Map My Brain

With every smell, memory, or flicker of emotion, tangled pathways of electrical activity light up in our brains and process the information, creating a concise impression of a world photoshopped by our neurons.

But these neuronal pathways don’t line up in a simple, linear transfer of information — there are trillions of synapses, and only recently have researchers really begun to dive into the extensive connections.

Each circuit is an intricate wiring of neurons that transmits signals through an electrical patchwork. Ultimately, every human function comes down to these “wiring diagrams” — maps of specific neuron connections that promote proper brain function.

Neuroscience is starting to move away from more traditional studies, like that of neuron structure or general functions in areas of the brain, and is shifting toward tracking connectivity. Scientists are trying to fill in the middle ground, to untangle the brain’s highly complex neural circuitry, and ultimately lay it out in a decipherable map.

Researchers are tweaking their techniques, incorporating elements of bioengineering and computational optics to expand the realm in which they can study the neuron and its connections in the brain. Some researchers have adapted Nobel-prize winning super resolution microscopy to scrutinize tiny details of neurons that were previously undistinguishable. Scientists hope that eventually these techniques can compile a new foundation for understanding cognition and mental health.

“Figuring out how the neurons come together to make these circuits is a big, rapidly advancing area of neuroscience today,” says Joshua Sanes, Harvard professor and researcher at Harvard’s Center for Brain Science. “Our motivations come from the fact that [neurons] underlay all brain activities, and that there are some psychiatric diseases that are suspected to occur through mis-wirings in the brain.”

In 2007, Sanes helped neuroscience reach a colorful breakthrough. Jeff W. Lichtman, Harvard professor of neuroscience and researcher at Harvard’s Center for Brain Science, and Sane’s research teams developed a technique known as Brainbow, a part of the Center’s Connectome Project.

Meant to tease apart the long tracks of neurons in the brain, the Brainbow method individually labels neurons with fluorescent proteins. These proteins express up to 100 different colors at a time, bringing colorful order to what was once an indiscriminate glob of neurons.

Sanes compares it to the wirings of a computer. All of the wires need to be accounted for and correctly connected, especially the ones involved in complicated circuits. Neurons are a lot like that, there are long “wires” that come from the bodies of neurons called axons and dendrites, and they hook up with other neurons to make precise patterns of connectivity. But if the wires aren’t correctly connected, the neural message gets distorted and can lead to mental deterioration.

“Having the wires in different colors lets you trace them and see where they go,” says Sanes. Currently, he and other scientists are building off of this colorful map to develop other research techniques that help chart connections in the brain.

Outside of the Connectome Project, other researchers at Harvard like Adam Cohen, professor of chemical biology and physics, and Venkatesh Murthy, professor of molecular and cellular biology, are using stimulation techniques to activate neurons and study their response in real time. Cohen has engineered a technique in which the neuron itself is able to make a protein that lights up to indicate electrical activity, and this light can then propagate through circuits of up to 100 neurons.

“The particular trick that Adam Cohen’s lab did is a phenomenally rational and beautiful design,” says Murthy. “It’s one of the best forms of this type of indicator.”

The light-up protein is called “Optopatch” and when engineered to a neuron, can be stimulated by a particular kind of light. This light activates the electrical impulse, and researchers can watch as Optopatch’s red glow fluoresces outwards, highlighting the signal’s path.

Murthy hopes to use this light-up pathway to help track neurons and even map the neural counterparts of particular smells.

While Murthy and Sanes aim to decipher larger neural circuits in the brain, researchers like Jan Tonnesson, at the University of Bordeaux, are taking a more detailed approach, zooming in on intricacies of the neuron that, until recently, have never been seen before. Tonnesson and his colleagues have applied the Nobel-prize winning microscopy technique called STED, more commonly known as super resolution microscopy, to study tiny details of the neuron — specifically, miniscule spines that extend from one neuron to the next, making the synapses that create the connections Sanes and Murthy are interested in studying.

“It opens up a completely new world for us,” says Tonnesson.

Super resolution microscopy allows researchers to clearly see images up to four times smaller than other microscopy techniques, and Tonnesson is taking advantage of that, exploring the microcosms of single neurons.

He and his colleagues at the University of Bordeaux stimulate each spine as if by another neuron and use the super resolution to gather data on how each spine responds individually to the contact. A single neuron may have thousands of spines, and while each spine is independently contacted, the total stimulation is what elicits a signal down the neuron, potentially propagating a circuit.

Tonnesson recognizes that, while super resolution is new to neuroscience, it offers a new angle in analyzing neurons and how neuronal structures may affect proper signal sending.

“We should treat a lot of this as on-going, moment-to-moment innovation,” says Murthy. “None of this is the final product, and I think part of the excitement is simply that we’re seeing what is possible. Sure, there are specific things that we are discovering now, but they’re opening doors to many more things in the upcoming decades.”

Accelerator Physicist Invents New Way to Clean Up Oil Spills

Four years ago, Fermilab accelerator physicist Arden Warner watched national news of the BP oil spill and found himself frustrated with the cleanup response.

"My wife asked 'Can you separate oil from water?' and I said 'Maybe I could magnetize it!'" Warner recalled. "But that was just something I said. Later that night while I was falling asleep, I thought, you know what, that's not a bad idea."

Sleep forgone, Warner began experimenting in his garage. With shavings from his shovel, a splash of engine oil and a refrigerator magnet, Warner witnessed the preliminary success of a concept that could revolutionize the process of oil spill damage control.

Warner has received patent approval on the cleanup method.

The concept is simple: Take iron particles or magnetite dust and add them to oil. It turns out that these particles mix well with oil and form a loose colloidal suspension that floats in water. Mixed with the filings, the suspension is susceptible to magnetic forces. At a barely discernible 2 to 6 microns in size, the particles tend to clump together, and it only takes a sparse dusting for them to bond with the oil. When a magnetic field is applied to the oil and filings, they congeal into a viscous liquid known as a magnetorheological fluid. The fluid's viscosity allows a magnetic field to pool both filings and oil to a single location, making them easy to remove. (View a 30-second video of the reaction.)

"It doesn't take long — you add the filings, you pull them out. The entire process is even more efficient with hydrophobic filings. As soon as they hit the oil, they sink in," said Warner, who works in the Accelerator Division. Hydrophobic filings are those that don't like to interact with water — think of hydrophobic as water-fearing. "You could essentially have a device that disperses filings and a magnetic conveyor system behind it that picks it up. You don't need a lot of material."

Warner tested more than 100 oils, including sweet crude and heavy crude. As it turns out, the crude oils' natural viscosity makes it fairly easy to magnetize and clear away. Currently, booms, floating devices that corral oil spills, are at best capable of containing the spill; oil removal is an entirely different process. But the iron filings can work in conjunction with an electromagnetic boom to allow tighter constriction and removal of the oil. Using solenoids, metal coils that carry an electrical current, the electromagnetic booms can steer the oil-filing mixture into collector tanks.

Unlike other oil cleanup methods, the magnetized oil technique is far more environmentally sound. There are no harmful chemicals introduced into the ocean — magnetite is a naturally occurring mineral. The filings are added and, briefly after, extracted. While there are some straggling iron particles, the vast majority is removed in one fell, magnetized swoop — the filings can even be dried and reused.

"This technique is more environmentally benign because it's natural; we're not adding soaps and chemicals to the ocean," said Cherri Schmidt, head of Fermilab's Office of Partnerships and Technology Transfer. "Other 'cleanup' techniques disperse the oil and make the droplets smaller or make the oil sink to the bottom. This doesn't do that."

Warner's ideas for potential applications also include wildlife cleanup and the use of chemical sensors. Small devices that "smell" high and low concentrations of oil could be fastened to a motorized electromagnetic boom to direct it to the most oil-contaminated areas.

"I get crazy ideas all the time, but every so often one sticks," Warner said. "This is one that I think could stick for the benefit of the environment and Fermilab."

[This article was written for Fermilab Today: http://www.fnal.gov/pub/today/] 

Epigenetics in the Fight against Cancer

All of biology lives and dies by four letters: A, T, C, and G — the components of DNA. Our functions and physicalities, our organs, blood and bones, all reduce to this one cardinal script.

But in this intricate system, even the smallest changes can trigger genetic disaster. Until recently, doctors and researchers focused on small, permanent changes, called mutations, in the DNA sequence as the main instigator of some diseases, like cancer. But researchers are finding that many illnesses arise from more than just genetic mishaps. They’re finding that changes on the surface of the DNA, rather than in the DNA sequence itself, increasingly affect the onset and subsequent treatment of the disease.

The idea of DNA surface changes has sparked a discussion about the very way scientists study cancer, leading one researcher to ask a novel, yet critical question: Is there an off button?

The emerging field is known as epigenetics. Epi (meaning over, outside of, or around) indicates that the modifications to the DNA do not take place in the sequence itself, but rather, as additions to chromosomes (compacted molecular sticks that contain DNA) or the proteins that help make them.

Epigenetics research is based in the idea that what we breathe, eat, or are simply exposed to can reprogram gene expression and change how physical traits manifest in our bodies. It’s not exactly “you are what you eat,” but researchers have made strong, and in some cases undeniable, connections between environment and disease. The link between smoking and lung cancer is a prime example: smoking not only changes the sequence of DNA itself, but also makes changes outside the DNA that influence how it’s expressed in the lung, which contributes to uncontrolled cell growth and tumors.

“Traditionally, most researchers look at the genetic effects and only treat the symptoms of the mutation,” says Liang Gangning, associate professor of research at the University of Southern California’s Keck School of Medicine. But treating the symptoms doesn’t necessarily treat the cause, he says.

Sibaji Sarkar, an instructor at Boston University’s School of Medicine, centers his research on exactly that idea, focusing on two main epigenetic changes that he thinks are linked to cancer onset and relapse. Both involve chemical additions that alter large scale DNA expression. Once bonded to the chromosome or protein, the chemical acts as a switch that shifts how the DNA gets expressed as physical characteristics.

Part of Sarkar’s research explores the concept that cancer mimics a natural process in our bodies called epigenetic differentiation. Though it sounds daunting, this process is a normal, and vital, part of how humans develop various tissue types. The lungs and liver, for example, comprise cells that all contain the exact same DNA, yet carry out two different functions. Different snippets of DNA called genes regulate different parts of the body, based on their activation patterns. For example, the genes that control lung function are active in the lungs, but not the liver, and the genes that control liver function are active in the liver, but not the lungs. It’s the changes outside the DNA sequence that control activation of these genes. Sarkar thinks this process mirrors how normal cells get changed, or activated, into cancerous ones.

Of course, epigenetic changes alone don’t cause cancer. Cancer progression is an enormously complex mechanism involving both DNA mutation and epigenetic changes. On the genetic side, if the DNA sequence becomes mutated, it sends out a message that’s inconsistent with the original molecular blueprint. RNA, DNA’s sister molecule, translates the DNA’s message into proteins, but if the DNA is mutated the proteins come out defective.

Sarkar compares the mutation process to the rankings of the military. He compares the DNA to a general who devises a strategy, the RNA to the lieutenant who relays the message, and proteins to the troops that fight and do the actual work. But mutated DNA compromises the genetic strategy, skewing the message, which leaves the protein troops unable to properly do their job. Depending on the protein, that means uncontrolled cell growth.

Flawed DNA, however, is only part of what causes cancer. On the epigenetic side, a process that adds chemicals to the DNA, known as methylation, attracts the most attention. During methylation, a string of carbons binds onto a section of DNA and prevents the cell from reading the gene’s instructions. Our cells contain genes called “tumor suppressors” which control cell growth. But methylation of the tumor suppressor gene interferes with its purpose. As a result, cells grow more than they should, which can lead to tumors.

Depending on what region of the DNA it affects, methylation can elicit a huge range of responses. But these changes aren’t necessarily permanent: the carbons can detach from the DNA naturally. This reversibility gives researchers like Sarkar and Gangning a new angle in developing drugs for cancer. These drugs aim to reverse or stop the methylation from impeding the proper function of the cancer-fighting genes by binding to and blocking the site on which methyl groups dock. In May 2014, Sarkar suggested the possibility of a cancer “on-off switch,” the idea that, if demethylated, silenced tumor suppressor genes could turn on again and stop tumor growth, and even future relapse.

Four months later, Gangning and his colleagues found that an epigenetic drug, called 5-Aza-CdR, did indeed reactivate some tumor suppressor genes by removing the methylation. Without the suppressive methylation, the genes can recover its original purpose—suppressing tumors.

Epigenetics and cancer researchers like Sarkar and Gangning don’t aim to replace radiation and chemotherapy with epigenetic drugs. They see it as a supplement. The epigenetic drugs work synergistically to increase potency of the traditional treatments and decrease the rate of relapse.

“These epigenetic drugs are fine adjustments to the treatments we have currently — fine but extremely important,” says Sarkar.

The FDA approved a handful of epigenetic drugs for some end-stage cancer therapies. But the drugs are not yet widespread in clinical recommendations, mostly because they are non-specific and affect the genome as a whole. That is, instead of just demethylating the tumor suppressor genes, the drug has the potential to demethylate any gene, at random. This concerns many doctors because it can lead to other serious genomic complications.

Currently, the National Health Institute is pushing to develop more specific ways to target just the cancerous cells for demethylation. Other epigenetic studies use animal models to explore treatment time frames, as well as decide the best technique to administer therapies.

“Cancer is very complex, and to totally eradicate it is equally as complex. You have to cover all the bases,” says Sarkar. “It’s not just DNA changes; it’s changes on the DNA too, and that’s why these [epigenetic] drugs are necessary.”