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Answering Life's Great Questions, Systematically

Fri, 12/10/2010 - 6:27am
Paul Livingstone

Not resting after a career full of achievement, Richard D. Smith is leading the charge toward the first comprehensive molecular characterization and modeling of biological systems.

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Richard D. Smith, 2010 R&D Magazine Scientist of the Year. Image: Pacific Northwest National Laboratory

A little more than 50 years ago, the exact masses of amino acids and small peptides were measured for the first time, based upon their ions’ mass-to-charge ratios. As this technique—mass spectrometry—has increasingly become the standard for biochemical analysis, as scientists continually improved and refined the techniques and instrumentation.

At the same time, researchers were unlocking the mysteries of DNA, using these tools to discover the instruction set for human cells locked within its genetic material. For many, the Human Genome Project was the touchstone of this effort.

Sequencing the full genetic code, however, does not provide the full picture of human biology—or any biological system. The human being is a vast system of interacting molecules far too complex to be understood by just its DNA, and R&D Magazine’s 45th Scientist of the Year, Dr. Richard D. Smith, has spent his career finding new ways to define and understand it.

A Laboratory and Battelle Fellow at the Department of Energy’s Pacific Northwest National Laboratory (PNNL) in Richland, Wash., Smith has, over a three-decade career, become nearly synonymous with advances in mass spectrometry (MS).

These accomplishments can be traced in many ways: hundreds of research papers, dozens of patents, and numerous R&D 100 Awards. Joining PNNL in 1976, Smith has made numerous fundamental advances in advanced microanalytical separations and accurate MS instrumentation. He invented an efficient new electrospray ionization (ESI) interface, which he combined with capillary electrophoresis in the mid-1980s. In 1999, he completed work on an ion funnel for MS; and, in 2003 he joined this technology with a high-throughput Fourier transform mass spectrometer. Most recently, he and his team at PNNL built an ion mobility spectrometer on a microchip, a technology that hints at the future of analytical instrumentation.

In all, he has won nine R&D 100 Awards since 1983, and by this measure alone has shown himself to be a prolific and creative inventor. But perhaps the best way to look at Smith’s lifetime of scientific research is in the context of life science itself. His philosophy, says former colleague Joseph Loo, has been that if he can increase sensitivity by a factor of 10, why not 100 or 1,000?

Most of his career has been spent pushing the boundaries of performance in analytical instrumentation. He continues to do so, but now the levels of sensitivity are so high he can begin to ask big questions about biology and life and the precise details of how they work. The key, he believes, is combining the advances he continues to make in proteomics with broader realm of ‘pan-omics’, a term Smith uses to describe the spectrum of ‘-omics’ measurements needed for comprehensive coverage of a cells’ molecular constituents. But proteomics is at its core.

The protein laboratory
As the Human Genome Project was coming to completion, Smith began to investigate the even more daunting puzzle of proteomics, which seeks to understand biology by studying the complement of proteins at work within organisms, tissues or cells. Over the past decade, his contributions to this field in analytical techniques and measurement capabilities have laid critical groundwork for breakthrough advancements in systems biology. His innovations have dramatically improved the sensitivity, accuracy, and speed of measurements.

Loo, a professor at the Univ. of California, Los Angeles, worked with Smith as a postdoctoral fellow then as a senior scientist in the 1980s and 1990s. At the time, the field of mass spectrometry for the analysis of large biomolecules was beginning to accelerate rapidly, primarily via the developments of electrospray ionization (ESI) by John Fenn and matrix-assisted laser desorption ionization (MALDI) by Franz Hillenkamp, Michael Karas, and Koichi Tanaka.

Smith, Loo says, had the early foresight to develop ESI as an interface to mass spectrometry for high-resolution capillary electrophoresis. After another researcher, John Fenn, demonstrated ESI for protein measurements, the team, which initially numbered just five including Smith, quickly began to push the limits of protein detection.

“Those were exciting times for us in Dick’s lab because we were one of only a handful of labs worldwide that were developing ESI-MS. Nearly everything we tried was new and publishable,” says Loo.

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Over a 30-year career Richard D. Smith has contributed greatly to fundamental advances in analytical science, earning nine R&D 100 Awards since 1983. Image: Pacific Northwest National Laboratory

The mass spectrometry group expanded steadily throughout the years. Now Smith is head of one of the leading proteomics research centers in the United States, headquartered at PNNL. He is also the principal investigator for the National Institute of Health’s (NIH) NCRR Proteomics Research Center. And while the biological systems of interest very greatly, such as the microbe environmental communities of interest to the DOE, the dual roles benefit from the same capabilities—“biology is biology”. Smith says that due to the complexity of both the technologies and the biology, that his lab could not do what it does without drawing on its many skilled and knowledgeable individuals. Having the resources of the DOE and NIH gives him the critical mass he needs to both make and apply key advances.

Smith’s first encounter with mass spectrometry was in graduate school. He worked and studied in the laboratory of Jean Futrell at the Univ. of Utah. His lab opened Smith’s eyes to the real power of analytical techniques. “[Futrell’s] laboratory specialized in mass spectrometry, and the people working with him included a fearless group of instrument builders,” says Smith. “There was an early recognition that this technology could do things that had never been done before.”

According to Loo, Smith isn’t the type of leader that dictated orders. “I think that was a strength of Dick’s—he tended to select people who could bring different skill sets and knowledge bases to the group that could help us all grow and complement each other,” he says. “As a result, we had experts in physics and instrument design to optimize the mass spectrometers, biochemists and biologists to optimize sample preparation and isolation, and analytical chemists to optimize the overall measurements.”

In the laboratory, electrophoresis-MS, a technique pioneered by Smith in the 1980s, allows researchers to ionize molecules at high efficiency: nearly every biomolecule in solution can now be ionized. When paired with ion funnel technology, these ions can be focused into MS with nearly 100% efficiency.

“It is going to be possible to take a biological sample and characterize it completely. It hasn’t been achieved yet, but we are getting closer,” says Smith. His work has demonstrated that optimization in all aspects of experimentation in MS can lead to dramatic improvements in analytical sensitivity and applicability. Smith has worked to improve practically every element of (ESI) mass spectrometry measurement: sample preparation and handling, separation science (e.g., capillary electrophoresis, microfluidics, and nano-scale very high pressure HPLC), the ESI source and ion generation, ion focusing and transmission, mass analyzers and ion detection, and data interpretation.

Many of the analytical strategies and methods that his group developed can be found in today’s commercial mass spectrometers. Ultimately, Smith’s work has directly reduced the amount of sample required for a measurement by at least six orders of magnitude.

Now, he is working on new projects that bring together many of these advances, and more. In pursuit of his ‘pan-omics’ vision researchers in Smith’s lab are disassembling populations of cells for increasingly complete characterization by mass spectrometry. The lessons they are learning will eventual allow us to model and re-engineer biological systems, Smith reports.

He also aims to extend proteomics measurements to the level of a single cell, to help understand the differences across populations of cell, something he believes will be essential for their modeling. One line of R&D involves manipulating individual cells and separating their components in microfabricated devices connected to mass spectrometers. In 2010, Smith earned an R&D 100 Award for an ion mobility spectrometer that fits on a microchip. Until now, the ability to gather efficient, useful information about a molecule in solution has been confined to the abilities of large, bulky instruments that require considerable expertise and effort to run.

“Things have changed completely. In the early days we couldn’t measure much, and when we could the sensitivity really limited what we could do. But now we’re at a point we can efficiently take a single molecule in solution, make an ion from it and get it to a mass spectrometer where we can analyze the molecule or its components. Moving to practical utility and analyzing single cells is the next big step,” says Smith.

The full array of biological molecules, including, proteins, lipids, carbohydrates, and more, can almost all now be measured using MS. But in comparison to a genome, the actions of proteins and other biomolecules are still poorly understood. “We can increasingly characterize biological systems. We can perturb it, look at the changes, and the ability to do this many times allows us to build increasingly detailed models of the biological system,” says Smith. He compares proteins to an automobile. It’s nice to know what all the components of the automobile are, but knowing the details of the pieces in isolation will not reveal how they work together, or more importantly, how to drive the car.

“With pan-omics we are going beyond proteomics,” says Smith. “What entices me now is the full characterization of biological system, especially as a basis for building a computational model of human beings.”

As a result, Smith’s lab has been focused on making measurements much more comprehensive in proteomics and also greatly increasing measurement throughput. If a computational model is to be made of an entire system, large numbers of highly comprehensive measurements will be needed.

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At his proteomics laboratory at PNNL, Smith and his colleagues are pushing the limits of performance in advanced mass spectrometry techniques to begin answering big questions, such as how to build a computer model that treats human biology at the molecular level. Image: Pacific Northwest National Laboratory

Biomarkers and beyond
As these more fundamental efforts progress, there are many more immediate applications of the technologies his laboratory are developing. This has included the discovery of new and more effective biomarkers.

These markers, he says—which are now sought out to enable early diagnosis of cancers and diseases like diabetes, Alzheimer’s, or Parkinson’s—have the potential of broad clinical impacts for not only diagnosis, but also prognosis and the evaluation of new therapies, as well as the development of protein targets for new drugs. Smith's research indicates that many neurodegenerative diseases leave a biochemical calling card, or biomarker, that may be used to predict early stages of brain impairment. Detecting disease states before symptoms occur could be a key to reversing many as-yet-incurable diseases. His laboratory is now leading in conjunction with Oregon Health and Sciences University the largest-ever comprehensive proteomics study providing in-depth proteomic measurements on over 3,000 individuals.

“This is tremendously interesting, and among other things it will tell us about real biological variations, not just genome differences,” says Smith. By monitoring changes in proteins over time—many thousands of changes for thousands of individuals—he and his team hopes to useful biomarkers for a number of diseases, as well as the basis for new drug development efforts.

Smith's work has also led to the mapping of proteins in brain tissues, which can be compared to protein portraits found within diseased brain tissues. If proteins can be targeted with drugs early enough, diseases like Alzheimer’s and Parkinson’s might be curbed before they can cause damage.

“Someday we’d like to completely understand these systems, what goes wrong, and how to nudge things in a way that reverses the damage,” says Smith.

With more than 800 published papers and 39 patents, Smith has come to embody scientific rigor at PNNL.

“Why does he produce so much ’research‘? Dick is competitive. He loves to publish papers. I think it started when he was a graduate student,” says Loo. While working in the lab of Jean Futrell at the Univ. of Utah, Smith set a publishing record for graduate students. Later, when he built a large research group at PNNL, he was able to generate a continuous stream of publications.

“Dick Smith is pretty much a big kid at heart who likes to play and take risks. He used to walk by the lab to ask about the latest results emerging. After some discussion, he might suggest an experiment that some of us would consider ‘off the wall.’ Maybe it had only a 1% chance for success. But Dick knew that if it worked, it would open up new ways to increase sensitivity or new areas to explore,” says Loo.

His inquisitive nature and ability to continually ask questions and try new things helps explain his productivity. The stability afforded by working at one of the Dept. of Energy’s National laboratories also contributes.

“The key is encouraging good interaction. It’s great to have a group of bright people working with you, and I’ve always enjoyed the vigorous give and take as new ideas are considered,” Smith says.

Smith sees his nine R&D 100 Awards as proof of successful collaborations between researchers that have resulted in practical applications. The real reward, he says, is in the R&D process.

“Biology is by far the research area where we as humans can have the most profound impact on not only us, but also essentially everything around us” says Smith.

Published in R & D magazine: Vol. 52, No. 7, December, 2010.

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