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Getting a glimpse of the shape molecules actually take in the cell

Getting a glimpse of the shape molecules actually take in the cell

Working at a medical school, every day I talk to scientists who are discovering ever more intricately detailed information about our bodies and our cells. With these daily amazements about what we do know, it’s always good to be reminded of how much is still unknown.

Case in point, I recently talked with Xuesong Shi, PhD, a postdoctoral fellow in the lab of biochemist Dan Herschlag, PhD. He has been trying to understand the many configurations and structures molecules and complexes of molecules take on. This may seem a bit abstract, but what the molecules look like – how many different shapes they fold into and how they interact with each other – can provide information that explains both how molecules behave normally, and also why they fail to work properly in some diseases.

For a long time now most of the information we have about the shape and structure of molecules came from turning those molecules into crystals of rigidly packed, identical structures. That’s a technique called X-ray crystallography, which people at Stanford carry out using the powerful X-ray beams at SLAC.

Herschlag points out that X-ray crystallography has been extremely valuable for helping scientists understand the molecules that make up our cells. But the crystals don’t necessarily give the whole picture. For example, molecules are thought to take on many different shapes when forming complexes, not just the single shaped found in a crystal. “The idea is that molecules have many forms in solution,” Shi said. Some molecules also don’t form crystals well.

Shi has been tackling this problem using an X-ray interferometry technique developed in the lab of biochemist Pehr Harbury, PhD, who collaborated with Herschlag and Shi on the work. It involves attaching tiny gold particles to known locations on molecules – in this case a snippet of DNA. Then, by using X-rays to look at where the gold particles are in relation to each other, scientists can piece together the myriad shapes the molecules take on when freed from a crystal lattice.

Shi was first author on a paper published online March 31 in the Proceedings of the National Academy of Sciences describing this technique. He told me that although that paper investigated the structure of DNA, he hopes to use the technique to better understand a variety of molecules where knowing the myriad shapes the molecule takes on is essential for understanding its function.

Bioengineering, Global Health, Medicine and Society, Stanford News, Videos

Music box inspires a chemistry set for kids and scientists in developing countries

Music box inspires a chemistry set for kids and scientists in developing countries

Over the past few weeks my colleague Kris Newby has been writing about the Foldscope, the 50-cent microscope developed by bioengineer Manu Prakash, PhD. Today Prakash is announcing another device that will bring high tech science to the developing world – and to kids.

The device won a contest from the Gordon and Betty Moore Foundation and the Society for Science & the Public to “Reimagine the chemistry set for the 21st century.” In the contest materials, the two groups cite the absence of chemistry sets on the market today that inspire creativity.

As the parent of two boys I have to agree. Chemistry toys these days come with prepackaged materials and set instructions for how to use them. Sure, I’m not enthusiastic about some of the dangerous chemicals in the kits that inspired an older generation of scientists, but a bit of creativity would be nice.

Prakash took inspiration from a simple music box to design a handheld chemistry set that can be programmed using holes punched in a paper tape. The prize came from the set’s use as a toy to inspire kids, but Prakash and graduate student George Korir also envision it being used to carry out science in developing countries. They say it can be built for about $5. Prakash told me, “I’d started thinking about this connection between science education and global health. The things that you make for kids to explore science [are] also exactly the kind of things that you need in the field because they need to be robust and they need to be highly versatile.”

My Stanford Report story goes on to describe how it works:

Like the music box, the prototype includes a hand cranked wheel and paper tape with periodic holes punched by the user. When a pin encounters a hole in the tape it flips and activates a pump that releases a single drop from a channel. In the simplest design, 15 independent pumps, valves and droplet generators can all be controlled simultaneously.

Prakash and Korir didn’t set out to make a kit for kids. Their idea was that a portable, programmable chemistry kit could be used around the world to test water quality, provide affordable medical diagnostic tests, assess soil chemistry for agriculture or as a snake bite venom test kit. It could even be used in modern labs to carry out experiments on a very small scale.

This chemistry set and the Foldscope are both part of what Prakash calls “frugal science.” There’s more about how the device works in the technical paper.

Previously: Stanford bioengineer develops a 50-cent paper microscope and Free DIY microscope kits to citizen scientists with inspiring project ideas
Photo in featured entry box by George Korir

Immunology, Neuroscience, Research, Stanford News

Double vision: How the brain creates a single view of the world

Double vision: How the brain creates a single view of the world

eyes close-upAbout a decade ago, Stanford Bio-X director Carla Shatz, PhD, found that some proteins from the immune system seemed to be playing a role in the brain. Not all scientists were on board with the protein’s double life. Then Ben Barres, MD, PhD, a neurobiologist at Stanford, started finding the same thing with a different set of proteins – these immune system denizens appeared to be functioning in the brain (here’s a write-up on that work by my colleague Bruce Goldman). And still, not all immunologists accepted that the brain might also be using these proteins.

Now Shatz has published a paper online March 30 in Nature that should put the disagreement to rest. She very carefully showed that a protein originally known for its role in the immune system, called MHC Class I D, or D for short, was present in the nerves of the developing brain. She told me, ”The nervous system has just as much right to these immune proteins as the immune system.”

The role D plays is in helping the brain trim back connections as it develops. I didn’t know this before working on my story, but the brain starts out with about double the number of nerve connections than it will eventually use. The ones the brain doesn’t use get trimmed back. Shatz studies this process in a part of the brain that tries to create a single view of the world out of signals coming from the two eyes. In my press release I wrote:

Shatz said the rule of which connections the brain cuts back to create that single vision follows a simple mantra: “Fire together, wire together. Out of sync, lose your link.” Or rather, if early in life the left sides of both eyes see the same duck motif wallpaper, those neurons fire together and stay linked up. When the top of one eye and bottom of the other eye form a connection, the nerves fire out of sync, and the connection weakens and is eventually pruned back. Over time, the only connections that remain are between parts of the two eyes that are seeing the same thing.

I spoke with Lawrence Steinman, MD, PhD, a neurologist at Stanford who studies multiple sclerosis, a disease of both the immune system and the nervous system. He has a foot in both worlds and has followed Shatz’ work from the beginning. He says part of the problem in gaining acceptance for Shatz’ findings was in a name. A rose by any name may smell as sweet, but a protein with a name like “major histocompatibility complex I” only sounds to a biologist like an immune protein. He says he teaches students that if Shatz had published her work first the protein would have an entirely different name and it would be the immunologists fighting to claim the protein’s role in their world.

“They clearly have major roles in both the nervous system and the immune system,” he said.

Previously: Protein known for initiating immune response may set our brains up for neurodegenerative disorders and Pioneers in science
Photo by Ali Moradmand

Neuroscience, Research, Stanford News

Elastic for floppy nerves

Elastic for floppy nerves

13545-touch_shutterstockHere’s something that was news to me: scientists don’t actually know how we sense touch. They know a lot about the neurons that send signals to the brain when you, say, touch your keyboard. But that initial sensation as the finger hits a key, when the skin is lightly depressed, what triggers the nerve to know the finger has touched something? That’s not known.

I wrote about some work this week from the Stanford Bio-X team of Miriam Goodman, PhD, and Alex Dunn, PhD, who work on this problem. A post doctoral fellow working in their labs, Michael Krieg, PhD, was looking into mechanical properties of the nerves that sense touch. One thing led to another, scientifically speaking, and eventually he found a matrix of proteins in these nerves that are not only involved in transmitting the signal of touch, but also seem to keep nerves resilient.

Dunn used socks to describe the difference between nerves that had this protein matrix, called spectrin, and those that didn’t. “When we looked at bending we realized that this looked a lot like an old sock. It looked loose and floppy,” he said. “We thought maybe what’s going on is the spectrin is acting like elastic.”

There’s more in the story about some cool measurements Krieg made into just how much tension the spectrin matrix puts on the cell. (How do you measure 1/1,000,000,000,000 of an apple anyway?)

Neuroscience, Stanford News, Videos

Middle school students get brainy

Middle school students get brainy

You know it’s going to be a good week when Monday morning starts with a bucket of whole human brains. I got to attend Brain Day, in which Stanford graduate students take a collection of human brains as well as a zoo full of animal brains into local middle schools to give students a lesson in biology they won’t soon forget. I describe the kids’ excitement in a story today, but this video by my colleague Kurt Hickman says it all.

Previously: Study shows “exploration first” model is a better way for students to learn, A day at med school for Bay Area teens, Image of the Week: Studying brains at Stanford’s Med School 101 and This is your brain on science: NIH funds eight K-12 neuroscience education programs

Cancer, Research, Stanford News, Surgery

Chemistry technique improves cancer surgery

Chemistry technique improves cancer surgery

mass spectrometer

For many cancers of the stomach and intestinal tract, removing the tumor is the best way of treating a patient. The problem is that the cancerous cells don’t necessarily look any different from the normal cells. I wrote recently about a new technique to pick out those cancerous cells and help surgeons completely remove the tumor.

What’s fun about this story is that the idea started with a chemist, Livia Eberlin, PhD, who’s a post-doc in lab of chemistry professor Richard Zare, PhD. Zare is a member of Stanford’s Bio-X and from that has experience working with colleagues across campus. He suggested to Eberlin that she find a surgeon who would be willing to collaborate with her and test her approach to identifying the cancerous cells.

Eberlin knew that surgeons rely on pathologists during a surgery to help them figure out if they’ve removed the entire tumor, but the initial results aren’t always accurate. In some cases, pathologists find out days later, when results of a slower, more accurate test are complete, that the patient might need to come back for another surgery to remove more tissue.

Eberlin called up surgeon George Poultsides, MD, to see if he’d like to collaborate on her idea. As I wrote in my piece:

Eberlin’s expertise is in mass spectrometry, a tool not commonly used in a hospital setting. It takes a sample in one end, turns the molecules into charged particles, then detects how long it takes each charged molecule in that sample to migrate down a vacuum tube. The result is a jagged mountain range of tens of thousands of peaks, each representing a single chemical in the sample. The height of the peak indicates how much of that chemical the sample contained.

The idea was that maybe some of those peaks would be different in tissue samples that had cancerous cells versus those that didn’t. If it worked, this mass spectrometry approach might end up being more accurate than the approach being used now.

It took a team of statisticians, pathologists, surgeons and chemists to develop and test Eberlin’s idea. In the end, their approach seemed to be more accurate than what’s being used now. They are going to try their approach on a larger group of stomach cancers and in other cancers to see if it can help improve the odds of completely removing all cancerous cells during surgery.

Previously: Good-bye cancer, good-bye stomach: A survivor shares her tale
Photo – of Livia Eberlin, PhD, at a mass spectrometer used to identify cancerous cells in tissue samples – by L.A. Cicero

Pain, Research, Stanford News

Toxins in newts lead to new way of locating pain

Toxins in newts lead to new way of locating pain

newtYou have to love a medical story that starts with newts. Newt eggs to be precise. Back in the 1960s, a Stanford chemist Harry Mosher (who died in 2001) collected eggs from newts on campus and isolated a toxin that turned out to be identical to the one in puffer fish. (Note to self: avoid eating newts or newt eggs found on campus.)

Many decades later, those toxins he studied and variants thereof are widely used in medical research. They latch on to tiny pores on nerve cells and prevent those nerves from firing—seen as a negative if you are eating a pufferfish, but a positive to researchers working in a lab trying to understand the inner workings of nerves.

Recently, Stanford chemist Justin Du Bois, PhD, teamed up with radiologist Sandip Biswal, MD, who studies the origins of pain, to see if this group of chemicals could be used to better understand (and maybe one day treat) pain. I wrote a story about the work and described Biswal’s frustration diagnosing the source of pain:

Biswal, an associate professor of radiology at the Stanford University Medical Center, spent a lot of time imaging parts of the body where people said they felt pain, trying to find the source. It was a frustrating task because often the source of pain isn’t obvious, and sometimes the source is far removed from where a person feels the sensation of pain. Other times, he’d see something that looked painful, surgeons would fix it, and the patient would still be in pain.

Along with some other collaborators, Du Bois and Biswal figured out a way to manipulate the toxins Du Bois had been studying so that they would latch onto nerves that send pain signals and be visible outside the body. When they tested the chemical in rats, they were able to see the location of pain in a living animal.

As with so much cool research, the team got its start with a seed grant from Stanford’s Bio-X. They recently started a company to see if they could develop their work into a useful drug or imaging technique.

Previously: Stanford researchers address the complexities of chronic pain, Exploring the mystery of pain, More progress in the quest for a “painometer”, Ask Stanford Med: Neuroscientist responds to questions on pain and love’s analgesic effects
Photo by Jason Mintzer Shutterstock

Neuroscience, Research, Stanford News

Dinners spark neuroscience conversation, collaboration

Dinners spark neuroscience conversation, collaboration

Sometimes big discoveries start with small conversations.

That was the idea at least when Stanford’s Bio-X program placed scientists from different backgrounds in adjoining labs of the Clark Center. Ten years later, that’s a proven success. Scientists bumped into each other and shared coffee, and now interdisciplinary projects are flourishing.

What I found interesting was how much big ideas grew when people from across disciplines – many meeting for the first time that evening – started dreaming together.

Our most recently formed interdisciplinary institutes, the Stanford Neurosciences Institute and the Institute for Chemical Biology, don’t yet have their own building and can’t spark conversation by proximity. Instead, they’re taking a time-honored approach to bringing people together:  food.

I got to attend one of these conversation starters at a dinner held by William Newsome, PhD, professor of neurobiology and director of the newly formed Neurosciences Institute.

Newsome asked the attending crowd of biologists, engineers, radiologists, neurobiologists and bioengineers to dream big about what they’d want to achieve if money were no object and they could collaborate with anyone on campus.

What ensued was an hour-long discussion about decision-making networks, a new generation of brain-inspired computing, devices to stimulate miniscule brain regions, and ever more complex ways of peering into and understanding the brain.

What I found interesting was how much those big ideas grew when people from across disciplines – many meeting for the first time that evening – started dreaming together.

Brian Rutt, PhD, professor of radiology, saw his original idea for improved brain imaging take on new life when engineers and neurobiologists jumped in with their own thoughts about how those techniques could be employed in human diseases. Rutt told Newsome that getting scientists to talk across disciplines is going to be critical for generating the kinds of projects that are critical for the Institute’s success. “I think one of your challenges is to find a way of getting your members to both speak the same language and also appreciate each other’s science,” he said.

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