A “Model” Career

At a Glance

• More than any other discipline, pathology offers the ability to explore a wide variety of scientific and medical interests
  
• I found my way to the field through a fascination with the inner workings of the cell and their effects on human biology and disease
  
• The path of my career has led me through mutator phenotypes, skin pigmentation, 2D and 3D imaging, and now phenomics
  
• For younger researchers with similar interests, I recommend cultivating a knowledge of biology and computational sciences – as well as curiosity, motivation and a good work ethic

I am often asked how, after choosing pathology as a specialty, I ended up with a research career as topically divergent as mine. The breadth of interests has led to a fascinating – and incredibly fun – exposure to an array of disciplines ranging from genetics and model systems to genomics and imaging. So what resulted in this diversity? I think it’s all thanks to the accident of my birth: my genetic nature, my family, our time in history, and being at the right place at the right time. The makeup of my genes has given me a strong sense of curiosity and wonder. None of these factors is unique or surprising on its own, but the way they came together to give me such a breadth of research interests tells a story that I hope is intriguing, fun, and most importantly, useful to my colleagues.

I was introduced to the idea of research by my father, who was a synthetic organic chemist. When I asked what had motivated him to make the drastic jump from navigator in the Chinese navy to a PhD in chemistry, he told me that the brilliant stars of the night sky made him realize how small we are in the universe and inspired him to make a difference. The desire to help others was natural to him, so he thought it would be interesting to synthesize new chemicals that could be useful to humanity. From this story, I learned how profoundly a sense of curiosity and a desire to help humanity could motivate a lifetime of work – and, from that day forward, I found myself inspired to do the same.

But how did that lead me to pathology? I discovered an affinity for the field early on in my career. It was during second-year pathology lectures in medical school that I learned about cancer, and was struck by the stark aggression of malignant cells as they invaded host tissues. That was impactful, but the true moment of decision came during my surgery rotation at Bellevue Hospital, when I discovered an entirely new meaning of cancer. This time, what I noticed was the variation between different cells in the same tumor – and that moment fixed my interest in devoting my career to the cellular aspects of human biology and disease, inspiring more and more research questions to pursue. On my other rotations, I couldn’t help being deeply affected by my patients’ suffering, which made research seem an especially good way to bring benefit to others as broadly as possible. By the year’s end, pathology had become an obvious choice – it was a way for me to make research discoveries that could have an impact on many people, rather than just one at a time.

I found magic when I started my residency training in anatomic pathology. The more I studied disease under the microscope, the more I wanted to understand it from a basic scientific perspective – so, during my residency at the University of Washington in Seattle, I decided to pursue a doctoral degree. A fellowship put together by Larry Loeb allowed me to research in any laboratory I chose. By first rotating through several laboratories, I found that I loved abstract thinking and, in particular, genetics – an affinity for which I thank my mentor, Gerald Smith, a leader in the study of recombination. At last, I saw a path to addressing medical problems on a larger scale than the one-on-one.

The science of skin color

My experiences in medical and graduate school highlighted the importance of the “mutator phenotype,” an elevated rate of spontaneous mutation, in the development of cancer. The mutator hypothesis states that this phenotype is necessary to explain the accumulation of mutations that causes human cancer, and during my postdoctoral studies, I opted to test this hypothesis by screening for mutations in a vertebrate model system. Thanks to golden, a recessive pigment mutant, I discovered two new interests: the zebrafish as a model system and, eventually, skin pigmentation as a model phenotype.

My goal in setting up my own research laboratory was to explore the possibility of a forward genetic screen in zebrafish. To do that, though, I needed an institution that could understand the boldness of this initiative – one with the temerity to allow me to pursue the idea despite low funding and high aims. I was lucky enough to find such an institution at the Penn State College of Medicine (Hershey, PA, USA), where I began my work in 1992. It took me four years to obtain my first genomic instability (gin) mutants – one of which did appear to cause an order-of-magnitude increase in cancer susceptibility among heterozygotes. Along the way, I began to wonder about the cellular basis of the decreased pigmentation in golden mutant zebrafish, so I investigated that as well. Curiosity led me to pursue the project outside of my funding, on a shoestring budget deeply dependent on collaboration.

It turned out that the human orthologue of golden, SLC24A5, contributes to human skin color. In fact, it is a determining contributor to pigmentation differences between people of European and of African descent. We suspect that it’s a modulator, rather than an “on-off” switch, which means that the more active this gene is, the greater the number, size and density of melanosomes in the skin cells and the darker the resulting skin color. Our discovery attracted a lot of attention – people wanted to know if SLC24A5 was “the gene for white skin color.” They hoped it would explain one of the most contentious issues in the last half-millennium of human civilization. I regularly get asked how people can modify their skin color, or cure vitiligo or other depigmentation diseases. Unfortunately, I can’t help with either – but I am interested in why people want so badly to change the color of their skin, and I’m hopeful that a more complete understanding of skin color genetics can demystify race. Perhaps that would allow humanity to focus less of its energy and resources on skin color-based discrimination and more on making the world a better place.

Looking at the whole organism

Skin pigmentation and cancer aren’t the only areas where genetically altered zebrafish are useful – they’ve become a powerful model for studying all manner of vertebrate biology and human disease. Just as physicians must learn normal anatomy and microanatomy so that they can recognize abnormality, the first step in conducting zebrafish experiments is to understand their normal gross and microscopic anatomy. To help, we’re generating a web-based 2D histology and 3D atlas of zebrafish microanatomy (1). It’s the first full lifespan atlas of its type, and we hope that it will someday provide a scaffold for gene expression and morphological data generated both in our laboratory and globally. We’d even like to expand the project to include comparisons with genetic, reverse genetic, and disease abnormalities; other types of imaging; cross-disciplinary development of new imaging technologies in collaboration with engineers and computer scientists; and integration with websites for other model systems. Most recently, we’ve begun working with scientists at the University of Chicago and Argonne National Labs to develop a high-throughput way of 3D imaging optically opaque tissues at histological resolutions, so that all cell types can be studied at once. Our plan is to involve pathologists around the world in providing a high-quality atlas that is well-connected between all model systems.

I consider “functional genomics” to be an approach that begins with phenotype and then uses a combination of genetics, genomics, bioinformatics and proteomics to solve biological problems. This kind of work is always exciting to me because I’m drawn to integrative solutions – and I admit I love the gadgets, too. Zebrafish functional genomics has a unique place in the study of genes and phenotype in the context of the whole organism. It’s great that we have a vertebrate model with a sequenced genome – one that develops ex vivo (meaning that embryos don’t need to be excised from the mother), is transparent during its early development (meaning any cell type can be visualized with fluorescence), produces many offspring very quickly (meaning that forward genetic and chemical screens are easy), and offers opportunities to use excellent, well-established reverse genetic tools. These unique features are the reason I have dedicated my career to the development of the zebrafish atlas, new imaging tools, and now a functional genomics core facility to encourage other laboratories to explore the possibilities for themselves. I’ve worked to foster coordinated cross-genomic activities that take advantage of the strengths of different model organisms, genomics approaches, proteomics, and high-throughput chemical screens, all with the goal of addressing important biological and medical problems.

The phenomics appeal

Lately I’ve become very interested in the idea of phenomics, which uses high-throughput phenotypic profiling as a tool to understand biology and disease. As pathologists, we are well familiar with the fact that multiple phenotypes are associated with individual genes (pleiotropy) and diseases (syndromes). Phenomics is a highly collaborative endeavor – so I’m trying to contribute from the perspective of an anatomical pathologist with the zebrafish phenome project.

What is this project? To enable morphological phenotyping at cell resolutions, I’m trying to create X-ray-based, micron-scale computed tomography as a 3D imaging tool – something that will require whole-animal examination of a small, vertebrate model. The fact that phenotype can affect any cell type, and commonly affects multiple organ systems simultaneously, drives the need for whole-animal phenotyping. Multiple factors (the work involved in covering large tissue areas, the geometric increases in file sizes, and the need for speed) demand the use of a small model organism. And to increase relevance to humans, we need a vertebrate model – the zebrafish, which is the smallest vertebrate model is well-developed as a genetic system. By using cutting-edge technologies from computer science, engineering, materials science and bioinformatics, we hope to place each genetic and environmental impact in the spatial, temporal and physiological context of the whole organism. The tools we’re developing for the zebrafish phenome project will be applicable to many human tissue samples, and in instances where we learn clinically relevant information, may even enter the realm of standard of care. To me, that’s a very exciting possibility, and that’s what makes phenomics so enticing as an area of study.

Advice for the new generation

So why is it important for me to share my story? A pathology researcher must have a strong sense of curiosity, self-motivation, and work ethic – those are the best predictors of success. You need a passion for science and a commitment to excelling in your field, because these things will encourage you to ask questions in a deeper way, engage in discussion and be open to learning new things. For today’s budding pathologists who are interested in going off the beaten path to find a productive career and make a difference in our discipline, I would encourage the study of both genetics and computer science; after all, we’re moving more and more toward high-throughput analyses and large-scale studies that involve a lot of data processing. We also need to become skilled at sharing our work – not only are good laboratory and computational skills important, but once a set of successful experiments is complete, effective packaging and communication of the message become critical. Ideally, your enthusiasm for your work can inspire more pathologists to get involved in research!

I’ve learned from my career that it’s exciting to culture a sense of wonder, passion, and curiosity. I’ve found that the key ingredients for happiness and a rewarding career are to stay motivated not just for yourself, but for the benefit of science and medicine, and to make passion and curiosity an engine for your activities. And if you keep an open mind while you explore, even serendipity can be a tool to answer the questions that arise.

Keith Cheng is director of experimental pathology, director of the Penn State Zebrafish Functional Genomics Core, and a distinguished professor of pathology at the Penn State Hershey College of Medicine, USA.