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A national x-ray free-electron laser facility for rapid, massive biomedical advance

3 February 2016
Accelerator builder Richard York's XFEL vision was already in hand when President Obama called for a US cancer "moonshot."

After President Obama called in his state of the union speech for a "new moonshot" to "make America the country that cures cancer once and for all," ideas for how to proceed quickly began appearing. In a Wall Street Journal op-ed, physician and former Republican US senator Tom Coburn (OK) urged Congress to "unleash big data." The New York Times presented four other possible "missions for a cancer moonshot": "Eliminate excessive government regulation and oversight of cancer programs," "A moonshot for a cure can also help cancer prevention," "Make it easier and more likely the patient data will be shared," and "A major government cancer effort can advance precision medicine."

But as I knew from several years of minor occasional involvement, accelerator physicist Richard York of Michigan State University had been developing a cancer "moonshot" idea long before the president spoke. It's one that's suggested by the ever-increasing applicability of physics methods and knowledge to biology. York believes the US should build a high-capacity national x-ray free-electron laser (XFEL) facility for biomedical research. It should be optimized to yield new fundamental knowledge, and to do so at a high rate. He constantly emphasizes that rapid, massive improvement in understanding the biological processes of living systems would mean rapid, massive transformation of medical science's abilities to confront cancer.

Full disclosure: My professional interactions with York began nearly a third of a century ago at the Thomas Jefferson National Accelerator Facility in Newport News, Virginia. I was a wordsmith. He was a critical member of a tiny team of physicists who had just shocked the world of big science by winning the US Department of Energy contract to build the next big accelerator for nuclear physics.

Today, to drive a national biomedical XFEL, York proposes—in a Physical Review Accelerators and Beams paper—what he sometimes summarizes as an accelerator with "a novel recirculated topology that multiplies worldwide capacity for XFEL-based research by at least 5, yielding more results much sooner with concomitant life-saving treatments." That's important, he observes, "since cancer annually strikes 1,700,000 Americans, kills 600,000, and costs $170B."

But a high-capacity XFEL for biomedical research would itself cost up to a few billion dollars, with annual operating costs of up to a few hundred million dollars. That's part of why York has been shopping his vision widely, in some cases calling to mind what the New York Times reported in 2014 under the headline "Billionaires with big ideas are privatizing American science."

Much of privately funded science, the Times reported, engages biomedicine. Lawrence Ellison of Oracle Corp, for just one example, created the Ellison Medical Foundation in 1997. "Hundreds of biologists have benefited from its patronage," the article said, "and three have won Nobel Prizes. So far, Mr. Ellison, listed by Forbes magazine as the world's fifth-richest man, has donated about half a billion dollars to science." Another example was Gordon Moore of Intel, who had spent $850 million on physics, biology, the environment, and astronomy. Another was James Simons, from the field of hedge funds, who had given $1.1 billion for math and science generally.

It's probably unlikely that a biomedical XFEL will get built by the usual US funder of huge accelerators and light sources, the Department of Energy. But if researchers come to share York's vision for biomedical breakthroughs, wouldn't he have reason to expect that a funding plan could evolve?

Although XFELs support research ranging from condensed matter to chemistry to materials science, their biomedical breakthrough potential compels attention to their prospects for life-saving advances. York's envisioned national effort would exploit new but proven accelerator and light-source technology. A biomedical XFEL could deliver x rays of sufficient intensity and brevity "to provide three-dimensional structural (picture) and temporal (movie) information of living systems with atomic resolution," he said. "This information promises to yield transformational insights into biological functions at the molecular level, leading to improved treatments and possibly cures." He added, "It is vital to note that a US biomedical XFEL would boost the presently limited worldwide capacity for such research by a much-needed factor of 5 to 10, delivering these breakthroughs decades earlier."

Such an XFEL would take advantage of recent advances, but as York is the first to stipulate, the basic vision isn't new. In Nature Structural Biology, the 1998 editorial "Bright future for x-ray FELs?" looked at XFELs for biology, noting that many biologists were "still becoming familiar with the big science of accelerators." Often that editorial's cautious outlook is still to be found among biomedical researchers, who—unlike nuclear and particle physicists—have little in the way of any tradition of banding together to thrash out a robust nationwide consensus about the scientific need for a national-scale research facility. Yet the editorial's final sentence merits quoting, even 17 years later—in fact, following the president's speech, especially 17 years later. It said, "Improving the technology of x-ray sources could open the doors to as yet unimagined experiments."

That editorial paused to explain XFELs:

What is an FEL, and how would radiation from an XFEL differ from synchrotron radiation? In simple terms, an FEL is a laser (a source of highly coherent radiation) that can be realized when a very compact pulse of high-energy electrons produces radiation in an undulator (a set of magnets of alternating polarity). The intense undulator radiation bathes the electrons traveling at relativistic speeds, causing them to bunch together in regions the size of the radiation wavelength. When this occurs, the electrons act coherently, giving increased emission, which in turn gives increased bunching and an exponential rise in output power down the length of the undulator. This is in contrast to the situation in a typical synchrotron source where the electron bunches are not as compact and do not behave coherently; in that case, the radiation emitted increases only linearly with the length of the undulator. The peak brightness of an XFEL could be more than ten orders of magnitude greater than that of third-generation synchrotron sources. In addition to the huge increase in brightness, the XFEL would produce very short x-ray pulses, allowing time resolution in the fs range, hundreds of times faster than can be achieved presently with synchrotrons. Such a tremendous leap in performance would clearly herald the coming of a new generation of x-ray sources. These sources would look very different from today's synchrotron sources. The very dense electron pulses necessary for XFEL operation cannot be produced by a circular machine such as a synchrotron, unless the machine is impracticably huge. Therefore the fourth generation sources will rely on high energy linear accelerators, which can produce much denser electron pulses.

In the July 2015 Physics Today article "Brighter and faster: The promise and challenge of the x-ray free-electron laser," Philip Bucksbaum of Stanford University and Nora Berrah of the University of Connecticut in Storrs framed XFELs as science history with physics at the center. They wrote, "X-ray imaging is unique, both because of the penetrating power of x rays in solid matter—as Wilhelm Röntgen discovered in 1895—and because x-ray wavelengths are short enough to resolve the interatomic spacing in matter via diffraction—Max von Laue's discovery in 1912. Those properties allow scientists to push forward fundamental physical sciences." They reported that success at Stanford's Linac Coherent Light Source (LCLS) "has bolstered plans for more accelerator-based x-ray free-electron lasers (XFELs) in Europe and Asia."

In keeping with most such discussions, however, Bucksbaum and Berrah left unmentioned any possibility of additional US XFELs. But they told why the new machines, wherever built, constitute a compelling opportunity:

The ultrabright femtosecond pulses generated by XFELs have properties far beyond previous sources. They carry a million times more pulse energy than synchrotron x rays, are 10 000 times shorter, and have coherence that can produce focused x-ray beams with intensities up to 1020 W/cm2, more than a billion times greater than any previously achieved. The XFELs demand new research methods that can take advantage of those characteristics.

The coauthors explained that an optical-technology limitation of FELs was overcome by realizing "that a relativistic beam, as a gain medium, has a unique property: It moves at nearly the speed of light and therefore can remain coupled to its own radiation for long distances, even dozens of meters. Thus the spontaneous synchrotron radiation can build up enough to begin the process of microbunching. That method of lasing, called SASE for self-amplified spontaneous emission, has no wavelength limitations."

They emphasized that SASE FELs enable exploration of "x ray–matter interactions in new regimes of time and intensity that synchrotron x rays cannot reach." Again invoking physics history, they observed, "Synchrotrons were originally developed by the physics community in the 1970s and 1980s, and they quickly became hugely important tools for molecular biology as well as for physics." Then they offered this tentative prediction: "The same trend may be repeating for XFELs."

Though they left investigation of that trend mostly to others, they summed up this way: "Scientific research with XFELs will add to our understanding of the interaction of matter with photons and reveal the intricacies of phenomena still not understood in physics, chemistry, and biology. The combination of short wavelength and femtosecond time structure provides a unique tool for investigating nanoscale structure and dynamics."

Though Bucksbaum and Berrah didn't dwell on biology, that field was addressed frontally in February 2015 when the accelerator-focused physics magazine CERN Courier published "XFELs in the study of biological structure" by Eaton Lattman of the Hauptman-Woodward Medical Research Institute and BioXFEL Center at the University at Buffalo, SUNY. The Courier encapsulated Lattman's argument in this thumbnail summary: "The femtosecond pulses and astonishing peak brilliance of x-ray free-electron lasers are enabling whole new classes of experiments for imaging biological structures." Lattman wrote:

X-ray diffraction on nanocrystals … reveals 3D structures at atomic resolution, and allows pump-probe analysis of functional changes in the crystallized molecules. New modalities of x-ray solution scattering include wide-angle scattering, which provides detailed pictures from pump-probe experiments, and fluctuational solution scattering, where the x-ray pulse freezes the rotation of the molecules in the beam, resulting in a rich, 2D scattering pattern. Even the determination of the structure of single particles is possible.

Lattman focused mostly on crystallography and time-resolved solution scattering. In his concluding paragraph, he wasn't arguing for a new US XFEL for biomedicine, but what he wrote invites that thought. He portrayed an evolving international XFEL scene without future additional US involvement:

Currently, the only operational XFEL facilities are at the SPring-8 Angstrom Compact free-electron LAser (SACLA) at RIKEN in Japan and the LCLS in the US, so competition for beamtime is intense. Within the next few years, the worldwide capacity to carry out XFEL experiments will increase dramatically. In 2017, the European XFEL will come on line in Hamburg, providing a pulse rate of 27 kHz compared with the 120 Hz rate at the LCLS. At about the same time, facilities at the Paul Scherrer Institute in Switzerland and at the Pohang Accelerator Laboratory in South Korea will produce first light. In addition, the technologies for performing and analysing experiments are improving rapidly. It seems more than fair to anticipate a rapid growth in crystallography, molecular movies, and other exciting experimental methods.

Many in the cancer research community express caution when it comes to wishing for huge boosts in research funding. At JAMAJournal of the American Medical Association—a recent commentary in the cancer-focused journal JAMA Oncology appeared under the headline "A call for value in cancer research." It questioned the practical worth of enormously expensive scientific instruments.

"In the fall of 2014," the commentary began, "2 spaceships entered similar orbits around Mars: NASA's $671 million MAVEN and India's $74 million Mars Orbital Mission." The authors wondered if the difference in scientific payoffs will turn out to justify the nearly $600 million cost difference. They went on to argue for the importance of "considering research investments in terms of costs as well as scientific productivity."

No doubt that's an important point for the envisioned US cancer effort. Still, as York regularly stresses, if you seek to truly understand something, somehow you must find ways to see it truly clearly. For understanding Mars, that means actually going there—just as it did for America's original effort to understand the Moon. And that original effort was the expensive national one for which the president named his national cancer effort: the moonshot.

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Steven T. Corneliussen, a media analyst for the American Institute of Physics, monitors three national newspapers, the weeklies Nature and Science, and occasionally other publications. He has published op-eds in the Washington Post and other newspapers, has written for NASA's history program, and was a science writer at a particle-accelerator laboratory.

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