Fall 2006
In This Issue:
Focus On Optical Materials
The Power of Light: Biophotonics Reveals the Inner Working of Cells
Ahmed Heikal's Laboratory for Functional Imaging and Biophysics of Biological Systems uses the power of light (i.e., photons) to understand the functioning of living cells at the molecular level. To do that, Dr. Heikal, an associate professor of bioengineering, uses ultrafast laser spectroscopy in combination with fluorescence (both confocal and two-photon) microscopy. “Whether it is an optical fiber or a very fancy crystal, everything we do is based on optical materials to manipulate light,” he remarked during my recent visit to his lab in the Department of Bioengineering at University Park.
“The idea with our integrated biophotonics approach is that once we see the cellular structure using fluorescence microscopy, we want to zoom in to see how biomolecules in a certain cellular compartment behave under certain physiological conditions,” Heikal elaborated. “Our multiscale, integrated biophotonics approach has benefits in both basic and applied research. Can we navigate the biocomplexity in live cells one protein, one organelle at a time? As you are aware cells are the building blocks of the human body. We are trying to understand the underlying molecular processes that regulate the cell's function. Remember these systems are interconnected, so this is very challenging.”
He and his research group have managed to surmount the difficulties by developing a unique laboratory setup that allows them to study processes in living cell (e.g., energy metabolism, protein-protein interaction, and structure-function relationship in biomembranes) at various scales of size and time. On the size scale, they are able to observe from molecular conformations (∼10 nm) up to cellular aggregates and tissues. In the time domain, they are able to monitor molecular processes on picosecond (a millionth of a millionth of a second) time scales, as well as study chemical kinetics that take place over seconds.
Heikal explained their approach: “When you look at a sample of biomolecules, you are averaging across different molecular structures and processes, so you lose access to interesting information. As a result, we have developed single-molecule techniques to remove the averaging that is inherent in bulk studies and obtained direct access to these processes. Our single-molecule approach is currently being used in both cell (e.g., diffusion on cell membrane and protein-protein interactions) and solution (e.g., protein dynamics and protein-DNA interactions) studies. We can look at hierarchical systems with all the tools that we need.”
The use of femtosecond lasers allows Heikal's group to study cell processes at the molecular level without damaging the cell. Rather than using dyes to stain cell features, they use naturally existing fluorescent biomolecules that are found in the cells, such as flavin and NADH, to investigate energy metabolism under different physiological conditions. Using this approach, his group has been able to accurately detect biochemical differences of NADH in cancer and normal breast cells, without drugs or invasive surgery.
Giant unilamellar vesicles (GUV) are model systems
for cell membranes. The fluid phase of this ternary
phase GUV is marked with DiI-C12, a fluorescent marker.
The ultimate tools for noninvasive investigation in living cells or tissues are biophotonic techniques, according to Heikal. His group pursues two other areas of interest using their femtosecond laser and fluorescent microscope systems. The first area is understanding structure-function relationship in the plasma membrane of living cells. The nanostructure of the membrane determines what enters and leaves the cell, he explained. Membranes regulate numerous biological functions, such as cell signaling, cell migration, and protein sorting. The goal of their research is to understand how the different domains of lipids that make up the cell membrane correlate with the membrane function.
A third area of interest is protein dynamics, in which his group attempts to understand how protein-protein interactions occur under various cellular conditions. Protein folding — the way in which the chains of amino acids in proteins fold up to perform their specific function — has been linked to diseases such as Parkinson's and Alzheimer's when the folding goes awry. Heikal would like to be able to see how these processes take place in real time at the molecular level as well as in their native environment in living cells.
“To do all this we need to be able to develop new techniques, new modeling, and new image processing,” Heikal said, looking around at tables crowded with electronics, lasers, microscopes, and computers. “We are pretty much at the cutting edge with what we have here. This laboratory also represent an excellent environment for training graduate, undergraduate, and postdocs in this new frontier.”
Heikal's biophotonic capabilities and research interests have resulted in collaborations that are wide and cross disciplinary. “They have put us in excellent company with other faculty at Penn State, such as Erin Sheets and Steve Benkovic in chemistry, my colleagues here in bioengineering Peter Butler and William Hancock, Graham Thomas from biology, and Zhiwen Liu in electrical engineering.” He is also co-leader, with Dr. Daniel Ou-Yang, of the Biophotonics division of the Center of Optical Technology (Lehigh-PSU).
Heikal's group is also cross disciplinary, with students from the Integrative Biosciences (IBIOS) graduate program in the Huck Institutes, bioengineering, chemistry, and biology.
After our tour, Heikal walked me to the entrance of the building. At the door we chatted for a few moments about his background and the sense of purpose it gave him. Heikal grew up in a small village in Egypt and was the first person in his family to learn to read and write. All through his career, he told me, his teachers and professors had encouraged and supported him. Now it was his turn to do the same for his students.
Although he did not mention it, I later discovered that one of Heikal's mentors, his Ph.D. advisor at Caltech, is the 1999 Nobel Laureate in Chemistry Ahmed Zewail. Prof. Zewail is the man largely responsible for the development of femtochemistry science. A hero in Egypt — a postage stamp bears his portrait — Zewail has received Egypt's highest honors. For Heikal, it must have seemed like an unbelievable journey from his own tiny Egyptian village to the laboratory of a Nobel Laureate at Caltech. Which would help to explain his puzzling refusal when I first asked to photograph him in front of his lab equipment. “It would seem presumptuous of me,” he responded. Yet once his available students were herded into the lab, he seemed perfectly content to let me take as many photos as I needed.
— WM
Contact:
Ahmed A. Heikal, Validate to view contact info
