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Bioengineering, Research, Stanford News

Researchers create rewritable digital storage in DNA

Researchers create rewritable digital storage in DNA

Scientists at Stanford have invented a way to store, erase and code digital data in the DNA of living cells.

Bioengineers used enzymes from bacteria to flip sequences of DNA one direction, then another. The back and forth represent the ones and zeros of digital information. By coding a section of DNA that determines if the cells fluoresce red or green, the researchers easily visualized the switch (see photo).

The team, led by Drew Endy, PhD, calls the flipping device a “recombinase addressable data” module, or RAD. Endy commented in a release on the method’s potential biomedical applications:

Programmable data storage within the DNA of living cells would seem an incredibly powerful tool for studying cancer, aging, organismal development and even the natural environment.

In developing the system, researchers had to control the precise dynamics of two opposing proteins, integrase and excisionase, within the microbes. The team found it was fairly simple to flip a section of DNA in either direction but needed to repeatedly and reliably flip the sequence back and forth to create a fully reusable binary data register. Getting the balance of protein levels right took researchers three years and 750 tries. As explained further down the release:

[First author Jerome Bonnet, PhD] has now tested RAD modules in single microbes that have doubled more than 100 times and the switch has held. He has likewise switched the latch and watched a cell double 90 times, and set it back. The latch will even store information when the enzymes are not present. In short, RAD works. It is reliable and it is rewritable.

For Endy and the team, the future of computing then becomes not only how fast or how much can be computed, but when and where computations occur and how those computations might impact our understanding of and interaction with life.

“One of the coolest places for computing,” Endy said, “is within biological systems.”

A paper on the device was published today in the Proceedings of the National Academy of Sciences. The team’s next goal is to scale up to a byte – equivalent to eight bits of programmable DNA.

Previously: Drew Endy contemplates new modes of computing in medical research
Photo by Norbert von der Groeben

Image of the Week, Medicine X

Image of the Week: Regina Holliday's Medicine X

In this richly-colored painting, artist and patient-rights activist Regina Holliday depicts central themes of the upcoming Stanford Medicine X conference. On the artist’s blog she explains:

In the foreground, two girls stand within rising water. They are patients in need of rescue from the coming flood.  One girl turns her back to the viewer and holds a smart phone in her hand. The other girl looks out of the frame and a blue twitter bird perches upon her finger. Though they look concerned but they are not panicked, because they have the tools of mobile health and social media to help them.

To the left of this piece, a series of people are pushing their rafts upon the rising water. Our blocks from the tower have become rafts to navigate the deluge. Here we have doctors, techs, academics, venders, designers and patients trying to find common ground. Each uses the pole in their hands to move forward in the water. As the pole crosses before their body each becomes the letter “X.”

We are the X in Medicine X. We are the unknown part of the equation. We are the mysterious other that has not been applied to the solution. We are the files locked in a cabinet and dismissed as other or strange. We are the ever arching story above and beyond the episode of care.

Via Medicine X blog

Cancer, Research

Google-like algorithm may reveal better biomarkers for cancer

Google’s PageRank algorithm sorts search results by relevance and now researchers are using a similar strategy to sift through thousands of proteins that affect the progression of pancreatic cancer.

German scientists from the Dresden University of Technology ranked cancer biomarkers and found seven proteins that predicted how patients respond to chemotherapy. The study was published in PLoS Computational Biology.

Cancer biomarkers have garnered considerable interest in medical and clinical research. They could be used to predict the outcomes of individuals with cancer and personalize therapy. But so far, few biomarkers have proved clinically useful. For example, controversy surrounds the effectiveness of measuring levels of prostate-specific antigen (PSA) as a way of screening prostate cancer; PSA levels are also high in non-cancerous enlarged prostates. In addition, biomarkers identified in different studies almost never overlap.

The German team worked around this problem by analyzing relationships between biomarkers. An article from e! Science News explains:

This problem has been circumvented using the Google strategy, which takes into account the content of a web page and also how these pages are connected via hyperlinks. With this strategy as the model, the authors made use of the fact that proteins in a cell are connected through a network of physical and regulatory interactions; the ‘protein Facebook’ so to speak.

“Once we added the network information in our analysis, our biomarkers became more reproducible,” said Christof Winter, the paper’s first author. Using this network information and the Google Algorithm, a significant overlap was found with an earlier study from the University of North Carolina. There, a connection was made with a protein which can assess aggressiveness in pancreatic cancer.

The group is currently running a clinical trial to evaluate these new biomarkers.

Previously: Value of disease biomarkers may be overrated

In the News, Medicine and Society, Research, Science

A critical look at the difficulty of publishing "negative" results

A critical look at the difficulty of publishing "negative" results

Science is supposed to work like this: A researcher tests a question with an experiment, produces results of the experiment and publishes the work so it can be evaluated by peers. Other scientists can then run the same experiment and see if they get the same results. But if the results don’t match the first experiment, it can be tough to actually get these “negative” findings published. And as an article in Nature News reports, this is a problem.

The article begins by discussing  a controversial study on premonition in college students. Ed Yong writes that three research teams tried unsuccessfully to replicate the study findings and were unable to publish their negative results – which isn’t an unusual thing:

Positive results in psychology can behave like rumours: easy to release but hard to dispel. They dominate most journals, which strive to present new, exciting research. Meanwhile, attempts to replicate those studies, especially when the findings are negative, go unpublished, languishing in personal file drawers or circulating in conversations around the water cooler. “There are some experiments that everyone knows don’t replicate, but this knowledge doesn’t get into the literature,” says [Eric-Jan Wagenmakers, a mathematical psychologist from the University of Amsterdam]. The publication barrier can be chilling, he adds. “I’ve seen students spending their entire PhD period trying to replicate a phenomenon, failing, and quitting academia because they had nothing to show for their time.”

Many in the field of psychology believe that things need to be change, but the extent of the problem is still debated:

Some scientists still question whether there is a problem, and [Brian Nosek, a social psychologist from the University of Virginia,] points out that there are no solid estimates of the prevalence of false positives. To remedy that, late last year, he brought together a group of psychologists to try to reproduce every study published in three major psychological journals in 2008. The teams will adhere to the original experiments as closely as possible and try to work with the original authors. The goal is not to single out individual work, but to “get some initial evidence about the odds of replication” across the field, Nosek says.

Some researchers are agnostic about the outcome, but [Hal Pashler, a psychologist from the University of California, San Diego,] expects to see confirmation of his fears: that the corridor gossip about irreproducible studies and the file drawers stuffed with failed attempts at replication will turn out to be real. “Then, people won’t be able to dodge it,” he says.

The article states that while psychiatry and psychology are the fields that have the greatest tendency to publish only positive results – studies where the hypothesis is confirmed – many disciplines face the same problem. Stanford researcher John Ioannidis, MD, regularly points out problems in medical research; in a now-famous essay in PLoS Medicine, he argued that most published research is false.

In a time where public distrust of science continues, this is disheartening. But I hope articles like this are a call to action.

Previously: John Ioannidis, MD: Research’s researcher and The Atlantic profiles Stanford’s John Ioannidis, “one of the most influential scientists alive”

Applied Biotechnology, Clinical Trials, In the News, Neuroscience

A closer look at the woman who moved a robotic arm with her mind

A closer look at the woman who moved a robotic arm with her mind

As has been widely reported today, paralyzed patients for the first time have moved a robotic arm using only their brain activity. In a small clinical trial described in a Nature paper, two patients each used a tiny device implanted in their motor cortex to move robotic limbs to reach, grasp and drink coffee from a bottle.

In an article from The Atlantic, writer Jessica Benko tells the story of one of the study participants, a woman who enrolled in the trial after a stroke left her paralyzed and unable to speak:

The study’s codirector, a conscientious young neuroscientist named Leigh Hochberg [MD, PhD], was blunt with Cathy: Whatever the failures or successes of the study, she could not hope that the results would assist her in her lifetime. “There are no expected benefits this early on in the research,” Hochberg told me. “What we’re doing, and what Cathy knew when we were starting and what she enthusiastically joined, is an endeavor to test and develop a device we hope will help other people with paralysis in the future.”

Cathy’s device was implanted in 2005, and the researchers first target was for her to control a computer cursor. As Cathy concentrated on moving her hand, her efforts unspooled on screens in front of the researchers, who tried to use the information from her brain as a sort of virtual mind-controlled mouse. When the researchers turned control of the cursor over to Cathy’s neurons, the cursor immediately began to move haltingly across the screen. Cathy couldn’t believe her eyes. “I was numb with shock and disbelief,” she wrote to me, “so I moved the cursor all over the screen.”

An article and video published by Nature News describe how Hutchinson smiled when she first used the robotic arm. “We’ll never forget that smile,” Hochberg commented.

Hochberg and his team are continuing their work in this area, and last fall Stanford announced it was collaborating with the group by serving as a trial site for BrainGate2. Jaimie Henderson, MD, is lead investigator of the Stanford branch of the trial.

Image of the Week

Image of the Week: Body Oddities

This intriguing image of a torso as a cabinet-of-wonders is called “Body Oddities 2.” The artwork is part of a series by Kelsey Niziolek. According to Niziolek’s website, “she holds a special love in her (he)art for science, health, and medical related topics, however always keeps an open mind.”

The artwork is annotated with facts about the body, including the following:

  • The body has about 60,000 miles of blood vessels
  • It is actually possible to die of a broken heart; cracks can develop in the heart as a result of depression
  • If all the bacteria from the intestines was squeezed out there would be enough to nearly fill an entire mug to the top

The full series, which includes two additional works, can be found in Niziolek’s portfolio.

Via Street Anatomy

In the News, Media, Science, Technology

Science, apps and wonder

Science, apps and wonder

Icelandic musician Björk combined art and science with her 2011 album Biophilia – it was released with a series of iPad apps featuring biological images such as a virus attacking cells and DNA replication. Multimedia designer Scott Snibbe was executive producer for the project and in a Nature Q&A published online today, he describes his interactive science-museum installations, science-based apps and how he came to work on Biophilia.

Here is an excerpt from the piece:

What draws you to interactive apps?

Other fields are limited by money, equipment and the laws of nature. But with computers, the only limits are technical ability, ingenuity and imagination. Nature has awed me since I was a child, but the educational system rarely conveys this wonder, transforming our Universe into boring multiple-choice questions. My programs recreate the wonder and magic to give people the kind of experiences that they have in wild places such as river banks. My apps borrow from nature, but the laws are slightly altered, as if in a parallel universe.

Can you describe your science-based apps?

With my Gravilux, you touch the screen and stars are attracted to your fingertips. I started with Newton’s gravity equations but didn’t get controllable patterns, so I removed mutual attraction. Bubble Harp draws Voronoi diagrams, based on a geometric algorithm first described by seventeenth-century philosopher René Descartes, and used to model the structure of cells, the pattern of human settlements and the gravitational influence of stars. With Antograph, you ‘paint’ a pheromone that attracts ants, but they swarm off the trail, just as real ants would. I’ve had reports of it being used to teach what pheromones are, and one user of Gravilux said that it helped him to get an A grade in physics for the first time.

Previously: Medical apps: They’re not just for medicine anymore

Cancer, Clinical Trials, In the News, Research

Patients' own stem cells may protect against toxins of chemotherapy

Chemotherapy saves lives, but it also kills healthy tissue like bone marrow. According to a new study involving three patients with glioblastoma, a deadly cancer of the brain, stem cells from cancer patients’ own blood may protect their bone marrow from the toxic effects of treatment.

Glioblastomas often carry an active form of a gene called MGMT, which is a DNA repair enzyme that protects the cancer cells against chemotherapy. To overcome that protective effect, doctors use benzylguanine, a drug that blocks MGMT – but that drug also makes bone marrow and blood cells vulnerable. For this study, scientists at Fred Hutchinson Cancer Research Center in Washington took a different approach by transplanting gene-modified stem cells into study participants.

From a release:

By giving bone marrow stem cells P140K, which is a modified version of MGMT, those cells are protected from the toxic effects of benzylguanine and chemotherapy, while the tumor cells are still sensitive to chemotherapy. “P140K can repair the damage caused by chemotherapy and is impervious to the effects of benzylguanine,” [lead author Hans-Peter Kiem, MD] said.

“This therapy is analogous to firing at both tumor cells and bone marrow cells, but giving the bone marrow cells protective shields while the tumor cells are unshielded,” said Jennifer Adair, Ph.D., who shares first authorship of the study with Brian Beard, Ph.D., both members of Kiem’s lab.

The three patients in this study survived an average of 22 months after receiving transplants of their own circulating blood stem cells. One, an Alaskan man, remains alive 34 months after treatment. Median survival for patients with this type of high-risk glioblastoma without a transplant is just over a year.

paper on the work appears today in Science Translational Medicine.  The clinical trial is ongoing and more research is needed to see whether the potential treatment will work for others.

Previously: Clinical trials: my next good chance, In-womb exposure to chemotherapy appears safe for babies and New discovery suggests tumor suppression can be had without killing healthy cells
Photo by the National Cancer Institute

Research

Researchers pinpoint key signals for immune cells

When you fall ill or have an allergic reaction, special immune cells churn out antibodies to identify invaders such as bacteria (or allergens like pollen). Now, scientists at The Scripps Research Institute have figured out how some of those cells know what to do.

As described in a release today, the first time young B cells find pieces of an invader, perhaps bits of a virus or bacteria, they learn how to make antibodies. Some B cells turn into plasma B cells and manufacture antibodies immediately, slowly ratcheting up production over time. Others become memory B cells, which can remain dormant for years until a second infection triggers them to respond.

Those memory B cells fall into different classes. Immune cells called helper T cells secrete chemical signals that tell the B cells which class to choose. One of them, the IgG class, is populated by B cells that respond to most viruses and bacteria. IgA-class B cells are found in mucosal surfaces like the intestines. Cells in the IgE class respond to parasites like intestinal worms.

Exactly how the cells choose which class to join has been unclear. The Scripps researchers nailed down two specific molecules needed to change young, ‘naive’ B cells into IgG2a-class memory B cells. The proteins are called T-bet and RORα, according to a paper recently published in the advance online edition of Nature Immunology.

“This is a real breakthrough, in the sense that we now have a much better understanding of how B cell class is regulated, and how we might target that regulatory process in vaccine and drug design,” said lead author Michael McHeyzer-Williams, PhD, in the release.

The discovery could help researchers design more-effective vaccines. With the addition of a specific protein, the vaccine itself could encourage cells to fall in certain classes and induce long-term immunity. For example, the vaccine might include addition of T-bet and RORα, to help push more B-cells into the IgG2a class, which is effective against viruses. The same concept, reversed, could discourage memory B cells and reduce over-the-top immune reactions common in autoimmune, allergic and lymphoma conditions.

“Being able to target just that class of B cell would be an obvious advantage over existing therapies, such as steroids, that knock down large parts of the immune system,” said McHeyzer-Williams.

Photo by Wellcome Images

Cancer, Research, Stanford News

Study finds huge genetic diversity in cancer cells

Study finds huge genetic diversity in cancer cells

Cancer tumors shed cells that circulate through the blood steam. And, according to a Stanford study published today in PLoS ONE, those mobile cells have a high level of genetic diversity even within a single patient.

For the study, researchers here looked at circulating tumor cells (CTCs) first in mouse cell-lines and then in blood drawn from breast cancer patients. To find the very small number of CTCs in blood, the team used a device they developed in 2008 called the MagSweeper, which zeros in on specific protein on the surface of tumor cells. Next, they measured the levels of 95 different genes using another Stanford technology: real-time PCR microfluidic chips, developed by Stephen Quake, PhD, professor of bioengineering. They found as many as five different groups of cancer cells – all with different patterns of genes turned on or off. 

Study senior author Stefanie Jeffrey, MD, explained the significance of the findings in our release:

The diversity, Jeffrey said, means that tumors may contain multiple types of cancer cells that may get into the bloodstream, and a single biopsy from a patient’s tumor doesn’t necessarily reflect all the molecular changes that are driving a cancer forward and helping it spread. Moreover, different cells may require different therapies. One breast cancer patient studied, for example, had some CTCs positive for the marker HER2 and others lacked the marker. When the patient was treated with a drug designed to target HER2-positive cancers, the CTCs lacking the molecule remained in her bloodstream.

These results don’t have immediate impacts for cancer patients in the clinic because more work is needed to discover whether different types of CTCs respond to different therapies and whether that will be clinically useful for guiding treatment decisions. But the finding is a step forward in understanding the basic science behind the bits of tumors that circulate in the blood

Previously: Researchers take a step toward understanding the genetics behind breast cancer

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