Chance » Reflections » Li

Encounters with BC

Lin Li / Molecular Imaging Lab, Department of Radiology, University of Pennsylvania

21 May 2011

Britton Chance was my mentor. I got to know Brit when I was a graduate student in the biophysics program at the University of Pennsylvania in 1994-2000. However, I did not have the chance to be his graduate student. Jack Leigh, one of Brit’s early postdocs, advised on my Ph.D. thesis on magnetic resonance imaging. It seemed to me then that magnetic resonance imaging was very far removed from the optics research Brit was doing. However, life soon became quite interesting. After I joined Jerry Glickson’s Molecular Imaging Lab on imaging cancer animal models in 2004, my research horizon was further expanded into other imaging modalities. I started to work with Brit in 2005, using his redox scanner to image cancer mouse models. I was fortunate to be able to work closely with him until the last few days of his life. My career has benefited tremendously from Brit’s guidance and support, his research on redox state and the legendary redox scanner.

As far back as the 1950s, Brit had conducted pioneering research on mitochondrial redox state and electron transport chain. The cryogenic NADH/flavoprotein fluorescence imager or the redox scanner was invented by Brit et al. in the 1970s to provide high resolution imaging of the in vivo mitochondrial redox state in tissue by snap-freezing and flying spot techniques.1-3 Today, more than thirty years later, we can fully appreciate the vision and impact of Brit’s early research. Redox state has been found to play increasingly important roles in various biological processes including growth, metabolism, apoptosis, gene expression, and signaling. Imaging tissue cellular redox state may further provide key information for understanding biology and the diagnosis and treatment of diseases such as cancer, diabetes, heart disease, and the neurodegenerative diseases.

Fortunately we have been able to continue Brit’s legacy of redox scanning for biomedical research at Penn during this tough period of research funding. We have identified redox imaging indices as potential biomarkers for human melanoma aggressiveness in mouse models.4, 5 We started with two human melanoma mouse xenografts, one more metastatic than the other. The differences between the two models were like the difference between “day and night” as Jerry said. Brit and Jerry immediately realized the potential value of this result for basic cancer research and clinical practice. With further encouragement from them, a linear correlation was obtained between the tumor redox ratios and invasive potentials for five human melanoma lines spanning the full range of progression to metastasis. The result was amazing -- one redox index to differentiate the five melanomas. Apart from providing potential biomarkers for the diagnosis and monitoring of tumor progression, these results also provided evidence for a novel connection between tumor metastatic potential and mitochondrial redox state. With Brit’s direct support, our work was further expanded to include breast cancer models and pancreatic pre-malignant models,6, 7 and obtained results consistent with the melanoma models. In 2009, Brit led us in the study of image redox state in stem cells.8 He not only initiated the project but also participated. Our preliminary data provided evidence that supports the association of the more reduced redox state with the stemness of embryonic stem cells. Brit envisioned a stem cell sorting machine based on redox state. He frequently emphasized studying redox state, tissue heterogeneity, and clinical translation. With his direct participation, we have been testing redox scanning on clinical biopsy samples. I also obtained an NIH grant to develop a non-invasive NMR method to image redox state in vivo. I know Brit would have been happy to see our continuing success toward the direction he led us.

I have learned much from Brit in daily work and personal life. Here I would like to share some of my memories and experiences.

1) Great science is not necessarily done with top-grade expensive instruments. When people think about Brit as the founder of biophotonics and his cutting edge biomedical research, they may envision his laboratory filled with expensive state-of-the-art instruments. On the contrary, Brit’s laboratory in the School of Medicine at the University of Pennsylvania was much like an electronic engineering lab or a machine workshop. The power supplies, fluorometers, and amplifiers we have been and are still using were homemade by those in the lab. Brit was a very hands-on person, and I saw him doing soldering in the lab even as late as in the fall of 2010. He would check on an instrument with technicians or postdocs when the machine did not run as expected. A number of optical instruments were invented in his lab to accomplish great science, including the miniaturized stop-flow device for kinetics of enzyme reactions, the dual wavelength spectrophotometer, RunMan for blood oxygenation and volume measurement, and a hand-held breast cancer detector, just to name a few. These instruments are widely used today and are not expensive, but conceptually they were really advanced in the field at the time of invention. They made it possible for many important discoveries and advancements in research labs all over the world. Another example of Brit’s legendary instrument is the redox scanner made more than thirty years ago, which is still running today and producing great research results. Brit was really good at doing outstanding research while saving unnecessary costs. This has become particularly meaningful in today’s research environment in the United States where medical costs are skyrocketing and research funding is shrinking.

2) Brit was genuinely interested in and dedicated to science. Brit had cycled between his home and the lab every day, six days a week, until 2008 at the age of 95. In his last two years when he had to make use of a wheelchair, he still arrived at the lab or attended meetings with other researchers several times a week. As his years were approaching the nearly 100 mark, he continued to travel to Singapore, Mainland China, and Taiwan for his biophotonics research, to develop new instruments, and to promote clinical translation. In the fall of 2010, he wanted to submit three NIH grants. He made me the PI for one of the grants. The proposal is about the development of a miniature metabolometer to non-invasively measure the nutritional status in human subjects, and preliminary data were obtained from his research collaboration in Taiwan. We finally succeeded in submitting the proposal in Oct. 2010. Other times Brit demonstrated to me his enthusiasm for and spirit of scientific inquiry by patiently guiding two summer intern students in the process of scientific thinking. The students did several imaging scans of mouse tumor samples. The mouse received drug treatment and we hoped to see whether the treatment would change the tumor redox state. Brit asked the students what type the drug was, the dosage, and what effects the drug might cause. They did not know. He said, “Aren't you interested in knowing what the drug is and what effect it may have and how it works? I am very interested in knowing that”. Even three days before his death, while hospitalized, he discussed our latest research with us.

3) Brit’s attention to detail and timely action. Once Brit and I talked about a research idea and decided to order a compound for a test. I meant to do the ordering afterwards. Instead he stood up right then, pulled out a company catalogue from the shelf, and started to look for the compound. He found it quickly and wrote down the compound name for me. I was impressed by his attention to the details. What I also learned from this experience was the importance of timely action. Mark Twin said "Action speaks louder than words but not nearly as often". Sometimes we tend to think or speak a lot but our action is limited. Another example - during his discussion with students about the treatment information as mentioned, I provided the drug name but did not know the dosage. I thought about getting dosage information from our collaborators before the meeting but did not do it in time. That discussion was not just a lesson for the two young students but also a good lesson for me.

4) Brit’s open-mindedness. Brit was always open to new ideas and the opinion of others. During my six years of working with him, I never saw him bluntly negate another person’s thoughts. Once when I was a graduate student at Penn, I gave a presentation about acupuncture at the student journal club in the Johnson Foundation library which was located adjacent to his lab. I did not know that he and his wife Shoko were paying attention until at the end of my presentation they indicated to me their interest in acupuncture. I was later on encouraged by Brit to work with people in his group to try using his RunMan instrument to monitor the effects of acupuncture on blood hemodynamics in legs.

5) Brit being modest, appreciative, and caring for others. Even with his fame and advancing age, Brit would not hesitate to visit other researchers for discussion about projects and learn from them, including his former students and postdocs. I was impressed that he would come to Jack Leigh’s office every Thursday late afternoon to have a research discussion and, of course, a bottle of beer with Jack. When he had to rely on the wheelchair for mobilization, he was equally ready to travel to other campus buildings for research meetings as before. I noticed that during his last few years at Penn, Brit was always very thankful no matter how little others had done for him. During all of our meetings I never saw him criticize or look down on anyone for “dumb” ideas or mistakes. He was always positive, supportive and tried to move things forward. Brit took special care of his students and those working for him. Once I saw him patiently guiding a graduate student in designing her thesis work. Later on the student had to transfer to another lab when Brit ran out of funding in 2007. On the day in 2010 when she was to defend her thesis, I was told that Brit came to the thesis defense in his wheelchair and insisted on staying in the committee meeting after the presentation until the committee passed her thesis defense. Another time I went to see Brit in a rehabilitation facility after he returned from Asia in 2009. His hospital room was on the 3rd or 4th floor. I was surprised and honored to see him waiting downstairs for me in front of the building. I also remember times when I was troubled or stressed, he would say to me “Sit down.” “Be happy!” “Relax, things will be fine”, which helped me to adjust. Brit was not only my mentor, he was also a caring grandfather figure.

I miss the extraordinary scientist and man – Britton Chance. Brit taught me not only about science but also more importantly, he taught me how to be a dedicated scientist and a caring person. His teaching, spirit, life and legacy will be remembered and valued forever.

Drs. Britton Chance (in front) and with Drs. Jerry Glickson, He N. Xu, Lin Z. Li and Shoko Nioka (left to right) at the University of Pennsylvania in 2009. Courtesy of Dr. Jerry Glickson.

– Lin Li

References:

  1. B. Chance, N. Graham & D. Mayer, "A time sharing fluorometer for the readout of intracellular oxidation-reduction states of NADH and flavoprotein", Rev Sci Instrum 42:951-957 (1971).
  2. B. Quistorff, B. Chance & F. Welch, "2- and 3-D mapping of the redox state in vivo. Recording of a hypoxic insult in the rat brain", Acta Neurol Scand Suppl 64:456-457 (1977).
  3. B. Quistorff, J. C. Haselgrove & B. Chance, "High spatial resolution readout of 3-D metabolic organ structure: an automated, low-temperature redox ratio-scanning instrument", Anal Biochem 148:389-400 (1985).
  4. L. Z. Li, R. Zhou, T. Zhong, L. Moon, E. J. Kim, H. Qiao, S. Pickup, M. J. Hendrix, D. Leeper, B. Chance & J. D. Glickson, "Predicting melanoma metastatic potential by optical and magnetic resonance imaging", Advances in Experimental Medicine and Biology 599:67-78 (2007).
  5. L. Z. Li, R. Zhou, H. N. Xu, L. Moon, T. X. Zhong, E. J. Kim, H. Qiao, R. Reddy, D. Leeper, B. Chance & J. D. Glickson, "Quantitative magnetic resonance and optical imaging biomarkers of melanoma metastatic potential", Proceedings of the National Academy of Sciences of the United States of America 106:6608-6613 (2009).
  6. H. N. Xu, S. Nioka, J. Glickson, B. Chance & L. Z. Li, "Quantitative Mitochondrial Redox Imaging of Breast Cancer Metastatic Potential", Journal of Biomedical Optics 15:036010 (2010).
  7. H. N. Xu, S. Nioka, B. Chance & L. Z. Li, "Heterogeneity of mitochondrial redox state in premalignant pancreas in a PTEN null transgenic mouse model" In Advances in Experimental Medicine and Biology Springer, New York (2011).
  8. H. N. Xu, R. C. Addis, D. F. Goings, S. Nioka, B. Chance, J. D. Gearhart & L. Z. Li, "Imaging redox state heterogeneity within individual embryonic stem cell colonies", Journal of Innovative Optical Health Sciences: accepted (2011).