Cryo-electron microscopy, scientific convergence and - again - why we need to fund basic science

Cryo-electron microscopy has won the Nobel Prize for chemistry this year, and while I did not expect it to make it quite so fast, nobody can deny the importance of the technique. As I wrote two years ago, it's a prime example of a tool-driven scientific revolution. And it has charted completely new vistas in the determination of the structure of biological molecules; entire protein assemblies, viruses, proteins too unruly to be symmetrically crystallized using x-ray crystallography.

But it's also an example of what we can call scientific and technological convergence. Often when a prize is awarded for a discovery or invention, it makes it sound like that discovery or invention stands on its own. But as the saying goes, no scientific advance is an island.

One of the most important things to realize about cryo-EM is how many fields had to co-evolve for it to become a reality. There was the long development of microscopy, of course, but two other inventions were absolutely critical in making the technique possible: detectors and computers. Computing power enabled by Moore's Law and cheap hardware combined with key advances in image-processing software have revolutionized a lot of fields in the last few years, from facial recognition to photography. 

And cryo-EM is not an exception. Joachim Frank who is one of this year's winners made his mark in the 80s and 90s by developing image processing software and mathematical techniques that could combine 2D microscopy images into a composite 3D picture. As important as the image processing was the development of detectors; one key invention made in 2013 that allowed much better signal-to-noise ratio and spatial resolution really seems to have pushed the method into a new realm of possibility (it's worth noting that a Nobel Prize was awarded for CCDs a few years ago - another very important technological advance). Finally, there had to be a way to introduce water into the experimental setup; this seemingly mundane process took quite some time to, well, crystallize.

So, computers, electronics and lab technique: all scientific tools, modern versions of string-and-sealing-wax science, all enabling groundbreaking new chemistry and biology. It's quite clear that the failure to advance on any of these fronts would have crippled the development of cryo-EM. 

Why is it important to realize this? For two reasons. Firstly, it really underscores how no scientific advance stands by itself, how it piggybacks on not just other developments in the same field but on those in other fields. The Wright brothers' rickety plane was a marvel of their innovative thinking, but it was also a marvel of, among other fields, materials science, aerodynamics and mechanical engineering.

Secondly and perhaps more importantly for our times, this recognition shows why it's crucial to support and fund basic science in multiple areas because it's only their co-evolution that can lead to an invention like cryo-EM. Simply funding the 'hottest' fields is not enough, because even the hottest fields have emerged from the nexus of several other fields. Scientific convergence is the answer to the question perpetually asked by lawmakers: "What is this good for?". A few decades ago they could have asked that question about some esoteric mathematical image processing technique, they could have asked it about new software, and they could have asked it about new ways to freeze biological samples. By themselves these were interesting phenomena, but nobody could have predicted their convergence in cryo-EM. That is why funding research across the board is so important, because it's all connected.

We have no idea whether politicians in the current climate will understand this interdependence of different fields that makes a major scientific advance possible, but a Nobel Prize for cryo-EM should at least help us make our case.

Leroy Hood and the tool-driven revolution in biology

The Galisonian view of science - named after historian of science Peter Galison - says that science is driven as much or even more by new techniques and instruments as by new ideas. Sadly most people have always placed theoretical ideas at the forefront of scientific revolutions, a view enforced by Thomas Kuhn's famous book "The Structure of Scientific Revolutions". But a study of the history of science shows that new tools have been as instrumental in opening up whole new areas of science as new ideas. In fact one may argue that ideas allow you to largely explain while novel tools allow you to largely discover new things.

From the viewpoint of tool-based science, scientists like Faraday, Rutherford, Woodward, and Lamb are as important as Newton, Dirac, Heisenberg and Pauling. To this list of tool-builders and users must be added the name of Leroy Hood. Hood is one of the most important pioneers of the genomics revolution. Seeing far ahead of most biologists in the 1980s when he was at Caltech, he invented four tools that were to revolutionize the theory and practice of genomics: the protein sequencer, the protein synthesizer, the DNA synthesizer and the DNA sequencer. At a time when most biologists positively looked down upon technology development and engineers, Hood blazed new paths in combining chemistry, instrumentation and biology. His tools not only allowed biologists to do things better, but allowed them to discover new things which they hadn't imagined before.

Luke Timmerman has written a valuable biography of Hood which would be of interest to anyone interested in the recent history of the gene. I picked it up encouraged by Keith's favorable review (http://omicsomics.blogspot.com/…/veteran-biotech-reporter-l…) and am glad I did. My only reservation is that Timmerman could have done a much better job embedding Hood's inventions in the bigger story of genetics and molecular biology. There were parts of the book where I thought the science could have been fleshed out much more, so if you are looking for a concomitant work of popular science along with a biography, this is not really it.

Hood's essential qualities were ingrained during a vigorous upbringing in rural Montana. His father was a peripatetic telephone engineer who did not give praise easily. He and Hood's mother taught their children to be self-reliant, resilient and hard-working. Throughout his career Hood has been a force of nature, displaying these qualities to an unprecedented extent and leaving behind some of his more talented competitors by sheer tenacity and dedication. As he recounts, the most valuable class for him in high school was not math or science but debating. He was also his high school's star quarterback. Even now, at the age of 75, he runs 3 miles every day and does a hundred push ups. He has also combined great scientific talent with a passion for public speaking and entrepreneurship; through these skills he has raised hundreds of millions of dollars from universities, funding agencies and wealthy philanthropists and made millions of his own. He has given generously to the cause of middle and high school education. No obstacle has been daunting for him, and by any of the usual metrics his career has been stunningly successful; as his website points out, "in addition to his ground-breaking research, Hood has published 750 papers, received 36 patents, 17 honorary degrees and more than 100 awards and honors, and has founded or co-founded 15 biotechnology companies including Amgen and Applied Biosystems."

Hood got his undergraduate and graduate degrees from Caltech along with an MD from Johns Hopkins. Caltech sought him out as an assistant professor right after graduation. Hood's early contributions were to immunology where he figured out the basis of antibody diversity. But soon he began to broaden his horizons and became one of the first biologists to truly appreciate the impact of new technology on biology. He had an amazing talent to spot big picture problems, drive himself mercilessly to crack them and recruit world class people to solve them. Using his unique skill set he built the first protein sequencer and DNA sequencer and licensed them out to the company Applied Biosystems. The DNA sequencer is at the very heart of the genomics revolution. Gene sequencing is no longer just a tool for faster and more efficient molecular biology, but it has transformed itself into a formidable instrument to explore stunning new domains of biology, from the creation of new organisms to the cracking of the genetic code for all kinds of diseases to the exploration of the world's biodiversity. Hood's work showed that not only can technology enable science but it can actually give rise to new science.

Unfortunately Hood's grand visions and the size of his lab and research projects (at one point his lab numbered more than a hundred people) soon ran afoul of Caltech's desire to stay a small, tightly knit school. Very soon he had a falling out with the faculty. One of his students who is now the head of research at Merck was then a professor at the University of Washington. He persuaded the medical school at UW to invite Hood for a few lectures. The chairman of the department in turn persuaded Bill Gates to attend those lectures. Gates who had started taking an interest in biology in the late 90s was entranced by Hood and immediately agreed to endow a $12 million dollar faculty position at UW for Hood. Hood's moved to UW was accompanied by breathless press releases proclaiming that his appointment was one of the most momentous events in the history of the university.

At UW Hood became the father of a new science: systems biology. He was no longer content to just explore genes and whole organisms, instead he wanted to bring about a completely unified view of biology by connecting atoms to molecules to cells, all the way to whole organisms and ecosystems. It was a grand vision, and one which only someone like Hood could pull off. Systems biology is now a mainstay of cutting edge biological science, bringing together biologists, mathematicians, computer scientists and other. But Hood got there first, being one of the first scientists to bring together interdisciplinary subject experts.

Sadly it was here that Hood's failings become clear, and Timmerman pulls no punches in narrating them. Hood was a big picture thinker, not a detail-oriented person. He left the day to day running of his labs to postdocs and research associates. More importantly, he was terrible at interpersonal relationships. He almost never took interest in his students' lives, never picked up the check when he "took them out" for lunch and regularly played favorites. He was not an unkind person, but he was simply too busy, driven to succeed and tone deaf to the everyday human relationships that make any endeavor successful. He was not above claiming credit for others' discoveries, not intentionally but because of his relentless drive to finish that simply left him clueless about such things. He rubbed people the wrong way at Caltech and UW and found even the generous support at UW insufficient for his systems biology vision. Predictably enough, when some of his key allies passed away, he had a falling out at UW too after he tried to sell them a plan for an independent new institute. Confident that his friend Bill Gates would fund it, he went to see Gates at Microsoft, only to be turned away with an icy dismissal (Gates: "I never fund things that I think are going to fail."). Undaunted, Hood poured $5 million of his own money into the institute. Personally too he faced a tragedy: his wife Valerie who he had married out of college succumbed to Alzheimer's disease.

Since then, the Institute for Systems Biology in Seattle has become a thriving research institute that is at the forefront of investigating both basic and applied genetics. Hood continues to be a powerhouse, crisscrossing the world giving talks about how biology is going to revolutionize human life. The system's research may or may not help discover new cures for important diseases, but what's more important is the vision and accomplishment of one man in achieving all that: Lee Hood. Hood is a fantastic example of what happens when passionate tenacity for a cause, a deep appreciation of the impact of technology on science, a passion for entrepreneurship and a relentless pursuit of the big picture come together to create an explosive mix. In the DNA sequencers that are humming softly in hundreds of thousands of industrial and academic laboratories and hospitals around the world, reading and rewriting the code of life, Lee Hood's legacy keeps humming on too.

Cryo-electron microscopy: A prime example of a tool-driven scientific revolution

Last week I had the immense pleasure again of having lunch with Freeman Dyson in Princeton. One of the myriad topics on the platter of intellectual treats on the table was the idea of science as a tool-driven rather than as an idea-driven scientific revolution. The framework was fleshed out in detail by Harvard historian of science Peter Galison in his highly readable book "Image and Logic" and was popularized by Dyson in his own book and article. I wrote a post on that particular paradigm last year.

Since physics had profited immensely from idea-driven revolutions in the 20th century (most notably relativity and quantum theory) that were enshrined by Thomas Kuhn in his idea of paradigm shifts, it took physicists some time to appreciate how tools like the cyclotron, the cloud chamber, the CCD and the laser have played an equal part in their revolutionary history. But as I told Dyson, chemists on the other hand have absolutely no problem accepting the idea of tool-driven revolutions. Chemistry more than physics is an experimental science where first principles theories are often too complicated to put into practice. Chemists have thus benefited much more from experimental toys rather than fancy theorizing, and in no other case has the ascendancy of such toys been more prominent than in the case of x-ray crystallography and NMR spectroscopy. It's hard to overstate how much these two techniques have revolutionized not just our understanding of the world of molecules but of other domains, like biology and engineering. Last year's Nobel Prize for microscopy was likewise a fitting tribute to the supremacy of tools in chemical and biological research.

Now a new technique joins the arsenal of structural weapons, and I have little doubt that it too is going to be part of a revolution - cryo-electron microscopy. ACS has a nice article on how much the technique has advanced in the last decade and how prominently it is poised to be applied to structural problems that have been recalcitrant to the old approaches. During the last few years use of the technique has skyrocketed: as this Nature article compellingly describes, cryo-EM can acquire structures of ribosomes in weeks or months that took Nobel Prize-winning scientists years to solve. And as the article says, even this revolution has benefited from a crucial tool-within-a-tool.

Over the years, gradual progress in computational power and microscope quality has yielded higher and higher resolution structures. Up until the past few years, most cryo-EM structures clocked in at well above 10-Å resolution, about the size of an amino acid. Between 2002 and 2012, only 14 structures determined by EM crossed the 4-Å threshold, dipping a toe in high-resolution territory. But a true breakthrough came in 2012 when a new toy—the direct electron detector—opened the gates, allowing for a flood of high-resolution cryo-EM structures. In 2014 alone, 27 structures have reached sub-4-Å resolution, and scientists keep pushing the boundaries. “The direct electron detector has been the biggest game changer for the electron microscopy field,” says Melanie D. Ohi of Vanderbilt University.

The direct electron detector joins a long list of specialized instruments like the Bunsen burner, the Kirchhoff spectroscope, the scintillation counter and the Geiger counter, all of which proved to be key appendages of the larger technologies which they were enabling. A good counterpart to the direct electron detector would be the CCD which revolutionized tools like cameras and telescopes and which was awarded a Nobel Prize a few years ago.

Cryo-EM will almost certainly make a big splash in the world of drug discovery in the upcoming decades. However, better experimental tools alone won't suffice for this revolution. It's sometimes underappreciated how important software and hardware were in enabling the routine application of NMR and crystallography to tough biological problems in drug design. The advent of cryo-EM similarly opens up attractive opportunities for the development of specialized software and hardware that can handle the often fuzzy, low-resolution images coming out of cryo-EM. This will especially be important for multiprotein assemblies like modular enzymes and ribosomes where multiple solutions exist for a given dataset and where computational model building will be paramount. 

As the technique proliferates, so will the data that it unearths. Someone will have to then make sense of this data, and scientific and financial rewards will await those who have the courage and foresight to found companies making specialized software for analyzing cryo-EM images. The founding of these companies with their custom hardware and software will itself be a paean to the tool-driven revolution in science, in this case one led by the computer. One tool both piggybacking on and enabling another tool, that's how science progresses.

Added: Here's a nice application of cryo-EM in resolving crystals of the protein alpha-synuclein that are essentially 'invisible'.

Image source