See other related articles by L. Pollack
The computational microscope provides a rare view of the electric field inside a nanopore of alpha-hemolysin.
Imagine how the prospectors who descended on California in 1849 would have fared had they possessed a functionalized hand that could simply reach into the Sacramento River and collect its gold. With their pans and sluice boxes the miners still missed the tiniest gold particles–that is, they had no way to capture the nano-sized flecks of the precious metal that graced the many rivers of the Sacramento River Valley. But what if a synthetic protein was crafted that specifically bound to gold and could aid in trapping gold nanoparticles. When Klaus Schulten heard about just such a mechanism, from the very scientist who had tediously labored to find a peptide sequence that affixed to gold, Schulten was intrigued. This eccentric scientist told Schulten he had indeed found a way to isolate gold from the Sacramento River, but wanted Schulten’s help in visualizing and explaining why the protein segment itself bound so well to gold. The situation warranted a tool to literally envisage the nano-world of the gold-binding peptide, and luckily Schulten had such a tool in his arsenal: the computational microscope. When Schulten agreed to illuminate the atomic details of the gold-protein system in 2001, he did not realize that this would also launch his entry into the field of bionanotechnology. But he soon discovered that the computational microscope was virtually ordained for bionano-applications.
Both the computational microscope and bionanotechnology are relative newcomers on the timeline of the history of science. Schulten coined the term “computational microscope” around 2005 to describe the imaging technique that can offer what no other traditional microscope can in terms of viewing nano-systems; furthermore, it is composed of unusual constituent materials. Scientific information from chemistry and physics, clever algorithms, powerful computers, and human imagination are but some of the elements comprising this novel microscope. Ideal for capturing behavior of living objects like proteins or ribosomes, the computational microscope, it turns out, can also illuminate what happens when you bring a biomolecule into contact with an inanimate nanomaterial, such as the protein on gold mentioned above. Bionanotechnology is the marriage between two fields that have usually been studied separately: biotechnology and nanotechnology. When experimentalists started to bring “wet” biological materials into contact with traditionally “dry” nanodevices, the combined systems of “wet” plus “dry” were so small that light microscopes did not have the resolving power to see the resulting interactions. What’s more, electron microscopy required freezing and thus could not capture progressing behaviors over time or image under natural (i.e. wet) conditions. Enter the computational microscope and Klaus Schulten’s research team, the Theoretical and Computational Biophysics group, located in the Beckman Institute for Advanced Science and Technology at the University of Illinois.
“The Beckman Institute is the United Nations of Science,” says Schulten about the place he has called home for twenty-six years. “All of the different sciences count equally; it’s not that one of them is better than the other.” The premise of the institute at its very conception was “multidisciplinary.” And Schulten is clear to point out he chose to go to Beckman because he needed to combine science with computer engineering principles to accomplish his goal of simulating biological systems on a grand scale. On top of that, the science he studied was a combination of biology, physics, and chemistry. His move to Beckman, with its accompanying turn to the engineers, however, was often remarked on with derision by colleagues. Yet Schulten still forged onward.
While Schulten embodies a typical scientist working at Beckman, as he entered the field of bionanotechnology at the start of the new millennium, he was well poised to illuminate such technology since the work often required teaming up with engineers or scientists from different fields to improve the sensors they studied. And while many scientists may shun applied science or technology, considering it not pure enough research, Schulten sees science and technology as partners. So it was natural for him to work on projects involving technology, and develop multidisciplinary collaborations, especially with experimentalists. He has been doing this to some degree all his professional life. And although the theoretical side of bionanotechnology–that is, simulating the creative systems the experimentalists imagine–is just starting to become recognized in this burgeoning field, Schulten says the experimentalists are thrilled to work with him and need little convincing of his potential contributions.
While Schulten entered the simulation side of bionanotechnology early, at that point in his career he had been honing the computer simulation of biological processes for almost two decades previously, and had a well-working technology in his group at Beckman. “Some of the questions that were relevant in bionanoengineering were actually pretty straightforward questions where the computer was already pretty good,” remarks Schulten. “And so basically I saw the computer could contribute to this field.” And what the computer offered was an unraveling of the measurement process going on with all the new and unconventional devices that Schulten’s collaborators were fabricating. In the laboratory the scientists would measure things, some never before undertaken by anyone, and the computer could help answer questions such as: What does the measurement mean? Where does it come from? And how should I interpret it? For example, why does it take longer for one end of DNA to go through a channel compared to the other end? Why is methylated DNA more mechanically stable? Why is my kinase sensor not working properly? The computational microscope helped provide answers to all of these questions, as well as many more, and in some cases aided optimization of the measurement process.
The technologies the computational microscope are demystifying in this new field of bionanoengineering touch on some of the hottest topics in biology: simplified and inexpensive DNA sequencing, proteins (the kinases) that often go awry in cancer and disease, and epigenetics. Nanodevices have been around for a long time and many forms of them are even found in common household products. Now nanotechnology is being combined with biological systems to make very good devices. Part of that is because the nanoscale is the smallest scale where one can still measure chemistry. As one nanometer is about the width of a typical protein, sensors can go almost to the size of a protein or a molecule and still take instructive measurements. Basically with such small samples, the bionano-device is tailored for single-molecule sensitivity, which is often desired, and makes this such a promising technology. For example, imagine the headaches saved at every level if biopsy of cancer cells only required a tiny amount, because the sensor for it worked at single-molecule specificity. But this tiny expanse of nanodevice plus biomolecule is the perfect size for Schulten’s computational microscope. While nanotechnology is now considered “sexy,” as he once put it, Schulten is clear to point out that he has been simulating nanoscale systems for forty years, for that is the scale at which processes happen in the cell. So a device with dimensions of 10nm × 10nm × 10nm is an ideal fit for the computational microscope.
This article will examine many fascinating nanodevices related to biotechnology, and specifically the role of the computational microscope in elucidating the inner workings of these bionano-applications. A theme running throughout is the multidisciplinary aspect of this work, for Schulten has teamed up with researchers from many disparate fields to work on the technologies revealed here. Indeed, as the Beckman mindset stresses work across many disciplines, this story embodies what happens when creative minds from all sorts of subfields come together to tackle a problem. Although the group at Beckman has worked on myriad projects in bionanotechnology since 2001, Schulten revealed he proceeded with no preconceived master plan. Most of his collaborations have happened by chance; topics appeared for consideration and he took them on. While the word “Technology” is part of the title of the Beckman Institute, Klaus Schulten is fully aware of the historical place of technology in science and how it shaped some of the scientific puzzles he had to solve when he entered this field of bionanotechnology. “Yes, you have to be intelligent and work hard,” he says about moving forward in research. “And you also need good opportunities. And opportunities now come very often through technology.” Schulten believes the many new systems and approaches of emerging technologies challenge the scientist with dilemmas to solve. Indeed, combining nanotechnology with biology in simulations has enhanced the range of the computational microscope, for it has uncovered a riveting array of new vistas, many of which we will visit in the coming pages.
“When I went to Beckman people said: Oh, Klaus, where are you going? You are going to the engineers. This will be your intellectual downfall. Don’t do it!” The people, in this instance, were other scientists (read: not engineers) who considered their work pure science, and certainly did not value collaborations with engineers or work focused on technology. At the time Schulten made his decision to become part of the Beckman Institute, around 1987, he was a theoretical physicist who studied biology. To take his research to the next level, he realized that he needed computer technology and input from computer engineers. The ridicule from colleagues about embracing computer technology was not new to Schulten, and did not dissuade him from joining Beckman; however, his path to the University of Illinois (home of Beckman) was anything but straightforward.
The homemade supercomputer Klaus Schulten built in 1988.
In the 1980s Klaus Schulten had a productive career as a theoretical physicist at the Technical University of Munich, where he did some of the most highly-cited work in his career. But for him personally, the atmosphere was a bit odd. He started to use computers more and more for his work in theoretical biology, and he paid a price with his colleagues. “Somehow today people accept computing more and more. But in those days,” Schulten says of the 1980s, “people thought literally that anybody who computes was a primitive person.” Any time Schulten used a computing word with his colleagues in the course of a normal conversation, they made jokes and even sexual innuendoes about it, and Schulten felt like a total idiot. Despite the hostile undercurrents, however, that didn’t stop Schulten from undertaking a perilous mission: building his own supercomputer on a meager budget.
The plan to build a homemade supercomputer stemmed from exciting work just down the road from Munich, undertaken by friends of Schulten’s at the Max Planck Institute for Biochemistry. By 1987 these friends, Hartmut Michel and Johann Deisenhofer, had crystallized and then determined a high-resolution structure of a membrane protein, a task once purported to be impossible. For this feat, they were awarded a Nobel Prize in 1988. Schulten had a front row seat to all the action, and when the structure was determined it was clear that exciting new calculations on a membrane protein could be run for the very first time. And Schulten wanted to be the first to do them. But a big roadblock stood in his way. For this type of calculation, Schulten would need to commandeer a supercomputer at some center, devoted exclusively for a year to his calculation. No center would be willing to accommodate this request.
Right around this time of the newly unveiled structure of the membrane protein, at the university in Munich, two young students in their early twenties assured Schulten he could indeed have his own supercomputer–they would build it themselves with his grant money. While this story is told in full detail elsewhere (click here to read the history of NAMD), suffice it to say that Schulten took them up on their offer and, risking everything, did finally procure a supercomputer all to himself.
With the promise of such exciting and original calculations to be run, and the unconventional, homemade parallel supercomputer under construction, none of Schulten’s colleagues in the Munich physics department paid any attention to him. Many had no interest in hearing about his plans for his computer, and most were just plain unaware. To summarize his treatment in Munich, Schulten here likes to point to a Bavarian saying: “I don’t even ignore you.” Ignoring means turning a head to look the other way, “but when you don’t even ignore it, it’s totally not there,” Schulten explains. “You don’t make any attempt even to look the other way because you pretend it’s just air. It’s just nothing.” Despite the indifference of his colleagues, Schulten marched forward with his plans to start using the computer more as a tool in his research, did not think about possibly finding a better environment to do his work, and even turned down a job offer that was unsolicited. But Schulten’s rejection of this job offer was not the end of the story.
Klaus Schulten had a funny feeling about the way the other physicists were acting after he gave his guest lecture in their department. It was 1985 and Schulten was temporarily living in the United States, on sabbatical from Munich. Since the University of Illinois at Urbana-Champaign was one of the few physics departments in the world at that time actually active in biophysics, Schulten agreed to give this invited talk in Urbana. He thus found himself in a small Midwestern college town, surrounded by flat farmland in all directions, which was a stark contrast to the skyline of New York City where he was spending his sabbatical. In between his lecture and the requisite evening dinner with the Illinois physics faculty, Schulten managed to sneak in a call to his wife. “I said to her: They act so strange. I hope they don’t offer me a position, because I don’t want to go to this god-forlorn place!”
The big black hole Klaus Schulten observed at the Beckman Institute construction site. Ted Brown, Beckman’s first director, is in the foreground. Photo courtesy of the Beckman Institute.
Schulten’s instincts were correct, however. Some of the faculty had an immediate meeting with their department committee and were ready by dinner to make an offer. Schulten respectfully declined. But the physicists in Urbana were undaunted and suggested Schulten and his wife, also a scientist, spend a term visiting at the university and getting to know the culture of the place, how they did science, before making a final decision. So Schulten moved his family to the Midwest from Munich in 1987 to give the University of Illinois a closer inspection.
Hours from a major city, surrounded by a “corn desert” as it’s called in local vernacular, unrelentingly flat, and near no large water bodies to speak of, Schulten was himself surprised to discover that he very much enjoyed his trial period at the University of Illinois. He admits that many Europeans, including himself, considered the Midwest boring. But it wasn’t the landscape that swayed this former urban resident. However, the landscape does contain some of the richest farmland on earth, and Schulten found some riches of his own. In fact, many factors coalesced to change his mind, the most important was probably a hole in that rich dirt.
Upon arriving in Illinois in the spring of 1987, the timing was such that Schulten found himself immersed in an exciting new development taking place at the university: the genesis of the new supercomputer center. In 1985, the National Science Foundation (NSF) announced it would devote $200 million in grants to create four centers in academia to bring supercomputer power to civilian researchers. Up to that time, powerful computers were mostly in the hands of U.S. defense department workers, and some industries, such as aircraft and automobile manufacturers or oil companies. But the four centers created in 1985 were specifically for researchers not in the aforementioned fields; Schulten was the kind of target audience the NSF hoped to reach with its new initiative. In Urbana, one of the original four places chosen by the NSF, the National Center for Supercomputing Applications (NCSA) opened for business in January 1986. Schulten, there in spring 1987, says it was a very fresh and exciting time, with so many new hires on staff with impressive backgrounds. They gave him a wonderful place to work, and he had access to fantastic computing facilities, particularly graphics equipment he made liberal use of. “It was definitely one of the JEWELS in my eyes of this place,” reiterates Schulten about the NCSA at the University of Illinois, “that they had this very concerted computational effort that I had been missing in Munich.”
While intrigued by how the university combined computing and science, Schulten also was drawn to the reputation of the physics department. His wife also felt comfortable in Urbana, with many friends in the chemistry department. However, Schulten points to one defining moment that really cemented his decision to move to the Midwest. His colleagues in Urbana told him that if he accepted their job offer, they could provide him with a laboratory in the new institute. When Schulten asked where it was on campus, they told him it was just being built and they would show him the construction site. What Schulten saw was just a hole in the ground, in the rich black glacial moraine of the Illinois soil. “It was really the largest black hole I had ever seen in my life, and it was so big that I realized, this is really a major institute,” explains Schulten. “So basically my decision to come here was because of the black hole that was supposed to become the foundation of the Beckman Institute.”
The roots of the Beckman Institute go all the way back to a small town in Illinois just over an hour’s drive north of Urbana. There in the city of Cullom, Arnold Beckman was born, and after serving in World War I, got a BS degree in chemical engineering and a year later an MS in physical chemistry in 1922 from the University of Illinois at Urbana-Champaign. Arnold would go on to get a PhD from the California Institute of Technology, where he worked for a while until he founded his own company, Beckman Instruments. Arnold Beckman was an inventor, and two of his most famous inventions were the pH meter and the DU spectrophotometer. While spending most of his time in California running his company, Arnold Beckman kept close ties to his home state, and served in some capacities at the university in Urbana, on boards and cabinets. He and his wife, Mabel, made a donation in 1980 to the university, which established the Beckman Fellowships for junior faculty.
So when some administrators of the University of Illinois in 1983 sat down to brainstorm about possible new projects that would be of such imaginative scope that they could attract the attention of private donors, and put the flagship university on the cutting edge of the research world, it was natural to approach Arnold and Mabel Beckman. But first they had to formulate an ambitious project for consideration. The resulting 1985 proposal was for a “multidisciplinary” initiative, one which would span physical sciences and engineering, as well as life sciences and behavioral sciences. Part of the proposal submitted to the Beckmans highlighted the already-strong interdisciplinary research going on at the University, and the new supercomputer center under development.
The large nature of the gift the Beckmans finally proffered even surprised the people working hardest to attract the donations for the new institute. At $40 million dollars, this was historically the largest single donation to the University of Illinois up to that point in October of 1985, and was additionally the largest gift made to any public university until that time. Ground breaking began in October 1986, and that winter Klaus Schulten viewed the big black hole that would become his future home, the Arnold and Mabel Beckman Institute for Advanced Science and Technology.
“The Beckman Institute was for me,” says Schulten, “a protectorate for interdisciplinary work, and a very beautiful one at that.” He is clear to point out, in retrospect, that he needed the umbrella of this institute to accomplish the goals he had set for himself as a physicist doing theoretical biology. First of all, he wanted to combine science and technology, in this case using the technology of the computer to aid and complement his studies in theoretical biology. To get science and computer technology together, he needed to go to the Beckman Institute, a place where he no longer heard cries of “it will be your intellectual downfall if you go to the engineers.”
The Beckman Way, according to Klaus Schulten, a resident of the Beckman Institute from its inception.
Schulten does not only want to use technology to facilitate his work, he wants to study it as well, research also consonant with the Beckman Institute. In fact, this article covers many promising new biology-related technologies at the nano-scale. These biotechnologies have been demystified by the computational microscope, a tool combining biology, physics, chemistry, and hardware and software, and honed at the Beckman Institute since 1989. A student of history, Schulten is aware of the close relationship between science and technology on the timeline of modern achievements. Not only has much good science come about through close contact with technology, but science can also contribute to emerging technologies. While Schulten appreciates the historical connection between science and technology, he also points to his roots in rural Westphalia, where he grew up surrounded by farmers. “I am much more a person who loves philosophy and mathematics,” explains Schulten, “but who just comes from a background that is much more grounded in reality, in my case literally in agricultural reality, in dirt.” He sees similarities between himself and his boyhood village farmers, who talked about lofty ideas but also had their feet on the ground. Schulten feels that having his feet grounded in the “dirty business of computing” is the way to get things done.
The atmosphere at the Beckman Institute is best encapsulated by Schulten’s quote about it, that “character is important, but not what kind of union card you carry.” He joined the institute for two reasons, to be able to conduct interdisciplinary work that truly treats all partners with respect, and to combine science and technology. He calls this “The Beckman Way,” in that science drives technology, and technology drives science. Schulten likes to point out that one instance of the first category–science driving technology–is how technology can pose new questions to scientists. For example, when first introduced, the atomic force microscope, which worked by a tiny tip tapping the surface of a sample to register a two-dimensional image, scientists discovered the contact with the tip could damage so-called soft biological samples. The question scientists then asked was, how could they re-invent this technology so it would not damage their soft samples? And non-contact mode was born.
Schulten is also clear to point out that the Beckman philosophy he coined is a two-way street, in that technology can drive science–with the obvious case that technology can give researchers the means to do their science. One example of this is the electron microscope, which made a whole subset of biological findings possible in the twentieth century. Closer to home, in Schulten’s world, the advances over two and a half decades in parallel computing have allowed Schulten to focus on the question that has motivated him for forty years: How do I describe biological organization? He knows this requires studying processes and societies inside a cell, which for Schulten means considering millions of molecules at once. And the technology of the parallel computer with its accompanying algorithms (many designed by his own group) has enabled Schulten to get closer and closer to his goal of explaining biological organization. Additionally, Schulten is using the technology behind the computational microscope to illuminate the bionanoengineering systems discussed below. His years of tweaking the computational microscope paid significant dividends indeed when it came to bionano-systems.
Technology, in fact, was one of the reasons Schulten got funding in 1990 from the National Institutes of Health, for his NIH Center for Macromolecular Modeling and Bioinformatics, which coincided more or less with his move to the Beckman Institute. These centers are funded by the NIH to create unique, cutting-edge technologies and software to advance the biomedical field. Schulten cites two reasons for his successful grant application. First and foremost was the parallel supercomputer he risked everything to assemble. “I had built this computer and thereby demonstrated that parallel computing can be useful in biology when you model macromolecules,” Schulten offers. Until that time, people were using only single processor computers, and parallel computing was in its infancy. The NIH, according to Schulten, had several centers already working on the premise of going parallel, but Schulten was farthest ahead with his newly constructed and whirring parallel machine. NIH was interested in giving this technology more opportunities to blossom. In fact, without containing his laughter, Schulten likes to point to the site visit for the 1990 grant, where he prominently displayed the homemade computer to show the visitors, and hoped they would be impressed by its blinking light, a sign that it was working hard at its task. He reiterated to the site visitors that he couldn’t turn it off, that it had to run for two years continuously. With the abundance of impressive graphics displays available in biomolecular modeling these days, a blinking machine would not be considered of much merit during a site visit. Schulten also thinks his work at the time on the brain was an attractive topic for the NIH. “I think they liked that too,” emphasizes Schulten, “that we were not just a one-trick pony show.” Schulten’s center was so successful that he would receive funding every five years for the next twenty-five years.