coverage and fully intended to fill that gap.

Then, they go on to shatter my reasons for writing by pointing out that at a period of time when the public’s regard for science was at it’s highest – soon after the Sputnik launch – science literacy was abysmal. In one survey at the time, just 12 percent of people understood the scientific method, yet 90 percent of people believed that science was making their lives better.

What that survey suggests is that even a scientific challenge like Ebola is unlikely to push Americans to be better educated about science. But perhaps with the perfect transition, or really outstanding analogy, those same scientifically illiterate Americans can be convinced that science is making life better and – I’m really dreaming here -should be funded?

If yes, maybe Borowitz’ fictional anti-science advocate will be proved right, and we will head down that slippery slope “in which a belief in science leads to a belief in math, which in turn fosters a dangerous dependence on facts.” One can hope!

Previously: Scientist: Just because someone’s on TV doesn’t mean they’re an expert

Dermatology, Research, Science, Stanford News, Stem Cells

The politics of destruction: Short-lived RNA helps stem cells turn on a dime

The politics of destruction: Short-lived RNA helps stem cells turn on a dime

Many stem cells live a life of monotony, biding their time until they’re needed to repair tissue damage or propel the growth of a developing embryo. But when the time is right, they must spring into action without hesitation. Like Clark Kent in a phone booth, they fling aside their former identity to become the needed skin, muscle, bone or other cell types.

Now researchers at Stanford, Harvard and the University of California-Los Angeles have learned that embryonic stem cells in mice and humans chemically tag RNA messages encoding key stem-cell genes. The tags tell the cell not to let the messages linger, but to degrade them quickly. Getting rid of those messages allows the cells to respond more nimbly to their new marching orders. As dermatology professor Howard Chang, MD, PhD, explained to me in an email:

Until now, we’ve not fully understood how RNA messages within the cell dissipate. In many cases, it was thought to be somewhat random. This research shows that embryonic stem cells actively tag RNA messages that they may later need to forget. In the absence of this mechanism, the stem cells are never able to forget they are stem cells. They are stuck and cannot become brain, heart or gut, for example.

Chang, who is a Howard Hughes Medical Institute investigator and a member of the Stanford Cancer Institute, is a co-senior author of a paper describing the research, which was published today in Cell Stem Cell. He shares senior authorship with Yi Xing, PhD, an associate professor of microbiology, immunology and molecular genetics at UCLA, and Cosmas Giallourakis, MD, an assistant professor of medicine at Harvard. Lead authorship is shared by postdoctoral scholars Pedro Batista, PhD, of Stanford, and Jinkai Wang, PhD, of UCLA; and by senior research fellow Benoit Molinie, PhD, of Harvard.

Messenger RNAs are used to convey information from the genes in a cell’s nucleus to protein-making factories in the cytoplasm. They carry the instructions necessary to assemble the hundreds of thousands of individual proteins that do the work of the cell. When, where and how long each protein is made is a carefully orchestrated process that controls the fate of the cell. For example, embryonic stem cells, which can become any cell in the body, maintain their “stemness” through the ongoing production of proteins known to confer pluripotency, a term used to describe how these cells can become any cell in the body.

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Cancer, Clinical Trials, Research, Science, Stanford News, Stem Cells

Drug may prevent bladder cancer progression, say Stanford researchers

Drug may prevent bladder cancer progression, say Stanford researchers

Bladder cancer is an insidious foe. About 70 percent of the time the condition is diagnosed while still confined to the bladder lining (in these cases, it’s known as a “carcinoma in situ,” or CIS). However, a subset of these localized cancers will go on to invade tissue surrounding the bladder and become much more deadly.

Now, developmental biologist Philip Beachy, PhD, a Howard Hughes Medical Institute investigator, and his colleagues have found that low doses of a drug called FK506 currently used to prevent the rejection of transplanted organs can prevent the progression of CIS into invasive bladder cancer in mice. Beachy collaborated with collaborated with urologist Joseph Liao, MD, and pulmonary specialist Edda Spiekerkoetter, MD, to conduct the research, which was published today in Cancer Cell. As Beachy explains in our release:

This could be a boon to the management of bladder cancer patients. Bladder cancer is the most expensive cancer to treat per patient because most patients require continual monitoring. The effective prevention of progression to invasive carcinoma would be a major advance in the treatment of this disease.

Beachy and Liao are members of the Stanford Cancer Institute. Together they’re hoping to initiate clinical trials of FK506 in people with CIS to learn whether the drug can also prevent progression to invasive cancer in humans.

The findings of the current study build upon previous research into the disease in Beachy’s laboratory and a long-time interest by Beachy in a molecular signaling pathway governed by a protein called sonic hedgehog. Beachy identified the first hedgehog protein in 1992; the protein (and the hedgehog pathway) have since been shown to play a vital role in embryonic developments and many types of cancers. Sonic hedgehog, Beachy has found, is produced by specialized stem cells in the bladder as a way to communicate with neighboring cells. They learned it’s required for the formation of CIS, but that it must also be lost in order for the cancer cells to invade other tissues. As Beachy explained in our release:

This was a very provocative finding. It was clear that these [sonic-hedgehog-expressing] bladder stem cells were the source of the intermediate cancers, or carcinomas in situ, that remain confined to the bladder lining. However, it was equally clear that sonic hedgehog expression must then be lost in order for those cancer cells to be able to invade surrounding tissue. We wondered whether the loss of this expression leads to increased tumor cell growth.

The researchers found that sonic hedgehog expression works in a loop with another class of proteins called BMPs. (You can read more about this in our release.) FK506 works by activating the BMP portion of the pathway in the absence of sonic hedgehog. Ten out of ten mice with CIS who received a low dose of the drug (low enough not to cause immunosuppression) were protected from developing invasive bladder cancer after five months of exposure to the carcinogen. In contrast, seven of nine mice receiving a placebo did develop the invasive form of the disease within the same time period.

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Science, Stanford News, Videos

The “simply amazing” work of Nobel Prize winner W.E. Moerner

The "simply amazing" work of Nobel Prize winner W.E. Moerner

Yesterday Stanford chemistry professor W.E. Moerner, PhD, was named a co-winner of the 2014 Nobel Prize in Chemistry for his work in super-resolution microscopy. In the video above, his colleagues – including Stanford Medicine’s own Lucy Shapiro, PhD, – share their thoughts on his work and the win. “The ability to now look at… mechanisms in a living cell is simply amazing,” Shapiro concluded.

Previously: Breaking the light barrier in medical microscopy: More on today’s Nobel-winning work and For third year in row, a Stanford faculty member wins the Nobel Prize in Chemistry

Imaging, Research, Science, Stanford News, Videos

Breaking the light barrier in medical microscopy: More on today’s Nobel-winning work

Breaking the light barrier in medical microscopy: More on today's Nobel-winning work

Earlier today, Stanford University’s W.E. Moerner, PhD, was one of three scientists to be awarded the Nobel Prize in Chemistry for work in super-resolution microscopy. Before this technology, the only way to look at structures inside cells was with electron microscopy. But that requires researchers to kill the tissue in order to prepare it for the microscope. Essentially, the objects being examined were frozen in place; scientists could make out cellular structures but couldn’t watch them in action.

Microscopes that use refracted light, or optical microscopes, can be used to observe living cells, but for decades, they were limited from going below 220 nanometers, a hard limit imposed by the wavelength of light. Eric Betzig, PhD, of Howard Hughes Medical Institute, and Stefan W. Hell, PhD, of the Max Planck Institute for Biophysical Chemistry in Germany shared the prize with Moerner for work that helped break that barrier. Now, researchers can peek inside cells as they are going about their business and observe real-time changes as they happen.

This morning, Moerner spoke to Stanford’s news office via Skype from Brazil about his work and how other researchers, including Lucy Shapiro, PhD, and Matt Scott, PhD, of Stanford’s School of Medicine are applying the new methods to medical research (see above video). Shapiro, a 10-year collaborator of Moerner’s, is examining structures inside bacteria and Scott is looking at subcellular signalling structures. (Shapiro provides comment on her work in a Stanford press release.)

“Because of this revolutionary work, scientists can now visualize the pathways of individual molecules inside living cells,” Francis Collins, MD, PhD, director of the National Institutes of Health, which funds some of Moerner’s work, said in a statement. “Researchers can see how molecules create synapses between nerve cells in the brain, and they can track proteins involved in Parkinson’s, Alzheimer’s and Huntington’s diseases.”

Below is a clip of Moerner describing what those studying Huntington’s disease have learned using the prize-winning microscopy technology.

Previously: For third year in row, a Stanford faculty member wins the Nobel Prize in Chemistry
Videos courtesy of Stanford University Communications

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