By Matthew Chin and Wileen Wong Kromhout
Three young researchers in the UCLA Henry Samueli School of Engineering and Applied Science are opening up new avenues of inquiry and developing new tools for the precise control of nanoparticles, figuring out new ways to “debug” the brain circuit and building ultrasensitive biosensors for the early detection of disease.
For their pioneering work, Dino Di Carlo, assistant professor of bioengineering, Yu Huang, assistant professor of materials science, and Jin Hyung Lee, assistant professor of electrical engineering, have been named recipients of the 2010 NIH Director’s New Innovator Award. Given to young faculty by the National Institutes of Health, the award includes funding of $1.5 million over five years for each investigator to support highly innovative research.
“The work Dino, Yu and Jin do today will have a profound impact on the future of biomedicine,” said Vijay K. Dhir, dean of UCLA Engineering. “Having chosen three young faculty for the New Innovator Award is another testament to the quality of our faculty and their unwavering dedication to innovative research.”
This NIH program is specifically designed to support creative new investigators with highly innovative research ideas at an early stage in their career, when they may lack the preliminary data required for traditional grants. The review process emphasizes creativity, innovative research approaches and the potential of a given project to have a significant impact on an important biomedical or behavioral research problem.
“It is an honor to receive the New Innovator Award,” said Di Carlo. “This award will enable me to support the students working in my lab as we develop important tools that can be broadly used by biologists to uncover unique aspects of cellular function that will impact human health.”
Dino Di Carlo: New tools for controlling nanoparticles within cells
Our understanding of biological systems and the ability to apply that understanding to improve human health or quality of life are being limited by current tools to explore and report on the micro- and nano-level at which life functions, according to Di Carlo.
“It is my belief that transformative rather than incremental changes to biomedicine will require a critical mass of reliable quantitative data describing the dynamics of cellular processes,” said Di Carlo.
By developing simple tools for the precise control of nanoparticles locally within cells, Di Carlo hopes it will be possible to understand and control aspects of cell behavior. The types of tools Di Carlo’s team hopes to develop will allow a more mathematical understanding of cell behavior. He anticipates that large amounts of data will be required to learn how cells statistically respond to stimuli, because, like people, each cell is a complex system with a unique history of past experiences that affect current behavior.
A variety of new high-throughput tools will be necessary in the coming decades. These new tools could, for example, allow for breakthroughs in fields ranging from biofuel production and gene therapy to cell-computer interfaces.
“If scientists today want to engineer cells to do something useful, this is a huge challenge,” said Di Carlo. “Most of the time it’s just simple trial and error. What we want to do is develop a tool for basic research that reduces the large number of unknowns. We want to be able to make the system more quantitative. Hopefully, we can then engineer cells more systematically and make them useful for solving pressing issues in energy production and the environment or to cure diseases.”
Di Carlo feels what’s critically lacking is a simple and robust approach to be able to precisely apply controlled amounts of chemicals, forces or heat at very specific points within a cell.
“We know that the location of biochemical signals is really important in directing cell behavior,” Di Carlo said. But currently there are no automated tools to help him understand, for example, how a cell reacts if a stimulus is placed near the nucleus rather than near the “feet” of a cell.
Ultimately, understanding cell behavior, Di Carlo hopes, will allow scientists, doctors and others to be able to manipulate cells for the benefit of medicine and the environment.
“In our lab, we work on microfabricated systems and have come up with these magnetic substrates or nano-active slides that we think will be successful,” said Di Carlo. These slides contain arrays of microscale dots of magnetic material which concentrate magnetic field gradients. This allows scientists for the first time to be able to quickly create and localize ensembles of magnetic nanoparticles inside the cells that adhere to these slides.“Our simplest tool is basically a slide that’s patterned so that cells stick in very precise positions,” he explained. “Further, there are magnetic elements on the slide so that when we place a permanent magnet near it, it magnetizes those elements. This allows us to control the positions of the nanoparticles inside the cells and get them to coalesce precisely within thousands of cells at a time.
“A joystick would then allow us to control the permanent magnet. With this approach, nanoparticles can be moved or repositioned in just minutes whereas before it would take hours to move the same nanoparticles inside the viscous environment within cells.”
Yu Huang: Building ultrasensitive biosensors to detect diseases
Detecting and identifying the presence of specific molecules and biological species are critical to medical diagnostics and biological research. For example, cancers and other diseases can be detected by the presence of specific proteins or molecular markers in the blood stream.
However, current detection methods either require complicated sample preparation, such as fluorescent labeling or amplification procedures, or are limited in sensitivities.
Huang, assistant professor of materials science and engineering, is proposing to build ultrasensitive biosensors using the nanomaterial graphene — a single atom-thick carbon lattice. This could make the detection process significantly more sensitive than conventionally used materials. Her NIH Director’s New Innovator Award will go toward this research.
“The potential ultrasensitivity in a biological sensor composed of graphene nanostructures could result in the detection of diseases at an earlier stage in patients than possible today,” Huang said. “For example, cancers could be detected when they are very small and perhaps even early enough where they are treatable.
When a molecule binds to a transistor surface, the charge that results can induce a change in the electrical current passing through the device. The ultrathin profile of graphene means that the total electrical signals of the graphene device can be easily modified by a small number of binding molecules, making these sensors very sensitive to the target molecules, such as cancer markers.
With Huang’s design, a large array of detectors may be created for highly parallel sensing. These multiplexed sensors could decipher a large number of molecular markers and may eventually enable personalized diagnosis and treatment.
“We have exciting projects in both nanoelectronics and biomaterials,” Huang said. “The NIH support allows us to break down the boundaries and put our efforts into making significant progress on the interface between the two”
Jin Hyung Lee: Debugging the Brain Circuit
At UCLA , Lee is leading research on advanced neuroimaging techniques. She is increasing their power, scope and precision by combining functional magnetic resonance imaging (fMRI) with optogenetics, a technology that allows genetically specified neurons to be activated through light.
This novel technique is called ofMRI. The NIH award will fund her research using ofMRI to image stem cells in the central nervous system.
Since the early 1990s, fMRI has been used to explore the inner workings of the brain. A special type of MRI, an fMRI, measures the blood and oxygenation level in the brain. Areas with heightened blood oxygenation levels are correlated with brain activity. The vivid contrasting colors of the brain scan imagery show that there is activity in areas of the brain, but are these blood and oxygenation level-dependent (BOLD) signals directly caused by the activity of neurons? More specifically, which neuronal element can trigger the BOLD response? These topics have been controversial in the field.
Recent research led by Lee and published in the journal Nature in June shed light on this topic through the use of ofMRI. The researchers showed that very specific neuronal elements can be triggered and monitored.
They introduced two genes into rat brain cells called excitatory neurons. One of the genes uses a fluorescent jellyfish protein gene to show where the cells responded. The other was a gene from algae that reacts to light. Using a light source to stimulate the excitatory neurons, scientists looked for the resulting response of the brain. They found a similar response to that generated by traditional fMRI.
“This technology shows that the BOLD signal can be generated causally by excitatory neurons,” said Lee, who holds joint appointments in the David Geffen School of Medicine (in psychology and biobehavioral sciences and in radiology). “And it also gives you a new platform to analyze and debug your brain circuit.”
Lee’s research has also shown that ofMRI has the potential to be a far more powerful and precise neuroimaging tool — one that can discern the brain’s specific internal structure, wiring and function in much greater detail than currently available.
For future research, she is working in several areas that will continue to bridge engineering and biomedical imaging to enable advanced applications for medical research. She is also working to help figure out the brain circuitry associated with neuropsychiatric disease, and apply those findings for potential cures.
“I feel fortunate that NIH had the vision to look past the risk and recognize the potential of my high-impact, high-risk project,” Lee said. “I am grateful for this opportunity to try out my innovative ideas, and I hope to achieve all the goals I laid out in my proposal. This project, upon its success, will provide key guidance for developing novel stem cell therapies for brain diseases.”