Milton L. Lee: LCGC’s 2016 Lifetime Achievement Award Winner

Milton L. Lee is best known for his achievements in capillary separation techniques (with an emphasis on column technology and instrumentation), his entrepreneurial activities in scientific instrument companies, and his tenure as a chemistry professor for almost 40 years at Brigham Young University (BYU), where he has held the position of H. Tracy Hall Professor of Chemistry from 1985 to the present.  Lee recently spoke to LCGC about his career and work.

Lee will be honored at the Pittcon 2016 conference in Atlanta, Georgia, in a symposium on Monday, March 7, (session 530, room B314), along with LCGC’s 2016 Emerging Leader in Chromatography, Debby Mangelings.

Were you always interested in a scientific career?

I came from a family that was always interested in education, especially science and math. My father was a chemistry professor and my mother was a primary school teacher. I had five brothers and three sisters, and we were always doing “kitchen” experiments growing up. All of us took at least the first year of chemistry at the university. I started university studies majoring in math, but quickly changed to physics, with the plan to become a patent attorney.  After my third year at the university, I finally decided that I really liked chemistry best, so I changed my major again and took two solid years of chemistry to graduate. Two of my brothers have PhDs in chemistry, two have MS degrees in chemistry, one has a PhD in civil engineering, and my sisters have degrees in nursing, special education (master’s), and medical technology.

How did you get started working with chromatography, in general, and capillary chromatography and electrophoresis, specifically?

The first chromatography that I ever did was capillary gas chromatography (GC) as a graduate student at Indiana University (IU). I actually went to IU for a graduate degree in inorganic chemistry, but became fascinated with capillary chromatography when I talked with Milos Novotny, who was just starting as a new assistant professor. I joined his research group, and everything else is history. I have always regretted that I did not get to know J. Calvin Giddings during my undergraduate years at the University of Utah. Strangely, I never crossed paths with him during that time, and did not even know what chromatography was until I went to Indiana University. I later became good friends with Cal Giddings.

Who was the biggest influence on your career when you were just getting started?

Milos introduced me to the world of chromatography, and has supported me throughout my career; he obviously has had the greatest influence. Keith Bartle was a visiting professor at IU when I was there, and he taught me how to be a good experimentalist, which has been invaluable. We have remained close friends from then on. The relatively short time I spent with my postdoctoral advisor, Ron Hites, at MIT significantly strengthened my training in mass spectrometry, which has served me well throughout my career Soon after I went to Brigham Young University as an assistant professor, Leslie Ettre took an interest in me, and gave me several opportunities to present my research to key audiences. This greatly helped me gain some visibility early in my career. I also met Pat Sandra in the late 1970s, which led to a life-long association. There are numerous other colleagues, including students, who I have associated with over the years, who have influenced and enriched my career and personal life in immeasurable ways. I sincerely express my gratitude to all of you.

Why did you choose an academic career path?

I actually applied mostly for industrial positions when I was close to finishing my PhD because I was worried that I might not survive the “publish or perish” rigors of academic life. However, I was contacted by the Chair of the Chemistry Department at Brigham Young University to see if I was interested in interviewing for a faculty position there. I guess they were willing to take a chance on me.

What has been the most challenging research project you have undertaken? What has been the most rewarding?

The most challenging was electric field gradient focusing, which is theoretically enticing, but technically difficult to perform. I cannot choose the most rewarding because I have been involved in many exciting projects over the years that have really been satisfying. One little-known project that worked out almost ideally was a geochemistry project on the origin of coal-bed methane.

Over the years you have mentored 64 PhD students, 8 MS degree students, and 28 post-doctoral researchers. How have your students impacted your career?

Obviously, without my students, my career would have been much different. For one thing, I would not have lasted very long in academics! I was blessed with bright and enthusiastic students who did phenomenal work when they were here, and have gone on to contribute much to society. I keep in close contact with most of them and consider them to be close friends.

Can you tell us about the development of the three instruments you commercialized (the capillary supercritical fluid chromatograph, atmospheric pressure ionization time-of-flight [TOF] mass spectrometer, and hand-portable gas chromatograph–toroidal ion-trap mass spectrometer)? How did you get started on those projects? What obstacles did you have to overcome to complete the development? How long did it take you to have a finished product?

Soon after I joined the faculty at BYU, Milos Novotny invited me to come back to IU for the summer to work on capillary supercritical fluid chromatography (SFC). I brought a student, Paul Peaden, with me, and we concentrated on the column technology. At the time, capillary GC stationary phases were not cross-linked, and they were not stable under SFC conditions. We performed our first experiments with free-radical crosslinking at that time, not knowing that similar work for capillary GC was going on in the laboratories of Kurt Grob and Pat Sandra. When we returned to BYU, we were able to further refine the column technology and demonstrate the first promising capillary SFC results using a Varian syringe pump, Hewlett-Packard GC oven, and PerkinElmer fluorescence detector. About that time, my department at BYU invited a patent attorney to give a seminar on intellectual property (IP). The attorney convinced me that capillary SFC could be patented, and two former graduate students encouraged me to help start a company, Lee Scientific, to commercialize the technology. This opened a whole new world of entrepreneurship to me.

In the late 1980s, I hired a postdoctoral researcher, Joseph Sin, from David Lubman’s group to work on a supersonic jet fluorescence detector for SFC. Joseph suggested that we might consider coupling a supersonic jet with an orthogonal acceleration time-of-flight (TOF) geometry. I encouraged him to build a system, and we demonstrated the first experiments coupling an atmospheric pressure ion source to orthogonal TOF mass spectrometry (MS). This was novel and led to another patent, and the beginning of a new instrument company. I convinced my brother, Edgar Lee, who did some of the original work on ion-spray MS with Jack Henion at Cornell, to leave his job at Midwest Research Institute and join me in this venture. The company, Sensar Technologies, produced an electrospray ionization (ESI)-TOF-MS system with a half-meter flight tube (no reflectron) that provided a resolution of 5000 and saved 5000 spectra per second in memory, more than adequate for high-speed liquid chromatography (LC) and capillary electrophoresis (CE). I believe this system still holds the record for highest resolution per length of flight tube.

When Sensar was sold, Edgar and I began to look for the next entrepreneurial activity. We were able to win a contract from the U.S. Defense Threat Reduction Agency to develop a person-portable GC–MS system, which led to the formation of Torion Technologies and the Guardion-7 product. The major challenge was to minimize the electrical power requirements such that the system could operate on a 24-V battery. We immediately looked at resistively heated column technology for the GC system and planar chip technology for an ion-trap MS system. We hired Steven Lammert, an expert on ion traps, who convinced us that a miniaturized toroidal ion trap would bring us to market faster than the planar trap technology. This adventure took approximately 10 years until the company was sold last year to PerkinElmer.

Can you tell us about the work your research group at BYU is currently doing in the capillary and micro/nano fluidic separations area?

We are currently working on two main projects: hand-portable capillary LC and thermal gradient microchip GC. We teamed up with people at VICI Valco to develop a nanoflow pumping system and Paul Farnsworth at BYU to develop an ultrasensitive UV-absorption detector. The small LC system can be battery operated. For microchip GC, a thermal gradient (decreasing temperature from the front of the column to the end) can overcome many of the compromises inherent in using microchips for columns to provide high performance.

What kind of work are you doing on monolithic column technology for capillary LC and instrumentation for field sampling and hand-portable GC–MS?

We have primarily concentrated on improving the chromatographic efficiency of polymeric monolithic columns for capillary LC, and have made great strides in this direction. Reducing the pore size and controlling the pore size distribution are the most important factors. We can now routinely produce columns that provide approximately 150,000 plates per meter. Obviously, there is still room for improvement.

 We just finished work on high flow rate air sampling for portable GC–MS. A multicapillary sampler or concentric packed cylindrical sampler can provide parts-per-trillion detection limits for short sampling periods. 

Your work also stands out for the broad range of application areas it’s applicable to, such as environmental, biomedical, and chemical–biological warfare analysis. Did you intend to target those application areas or did the research lead you there naturally?

It is best to develop an analytical instrument to solve a specific problem or need. Unfortunately, I have often done the reverse-that is, I’ve become fascinated with a new technology and then had to search for its useful applications later. Luckily, we usually found them.

Of the 20 U.S. patents you hold, which one (or ones) do you think has had the greatest impact?

Directly, to date, probably the miniaturized toroidal ion trap patent. However, it is difficult to measure the full impact (direct and indirect) of a patent. For example, our capillary SFC patent led to Lee Scientific, which produced a supercritical fluid chromatograph and then a supercritical fluid extraction system, which in turn led to the Dionex accelerated solvent extraction (ASE) product after Lee Scientific was purchased by Dionex.

While academic scientists occasionally form start-up companies, you have started three. How have you been able to create so many? What did you learn from that experience and what advice would you offer a scientist trying to start a new company?

I really didn’t start out to create companies-they just seemed to come naturally as the opportunities presented themselves. In fact, each time one of my companies sold, I was extremely relieved to have such a huge burden lifted off my shoulders, and I vowed never to start a company again. However, as time erased the memories of the difficult times, I found myself doing it again. The entrepreneurial spirit became almost impossible for me to shake. It became sort of an addiction.

Your have an impressive body of publications. How important is it to you to share your work with the scientific community? Has anything you published led to unexpected collaborations?

My major academic goal has always been to do the best job I could in the classroom for the students in the courses I was assigned to teach. Second to that was to provide the best training and opportunities for graduate students. The primary measurement of the latter was publishing papers, so I always emphasized to the students that their research efforts should always lead to papers. This helped them focus on the experiments that needed to be done to complete the requirements for solid research papers, one at a time. These papers became the substance of most of the chapters in their dissertations.

I believe strongly in collaborations. Good research can be most efficiently done by involving people with different expertise. In most cases, I have actively sought collaborations at the beginning of projects; however, periodically, people have approached me, requesting analytical help with their projects. These have often led to interesting collaborations and new research directions.

What chromatography problem would you most like to see solved in the next 5–10 years? Do you have any plans to solve it yourself?

I strongly believe that the future of analytical instrumentation is miniaturization and simplification, so that the instrument can be taken to the sample instead of the sample to the instrument in a laboratory. My interest in this direction began approximately 15 years ago, resulting in a person-portable GC–MS system. We are now working on a hand-portable LC system. I believe that analytical instrumentation will follow trends set in the electronics industry-smaller, simpler, and more efficient.

What advice would you offer a scientist just starting out?

Other than the typical suggestions, I would emphasize the importance of continually improving communication skills, both oral and written; assembling compatible and dependable collaborators around you; and providing an environment in which your students and researchers can maximize their creativity.