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Science at the Speed of Light

Inder Verma and Dino Morvinski

Postdoc Dino Morvinski and Inder Verma

Evasive and deadly, glioblastomas resist the harshest of treatments. They might lie low for a while, encouraging the faintest glimmer of hope in patients who have endured withering therapies, only to strike back with a vengeance.

Salk scientist Inder Verma's recent work on glioblastoma found entirely new evidence that 30 to 40 percent of blood vessels in tumors were originating from tumor cells themselves, explaining why drug therapy to inhibit blood vessel formation, while successfully used to treat many other types of tumors, might not be effective to stop glioblastomas in their tracks. "They are the ultimate shape shifters," says Verma, an American Cancer Society professor in the Laboratory of Genetics and holder of the Irwin and Joan Jacobs Chair in Exemplary Life Science, but he had a difficult time convincing other scientists.

"We showed this data in a paper, but the reviewers came back and said we needed much better resolution to show that these blood vessels really originated from tumors themselves," he explains.

Fortunately, Verma would soon have access to a brand-new, cutting-edge imaging resource that would provide the imaging resolution the panel demanded: the Waitt Advanced Biophotonics Center.

"We couldn't do that until the biophotonics laboratory was set up," he recalls, "but then we were able to do the high-resolution imaging that bore out our results. The paper is now published and hopefully will have an impact."

Beaming science forward

Ted Waitt and Ron Evans

Ted Waitt and Ron Evans

While biophotonics capabilities have been expanding at the Salk Institute for several years, the science of manipulating light to investigate biological functions took a giant leap forward when the Institute launched the Waitt Advanced Biophotonics Center, made possible thanks to a landmark $20 million gift from the Waitt Foundation. Officially dedicated in February, the Waitt Center serves as a state-of-the-art research hub within Salk, enabling investigators from across many disciplines to gain unprecedented insight into the inner workings of cells and tissues, probing molecular mechanisms of life at microscopic resolutions that not long ago were unimaginable. It also ensures that the Institute remains at the forefront of this rapidly evolving technology.

James Fitzpatrick

James Fitzpatrick

The center is made up of two complementary parts that together provide Salk investigators with state-of-the-art biophotonic and analysis technology required to answer today's key biological questions: a core facility and faculty laboratories. The core facility provides state-of-the-art visualization and analysis tools to Salk investigators from across many biological disciplines. The faculty research labs housed within the Waitt Center are engaged in both next-generation technology development and answering fundamental life science problems through imaging-rich investigations.

"By putting these incredible tools in the hands of Salk investigators in an interdisciplinary teamwork environment, breakthroughs are bound to happen," says Ted Waitt, vice-chair of the Salk Institute board of trustees and chairman of the Waitt Foundation.

Advanced biophotonics will allow Salk investigators to observe how single molecules and cells function in real time, for instance, and provide visualizations of how living systems function at the molecular level. Researchers will be able to watch the changes when a living cell malfunctions; how it turns cancerous and responds to drug therapy; or how neurons in a living brain respond to stress, exercise, learning and diet, to name just a few examples. The aging process could be viewed as it happens at the cellular level.

"In the past, scientists were limited to snapshots of cells frozen in time," explains James Fitzpatrick, who joined Salk from Carnegie Mellon University in December 2009 to direct the center's core facility. "Now it is possible to watch highly dynamic cellular processes, such as viruses invading their host cell, in real time and at high spatial resolution."

From image to discovery

Light microscopy

Light microscopy has come a long way since Jonas Salk observed poliovirus-infected cells through his simple microscope (shown farthest left). Today, Salk scientists work with fully automated million-dollar microscopes controlled by computers.

While the buzz about biophotonics may revolve around advanced microscopy and the remarkable images it produces, the ability to peer into the complex workings of a living cell generates an avalanche of new data. A single experiment can require hundreds of gigabytes, so data management and image analysis are crucial parts of the Waitt Center's function.

The center also provides training in the different technologies so investigators understand the possibilities and learn how to use the options available to them. "The core trains us and empowers us to use these tools whenever we need them," says Satchidananda Panda, an assistant professor in Salk's Regulatory Biology Laboratory. "We feel like this is part of our lab."

Perhaps the most important aspect of the biophotonics core facility, however, is that it encourages creativity by freeing researchers from the responsibility of costly investment in technology for individual experiments. Traditionally, at many other institutions, researchers decide they need a particular instrument and then pay for it out of their own funding, or the institution provides it for them. In contrast, the biophotonics core facility provides all Salk faculty with access to a much vaster array of advanced imaging technologies than they could acquire independently. This is a transformative approach to research because it allows investigators to formulate new experiments they may not have considered before and gives them the freedom to explore without the burden of developing, funding and learning to use costly technology on their own.

"The core facility is not just a service; it's a collaborative environment, like the Salk Institute itself, where people can do imaging-based cellular research," Fitzpatrick says. "We've worked hard to create a facility where investigators come and say, 'Here is the type of experiment that I want to do,' and we direct them to the right techniques and technology, and work with them on training for the imaging and also on data analysis."

Axel Nimmerjahn: Microscopy in miniature

Axel Nimmerjahn

By putting new tools into the hands of researchers, it allows them to directly address longstanding questions they have been unable to answer before.
-Axel Nimmerjahn

At the center's opening in February, physicist-turned-neuroscientist Axel Nimmerjahn demonstrated an advanced microscopic tool that exemplifies the kind of transformative technology the faculty labs will bring to the new Waitt Center: a miniature epifluorescence microscope, no bigger than a penny, and weighing the equivalent of a paperclip. Mounted on a mouse's head, it enabled and produced the first-ever optical recordings of brain cells functioning in freely behaving mammals.

"This type of technology represents the ideal of the Waitt Advanced Biophotonics Center," says Nimmerjahn, assistant professor in the Waitt Center and holder of the Richard Allan Barry Developmental Chair. "By putting new tools into the hands of researchers, it allows them to directly address longstanding questions they have been unable to answer before."

Nimmerjahn, who joined the Salk Institute last November, began creating miniature microscopes in graduate school at the Max Planck Institute for Medical Research in Heidelberg, Germany, and since then has used this and other technology for his research into how glial cells, which constitute the majority of human brain cells, interact with neurons and other cells. Once thought to play only a passive, supportive role, glia are now known to be critically involved in the healthy brain's function. Additionally, they play major roles in disease onset, progression and regeneration.

In the Waitt Center, he will continue pursuing his research into the function of glial cells while also developing new technologies such as miniature microscopy that can be applied to other areas of biological research. "The Advanced Biophotonics Center, along with the remarkable environment of the Salk, is the main reason I decided to come here," he says. "The opportunities are extraordinary."

Björn Lillemeier: Decoding cellular signals

Bjorn Lillemeier

From left: Rudolf & Sletten's Martin Sisemore (president) and Rene Olivo (vice president of operations) get an insider's look at Björn Lillemeier's super-resolution microscope.

Björn Lillemeier, assistant professor in both the Waitt Advanced Biophotonics Center and the Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis, uses advanced biophotonics to study the complex structure of plasma membranes—the outer shell of cells—and how they contribute to relaying molecular signals in T-cells.

Studies of plasma membrane—associated signaling had been hampered by the limited resolution of light microscopy. Lillemeier's laboratory is overcoming that problem through the development of high-resolution imaging techniques that allow researchers to observe directly the spatial distribution of membrane-associated molecules on a nanometer scale.

Using advanced biophotonics, for example, Lillemeier discovered that membraneassociated proteins are clustered into what he calls "protein islands," which led to a new concept about the architecture of plasma membranes. In the past, he explains, it was possible to see that signaling molecules would come together in clusters, but where the molecules ended up within a cluster was thought to be random. Now, with the ability to look at them in much more detail, it is clear that these clusters have sub-organizations to them, which affect the molecular mechanisms of signaling.

"We are now developing super-resolution microscopy that basically can measure molecule distributions down to ten nanometers," Lillemeier says. "The great thing about these new technologies is that we can now close the gap in our understanding of how these mechanisms become altered in diseased cells, which will provide routes to potentially new therapies for autoimmune diseases and cancer."

Martin Hetzer: Training a spotlight on the nucleus

Martin Hetzer

The Waitt Center core facility is vital to our research because of its live cell imaging capacity.
-Martin Hetzer

Nuclear pore complexes, the communication channels that regulate passage of molecules to and from a cell's nucleus, are made up of proteins known as nucleoporins. In studying nucleoporins, Martin Hetzer, Hearst Endowment associate professor in Salk's Molecular and Cell Biology Lab, discovered that the organization and architecture of the cell nucleus influences gene activity, playing a role in the organization of the genome and a very direct role in gene expression. This finding is significant because one of the hallmarks of cancer is abnormal organization of the cell nucleus.

"Over the past 50 years, scientists were limited to studying molecular mechanisms either in the test tube or on fixed cells," he says, "but this has major limitations. The Waitt Center core facility is vital to our research because of its live cell imaging capacity."

Using conventional light microscopes, nuclear pore complexes appear simply as fuzzy dots of light. Even electron microscopes, which have a superior resolution, cannot be used to study these protein complexes in living cells. Advanced microscopy in the biophotonics core facility, however, has allowed Hetzer to visualize the nuclear pore complexes at the structural level as they are assembled and inserted into the nuclear membrane. Looking ahead, super-resolution microscopy will allow him to drill still deeper into the individual components of nuclear pore complexes in living cells.

"Our goal is to visualize transcription and expression of a gene inside a nucleus in real time as tissue undergoes developmental processes," he says. "What makes this so exciting for us is that nucleoporins are key regulators for developmental genes and also potential markers for causes of cancer."

Satchidananda Panda: Illuminating visual processing

Satchin Panda

Satchin Panda

For nearly a century, scientists believed that only the photoreceptors rods and cones in the retina converted light into electrical signals to the brain. That changed with Satchidananda Panda's discovery of melanopsin, a photoreceptor in the retina that sends signals to the body's biological clock and that is only present in a few thousand cells embedded in the retina.

Before the advent of advanced biophotonics at Salk, Panda's work required lengthy imaging processes that ultimately didn't produce the kind of visualization he and his colleagues wanted. But his research into melanopsin has evolved along with the expanding capacity of advanced biophotonics at the Institute. With the installation of new microscopy technology, Panda changed his research strategy to work with imaging that became significantly more precise. "Suddenly," he says, "we could go to the biophotonics core and get a beautiful three-dimensional view of the retina—and a nice view of the brain to see where mRGCs connect."

Panda and his collaborators used advanced biophotonics to discover that melanopsin-expressing retinal ganglion cells, or mRGCs, reach out to visual processing centers in the brain, where they relay information about the brightness of incoming light. The findings reveal a new role for melanopsin during image-forming vision that could make a significant contribution to support vision in people with advanced retinal degeneration.

Clearly, biophotonics has broad application across multiple areas of investigation. But what does the dawn of the biophotonics age mean to biomedical research?

"Biophotonics is one of those transforming technologies that will impact nearly all the science being done at the Salk Institute," says Inder Verma, who was one of the driving forces behind the establishment of the Waitt Center. "By opening new vistas at the level of individual cells or molecules, it will revolutionize our understanding of the brain, the aging process and the development of cancer and lead to new diagnostic tools and treatments for hitherto intractable diseases."