ConvURGENT Bioscience

Like an artist sharing her latest Starry Night, geneticist Le Trinh invited her colleague to come see her experiment.

Hunched over a microscope, Vikas Trivedi watched what looked like tiny bumper cars meandering inside a petri dish. Every so often, something inside a dot would jump — like a sleepy driver jolted awake.

The little jump was a heartbeat. Trivedi was looking at live, day-old zebrafish embryos. Using the zebrafish as a model, Trinh researches how the heart forms in the developing embryo. Considering that a leading birth defect in humans occurs during the development of the heart valve, Trinh’s research is crucial in identifying what can go wrong.

Still looking through the microscope, Trivedi nonchalantly mentioned that he could better analyze the data by creating an algorithm to “unwrap” the embryo.

Trinh’s heart jumped a little, too. Trivedi’s algorithm would reconstruct the developing embryo with red and green labels through a 3D computer simulation. This was a giant leap for Trinh, an expert biologist and geneticist, but admittedly no mathematician.

“Voilà,” said Trinh, a senior research scientist in the laboratory of Scott Fraser, Provost Professor of Biological Sciences and Biomedical Engineering at USC Dornsife. “We now have this.”

Trinh waved an arm toward her computer screen, depicting a developing zebrafish heart in 3D. The movie shows how the heart begins with two halves and slowly merges into one.

Those halves that meld to form one beating heart could be a metaphor for Fraser’s office layout.

Sitting across from Trinh is Trivedi, a Ph.D. student in bioengineering who developed the algorithm. Working next to Trinh is research scientist Thai Truong, a trained physicist. Among other pieces of equipment, Truong and his team built the two-photon light sheet microscope — to which they hold the patent — that created Trinh’s 3D movie. Although the zebrafish heart beats 150 times per minute, the microscope photographs so fast that the slides that became the movie were ultra-sharp.

By converging their fields, the molecular genetics of a beating heart — the scientists also use quail embryos as models — can now be visualized in real time.

“This could never be done simply by using pure genetics or pure physics or pure mathematics,” Trinh said. “It took the three fields coming together and sharing our expertise to create this.”

Fraser’s triple-threat system is a microcosm of the upcoming USC Michelson Center for Convergent Bioscience. In January 2014, retired orthopedic spinal surgeon Dr. Gary K. Michelson and his wife Alya donated $50 million to USC to fund the center bearing his name.

Bigger, Braver, Bolder

The center will be the hub of a new collaboration between USC Dornsife and the USC Viterbi School of Engineering that takes interdisciplinary research in biomedical sciences to new heights.

The USC Michelson Center will stand in the southwest quadrant of the University Park campus, home to most of the science and engineering buildings. The facility will house 20 to 30 principal investigators with laboratories employing hundreds of researchers and students.

The days of seeing a chemist clad in rubber gloves, toting a tray of liquid-filled flasks and beakers across campus to use a light or magnetic resonance imaging (MRI) microscope in an engineering building are nearing an end. Some of the most advanced microscopes in the world — like the GE DeltaVision OMX Blaze that can generate 3D images of objects at the nanometer scale — will be housed at the Michelson Center.

“This center will usher in a new age of exploration and innovation at USC,” said President C. L. Max Nikias. “It will unite the most gifted minds from many academic areas, creating a powerful partnership that will extend across several different disciplines.”

Along with the biologists, physicists, mathematicians and chemists at the center will be engineers, who will build the latest technology capable of taking precise measurements inside cells. Together they will tackle the biggest health challenges by first building a biological “knowledge base,” then expediting the detection and cure of diseases.

USC Dornsife Dean Steve Kay, professor of biological sciences, said systems biology — which integrates biological data to better understand how biological systems work — was a precursor to convergent biology.

“Systems biology was a great example of what you can begin to see when you bring mathematics, computational science and biological sciences together,” Kay said. “But convergence is something bigger. I think it’s bigger, braver and bolder.”

The Michelson Center will house Fraser’s laboratory and the lab of Kay, whose investigations have contributed to the understanding of the genetic basis for circadian rhythms, which serve as the body’s clock for timing the day/night cycle.

Kay noted how differently the engineer and biologist think.

USC Dornsife Dean Steve Kay and his team have identified the existence of biological clocks inside the cells of plants controlling and acting at the level of DNA. These “clock genes” switch on and off on a regular basis (indicated here by bioluminescence), allowing a plant to adapt to its environment in a more competitive way. Kay’s lab analyzes biological clocks or circadian rhythms across multiple organisms to better understand molecular controls over whole organism behaviors. This research may provide better targets for clinical applications for the treatment of diseases such as diabetes. Image courtesy of Steve Kay’s laboratory.

“Engineers build things from the bottom up,” Kay said. “So they start off with a piece of paper and say, ‘Let’s design a new jet.’ The biologist takes a cancer cell and asks, ‘Why is this cancer cell responding to that drug but not this one? What is going on inside the cell that allows that to happen?’ So they start from the top down.

“Merging these together is a completely different process than, for example, the pharmacologist working with a biochemist or a cell biologist working with a developmental biologist,” Kay said. “Convergence is about bringing multiple people together with very different training and expertise.”

Kay emphasized that USC Dornsife’s partnership with USC Viterbi and its dean, Yannis C. Yortsos, will be critical to advancing not only collaboration, but real-world solutions.

“The hardcore, physics-based, material scientists might not realize the nanowires they were creating can become an essential biosensor and ultimately be used as a diagnostic for diseases,” Kay said. “But working in a convergent environment can bridge that gap.”

For a recent Proceedings of the National Academy of Sciences paper, Kay’s lab worked with chemical engineers at the University of California, Santa Barbara. Through analysis and computer modeling, the collaboration shed light on factors that affect circadian rhythms, the roughly 24-hour oscillations of biological processes that occur in many living organisms.

Circadian rhythms help people adapt to predictable daily changes in the environment. But too much light at night, not enough sleep, or eating or exercising too late can offset the necessary nighttime-phase cellular activity. This can lead to diabetes, heart disease and obesity. Alzheimer’s disease and some liver conditions also have been linked with so-called low-amplitude rhythms.

Kay’s effort aims to better predict how to target circadian proteins with therapeutics that can battle sleep disorders and neuropsychiatric diseases such as bipolar disorder.

Kay’s paper is an example of how biologists and chemical engineers can work together to fight key disorders, but merging such widely dispersed fields has culturally been difficult.

“First and foremost, there must be a willingness to bring them together,” Kay said. “Then, you need a venue.”

Enter the Michelson Center.

“This will be a place to meet and create an integrated culture,” Kay said, adding that the facility is expected to help draw even more talented researchers to push the frontiers of science at USC Dornsife.

Now I See

Fraser, director of science initiatives at the university with a joint appointment at USC Viterbi, is among the rare scientists who are experts in biology and physics. In Fraser’s lab, biologists love nothing more than to “steal tricks” from engineers.

There’s Ellis Meng, assistant professor at USC Viterbi, who has a spectacular ability to make devices.

“So she’s making electrodes that can float in the brain and let us record from many neurons at once,” Fraser said.

His team “steals” techniques from others such as Carl Kesselman, professor of industrial and systems engineering, who makes tools that let researchers interact with complex data sets.

“The important thing for me is that the way he structures these fosters my analysis and my collaboration with others,” Fraser said. “He’s truly an artist who makes the tools so they can aggregate heterogeneous data.”

A perfect example of convergent bioscience came during Arnold and Mabel Beckman Foundation meetings, Fraser recalled. The foundation invited nanoscientists and chemists working on artificial photosynthesis — or synthetic ways to harvest solar energy and turn it into chemical energy that could eventually charge a battery.

Also invited were bioengineers seeking to restore vision, such as University Professor Mark Humayun, professor of biomedical engineering, and cell and neurobiology at USC Viterbi.

During these gatherings, participants realized maybe they could take the chemicals they were using for artificial photosynthesis and inject them into the human eye to see whether the injection could make the cells that don’t normally, respond to light in the retina, Fraser said.

“And it looks like it’s working,” he added.

Humayun, after nearly 20 years of work, became the main researcher behind the world’s first commercially available artificial retina, a breakthrough that helps the blind see.

“The Beckman Foundation decided to hold meetings, intentionally trying to stir the pot,” Fraser added. “Now imagine if you had that whole thing working every day, stirring the same sort of pot.”

Heads Up

Underscoring the vision and support of Nikias and Provost Elizabeth Garrett, Executive Vice Provost Michael Quick said that convergent bioscience at USC is about more than a building or creating tools.

He cited Kay’s comparison of people who do heads-down research to those who do heads-up research.

“That is, are they looking down on the lab bench just focusing on their own science, or are they looking up and around and saying, ‘Who can I pull into a group to go solve this problem? It’s not so much what these people do, it’s how they do it that determines whether they’re part of this convergent bioscience movement.”

The education component of convergent bioscience is key, said Quick, professor of biological sciences at USC Dornsife. He pointed to the Health, Technology and Engineering program at the Keck School of Medicine of USC, which brings together medical and engineering Ph.D. students to work in clinics learning about problems that must be solved. Then they work in the laboratory creating medical devices.

“Ph.D. students should be well-trained in a discipline,” Quick said, “but they have to learn the mentality of interaction.”

Distinguished Professor of Chemistry Arieh Warshel recalled the difficulty in collaborating with researchers outside his field in the early stages of his scientific career in the 1960s and ’70s. 

“If I went to the best professors in electricity to ask them about a problem I wanted to solve, for example models for electrostatic effects in proteins, they had no clue what I was asking,” said Warshel, who in October 2013 won the Nobel Prize in Chemistry for helping to develop the principles behind computer simulations now indispensable in the study of the action of proteins.

“Maybe because the questions were strange to them. I had these problems and had to develop the methods to solve them myself. [My ideas] were too different in the way they thought about it.”

But after Warshel already had a good handle on the problem, collaboration with researchers in diverse fields proved extremely useful. “Exploiting what you already know is very helpful in productive collaboration,” he said.

Warshel is looking forward to collaboration at the Michelson Center, where he will continue his research on G protein-coupled receptors, which can lead to clinical treatment for everything from cancer to heart disease to type 2 diabetes.

“In this type of problem the direct collaboration with experimentalists who are studying the same system is indispensable,” he said.

Tear Down That Wall

In Assistant Professor of Physics Moh El-Naggar’s lab, physics doctoral student Ian McFarlane and undergraduate chemistry major Julia Lazzari-Dean examine semi-conductive nanofibers (yellow) produced by bacterial cells (blue), which could hold the key to new, cheaper solar cell or transistor technologies. Image courtesy of Moh El-Naggar’s laboratory.

Moh El-Naggar, an assistant professor of physics at USC Dornsife who has received the 2012 Presidential Early Career Award for Scientists and Engineers, likes where all this is going. His research combines biology and physics.

“When we talk about removing boundaries, sometimes we’re talking about removing actual walls that separate labs,” El-Naggar said. “We already work like that here. Our graduate students in physics work with graduate students in chemistry, biology, engineering and earth sciences.

“Many of the faculty have joint appointments and we’ve been doing that for a while. The one thing we’ve been lacking is an actual home for that kind of attitude. So in concrete terms, convergent science is about removing actual walls.”

El-Naggar’s research involves tapping into anaerobic bacteria found in plain dirt to create energy. His research revealed how the bacteria grow protein nanowires to move electrons around in their surroundings.

Using this bacteria, he aims to harness the microbes’ metabolism to power electronic devices from cell phones to car chargers. The bacteria’s metabolism may also result in new nanostructures and semiconductors for clean-energy technologies such as solar cells. This can all lead to a cheaper and more versatile energy source.

“The more we understand about charge flow and energy transfer in cellular systems, then we’ll be able to control them and maybe reach the level of sophistication with biological systems that we’ve already reached with metals and semiconductors and computers and so on,” El-Naggar said. “But that requires developing some fundamentals that are unknown, because we’re starting pretty much from scratch.

“In order to actually develop applications based on energy and charge transfer in biological systems, we have to be able to collaborate with people who think in a more applied context, like applied physicists and engineers.”

Richard Roberts, professor of chemistry, chemical engineering and biological sciences with joint appointments at USC Dornsife and USC Viterbi, is like-minded. He uses the tools of chemistry to understand and control biological processes. Roberts designs peptides and proteins using in vitro selection experiments. He conceived the messenger RNA (mRNA) display, a technique he uses for polypeptide design.

His team has re-engineered the protein synthesis machinery to create unnatural mRNA display libraries. This project, a nanoscale engineering effort, merges the power of display selections with the flexibility of combinatorial chemistry.

To do this, the scientists have worked to extend mRNA display beyond the natural genetic code. Their effort has created new and richly diverse compositions of matter for ligand design, drug discovery — and beyond.

The beyond involves analytic tests used for screening diseases such as pancreatic cancer, which is typically diagnosed late in its development.

“It’s not like your lungs, where if you start having problems you will cough and blood will come up and you’ll have overt problems,” he said. “If you have cancer developing in the pancreas, there really is no outward sign.”

Roberts is developing techniques to diagnose early and even before a disease manifests.

“In the next 20 years, you will be able to go in, get a test, and the doctor will say, you’re high in this, this and this,” he said. “You have a very good chance of having prostate cancer, or lung cancer, or another disease. Right now, there are very few analytic tests that are used for screening.”

For inspiration, Roberts keeps on his desk a replica of the Rosetta Stone, an ancient discovery showing writing in two known languages, but one mysterious script — Egyptian hieroglyphics.

Using clues from the two known languages, linguists were eventually able to decode the hieroglyphics. Roberts is doing something similar — he’s working to decode proteins to create drugs and diagnostic tools to fight diseases.

It could be argued that convergent bioscience is an extension of decoding the Rosetta Stone, using what we know to harness the unknown. Roberts and others at USC understand the urgency.

Read more about Gary K. Michelson

Read more stories from USC Dornsife Magazine‘s Spring-Summer 2014 issue