Petra Fromme, an Arizona State University professor of chemistry and biochemistry, has been appointed by President Michael M. Crow to lead a new Biodesign Institute initiative that will have a significant impact on the fields of bioenergy, enzyme catalysis and drug discovery, called the Center for Applied Structural Discovery.
Petra Fromme and her collaborators have developed new techniques, powerful tools and instrumentation to make molecular movies of the inner workings of proteins, all the way down to the atomic scale. Photo by: Glenn Roberts, SLAC
“Petra Fromme’s research promises to crack nature’s code and replicate fundamental biological processes, such as photosynthesis, for profound societal benefits,” said Crow. “The establishment of this center reflects ASU’s evolution as a leading research university, and it underscores our commitment to innovation in the pursuit of solutions to some of the world’s most pressing problems."
Spurring bioenergy and biomedical advances
Fromme has been a critical contributor to an ASU group that, for the past generation, has been one of the world’s leading photosynthesis groups in the world. And if scientists can successfully mimic photosynthesis – the way plants use sunlight energy to break apart water molecules into hydrogen and oxygen – they could help to usher in the hydrogen economy. But to date, no one has been able to unlock plants’ secrets to produce a clean, cheap and scalable renewable energy alternative.
“A crucial problem facing research groups around the world is discovering an efficient, inexpensive catalyst for oxidizing water to oxygen gas, hydrogen ions and electrons,” said ASU Regents’ Professor Devens Gust, who directs the Center for Bio-Inspired Fuel Production (BISfuel). “The research by Fromme and coworkers gives us, for the very first time, a look at how the catalyst changes its structure while it is working,” Gust added. “Once the mechanism of photosynthetic water oxidation is understood, chemists can begin to design artificial photosynthetic catalysts that will allow them to produce useful fuels using sunlight.”
Fromme was part of the BISfuel center led by Gust that had received $15 million from the Department of Energy for their bio-inspired solar energy conversion project.
The same research acumen and expertise has also been assembled at ASU to equally transform health care and biomedicine.
“Petra’s expertise will significantly complement, enhance and expand on our efforts to advance protein research and discovery for the early detection and prevention of disease,” said Raymond DuBois, executive director of the Biodesign Institute. “Only by understanding the structure, function and dynamics of the complete set of the million or so proteins found in our bodies, called the proteome, can we truly make an impact on identifying new drug targets for health care.”
“I am so much looking forward to continuing and expanding the exciting research on protein structural discovery toward making molecular movies with my colleagues and students here at ASU in the new Biodesign Institute center,” said Fromme. “The new tools we have developed, and the research and discoveries we have made, open up an entirely new avenue for solving protein structures, and will have a huge impact in a lot of areas, including development of clean energy and the medical field. For instance, the determination of protein structures will lead to the development of new drugs against cancer and infectious diseases by manufacturing drugs that fit into the catalytic center of the proteins like a perfect key in a lock.”
Fromme leads a $7.5 million effort, the Protein Structure Initiative: Biology Center for Membrane Proteins in Infectious Diseases, sponsored by the National Institutes of Health, to solve protein structures involved in the world’s leading cause of death.
Making molecular movies
Fromme and her vast network of collaborators have developed new techniques, powerful tools and instrumentation to make molecular movies of the inner workings of proteins, all the way down to the atomic scale.
This cutting-edge arsenal of physics-based and computational methods ultimately promises to allow scientists, in a process akin to freeze-frame photography, to take superfast snapshots to freeze proteins in time. To do so, they use a short X-ray pulse to shoot molecular movies that allow the fine details of these biomolecules to be seen at work like never before.
X-rays have long transformed medicine and captivated the public imagination after German physicist Wilhelm Conrad Röntgen first developed them in 1895. For his achievements, Röntgen won the Nobel Prize in 1901, and since that time, X-rays have driven others in their Nobel discoveries.
A half-century ago, X-ray technology was first used to solve the 3-D structure of the molecule of life – DNA – by James Watson, Francis Crick, Maurice Wilkins and Rosalind Franklin. The very first protein structure, myoglobin, was determined by John Kendrew, Max Perutz and others in 1958. Now, more than 100,000 protein structures have been solved.
But the structures for the vast majority of the estimated million proteins in the human body remain to be solved, and because X-rays can damage the protein crystal needed to solve the structure, it can take years of effort to solve a single protein structure. For instance, it took Fromme and her team about a dozen years to solve the structure of the complex solar energy conversion proteins of Photosystem I and II that convert light energy from the sun into chemical energy, thereby providing all the energy for higher life on Earth. “The unraveling of the structure and function of proteins is one of the most challenging goals in the post-genomic era,” said Fromme.
“From the beginning, the resolution of images recorded by biologists has been limited by damage due to the radiation used,” said physicist John C.H. Spence, Regents’ Professor in ASU’s College of Liberal Arts and Sciences, one of the principle scientists on several related grants, and core collaborator of Fromme's on the new concepts of structure determination with X-ray Free Electron Lasers. “But what happens if a pulse of imaging radiation is used that terminates before damage begins, yet contains sufficient photons to generate a useful scattering pattern, a principle termed 'diffract-before-destroy?'"
Fromme has been part of a large interdisciplinary team of ASU faculty members from the Department of Chemistry and Biochemistry (including Alexandra Ros, Tom Moore and Anna Moore) and the Department of Physics (John Spence, Uwe Weierstall, Kevin Schmidt and Bruce Doak) that have worked together with national and international collaborators on a groundbreaking X-ray laser technology to gain a fundamental understanding of proteins.
Their high-impact research and first proof-of-concept using the world’s brightest, fastest and most powerful X-ray laser technology – called time-resolved serial femtosecond X-ray crystallography – was recently published in the prestigious journal Nature. In 2012, the research team reported on the first novel structure determined at atomic detail, which was chosen by Science magazine as a top 10 breakthrough of the year. In just the past three years, the research group has published more than a dozen papers in the periodicals.
The X-rays are produced from accelerated electrons. Like light shined through a prism, X-ray pulses billions of times stronger than traditional sources are scattered when a single protein nanocrystal is sprayed like an inkjet printer onto the oncoming traffic of the ultra-bright X-ray beam. A single X-ray shot of the X-ray Free Electron Laser (XFEL) destroys any solid material in its path, ripping off the inner electrons of the atoms before a plasma is formed along with temperatures that become higher than the inside of the sun.
Many in the scientific community didn’t believe such an experiment would be possible and could lead to the determination of protein structures, however, the ASU team and their collaborators accomplished the proof of principle with the first diffraction experiments on protein crystals ever conducted at XFEL. In their first groundbreaking paper published in the journal Nature in 2011, they showed that the X-ray pulses, which are shorter than 15 quadrillionths of a second (or the time it takes for a particle of light to travel through a single human hair), are scattered from the intact undamaged crystal just before it explodes, allowing for the unraveling of protein structures.
Scientists use the X-ray patterns beamed onto a detector and powerful computers to reconstruct the 3-D structure of the biomolecules "in action."
A global center for protein innovation
President Crow sees the establishment of Fromme’s center as an inflection point for ASU research into an ever-greater and more ambitious level of science on a global scale.
“Our overarching plan is to build a new center housing professor Fromme's lab that will house the next generation of X-ray and protein technologies needed for this groundbreaking science.” ASU officials are also seeking to strengthen connections with Fromme’s collaborators in Germany in order to develop a large-scale transnational research effort.
The current costs for doing the original, groundbreaking proof-of-concept work relied on the reconversion of the 1 kilometer-long Stanford Linear Accelerator, supported at a jaw-dropping billion-dollar cost. Booking time on the instrument is also a challenge, allowing for just a few experiments every year.
“In 2009, we showed the first proof of principle after the world’s first high-energy, free-electron laser had become operational in Stanford,” said Fromme.
The driving force behind the development of the next-generation X-ray laser, much like the computer industry, is a mantra of faster, cheaper, smaller.
“Our goal is to develop a revolutionary attosecond laser that will shrink down the X-ray Free Electron Laser from 1 kilometer to a single meter, at a reduced cost of $1 billion to $20 million, and at an even greater spacial and time resolution,” said Fromme.
“This investment is necessary in order to make an impact on research that leads to the cures of diseases, and clean energy conversion from the sun for the future of mankind. It will give birth to a new era in protein structural biology, and provide the necessary training of personnel and students that are a true win-win for the state of Arizona and the international scientific enterprise.”
The opportunity to develop an entirely new field is rare in science, and ASU, with the leadership of Fromme and her colleagues, is the current world-leader in XFEL technology. Already, investment in ASU has brought the state of Arizona a return-on-investment of more than $30 million in research grants for Fromme and her colleagues, and has also attracted top talent and trained scores of students for new careers.