Solo researcher links
insulinlike growth factor family
polymorphisms to rare diseases

Published November 01 2017

Peter Rotwein is vice president for research at Texas Tech University Health Sciences Center in El Paso. courtesy of peter rotwein

Insulinlike growth factors, or IGFs, are essential for physiological processes, such as somatic growth and development, in humans and other animals. They promote proliferation, differentiation and survival of various cell and tissue types. In rare cases, something as small as a mutation in one gene — IGF1, for example — can cause huge problems for a person, ranging from growth and developmental defects to intellectual abnormalities.

Many questions about IGFs remain unanswered: How prevalent are variations in IGF family proteins in the human population? Are these variations predictors of disease susceptibility? Can they be used to track evolution?

While more and more publications display a multitude of coauthors, publicly available databases have opened a new door in the scientific field, allowing a single investigator to dig into the depths of genomic and proteomic data. A recent paper in the Journal of Biological Chemistry comes from an author who took advantage of this new opportunity. Physician-scientist Peter Rotwein interrogated the exomes of more than 60,000 people to assess variations in genes in the IGF family. These exomes are part of a database made publicly available by the Exome Aggregation Consortium, or ExAC, a group of geneticists who study human biology on a large scale.

Rotwein’s population-based genomic study revealed alterations in the coding regions of 11 IGF family genes. His analyses show limited population variability in IGF1 and IGF2 genes, more common amino acid modifications in IGF receptors, and a wide range of variation in IGF binding proteins and the IGF acid labile subunit, proteins that function primarily as transporters of IGF1 and IGF2 in blood and extracellular fluid.

In an extensive interview with ASBMB Today contributor Lee D. Gibbs, Rotwein described his career path from physician to scientist and offered advice for others. The interview has been edited for length, clarity and style.

How did you pursue this discovery as a single investigator?

I was previously faculty and chair of the department of biochemistry and molecular biology at Oregon Health and Science University, and three years ago I made a transition into an administrative role as vice president for research at Texas Tech University Health Sciences Center in El Paso. As I transitioned out of doing lab-based molecular biology, I became really interested in population-based molecular genetics and the large-scale analysis of genomic data. During my transition from the wet bench to administration, I found that publicly available genomic databases provided valuable and robust data that I could analyze. That allowed me to continue my pursuit of understanding mechanisms of action of IGF family members.

What is the Exome Aggregation Consortium?

The Exome Aggregation Consortium, or ExAC, consists of a group of geneticists who joined forces to study human biology on a large scale. They published their first papers in the fall of 2016 examining a series of themes resulting from analysis of the exons of genes sequenced from over 60,000 people but primarily focused on the big data aspects of it. Since the ExAC data are publicly accessible for anyone to study, I thought it would be useful to examine a few genes in detail as a test case of what a single scientist could do with the information. I then started looking at the entire IGF gene family. Once I had the primary data analyzed, which consisted of assessing every potential modification scored by ExAC, I then connected the results to other databases, such as Online Mendelian Inheritance in Man and a few others that examine human disease, and I came up with this paper.

My hope is that scientists who are interested in mechanistic aspects of human biology can first look at their favorite genes and the derived proteins in ExAC and then test the potentially most intriguing specific variants experimentally. I would hope that some of their goals would be to determine how single amino acid changes prevalent in different human populations might affect both protein structure and function and to learn if these changes could have an impact on human physiology and maybe even disease susceptibility.

As a physician, what led you to pursue a career as a researcher? Did you always know that you wanted to go into research?

Ha! It was not a direct route. I fumbled along for a while. I was interested in biological sciences and I had really no mentorship in that area, so I decided to go to medical school. There, I found what appealed to me more than anything was biochemistry. As I went through and wanted to figure out a field of medicine to pursue, I focused on endocrinology, in part because it was the most biochemical field and it always appealed to me how molecules work and pathways. Also, the influence of people who were available at the appropriate time as guides made a difference in the choosing of my career path.

During my medical training, I found that, more than endocrinology practice, it was the science that appealed to me most. At that point, I had the opportunity to work in a molecular biology lab and discovered that I loved both the technical and intellectual aspects of it. This was the early 1980s, and there were no kits for anything, and no PCR! I thus spent considerable time doing plasmid and bacteriophage preps and generating cDNA and genomic libraries but also, most importantly for me, reading about molecular biology. This of course took a few years, but along the way it seemed like the right career path for me.

Is there any advice you can provide to students who would like to pursue a career in research?

If I had known what I know now, I would probably have done a combined M.D.-Ph.D., which would have allowed me to get rigorous training on both sides and then see how to fit them together. In fact, during my career in Oregon I was head of the M.D.-Ph.D. program for eight years, so I have often preached that. But if you are a physician who wants to be a scientist, you have to really put in the time and work to learn how to really do it well. One way you can meet this goal is by getting a really good mentor and surrounding yourself with people in the lab who can help and teach you. You have to expect that this will take some time and know you are going to mess up a lot and do really stupid things in the lab and botch experiments, while understanding that you will learn through experience and this will prepare you to become both technically and intellectually proficient. At some point you will be ready to run your own lab.

When I was an endocrine trainee, I did clinical and lab work part time for two years, then was full time in the lab for another three-plus years before I was ready. So five years of postdoc on top of a total of five years of clinical work — that’s what it took for me to be good enough to get a faculty job and get enough data to write manuscripts and grants and enough feasible ideas to develop my own research program. Everyone has to find out what is right for him or her, and that is the toughest thing to do. You have to find out what type of career you want and what will make you professionally satisfied and provide whatever challenges you think you need to have a rewarding professional life.

Can you share any advice on how to overcome the challenges of a career in research?

My key to overcoming challenges during my years as a junior faculty person was my family. Having my wife, Bonnie, and our four daughters around when things were tough reminded me there are other things more important in life. The deal Bonnie and I made when the girls were young was that I always had to be home for dinner. I could go back to the lab at night as long as all the kids were asleep, and I would have to sometimes do grocery shopping at midnight. I spent a lot of time in the lab as a postdoc and junior faculty.

You are going to have hard times. You will have papers rejected, grants rejected, and you will have to try to learn from each one of those. And not everything you do will be successful, but if you are persistent, if you reach out for advice from others and work hard and focus on important scientific problems, you will find a path where you can do much of what you want to do as a scientist. For me I can’t think of any other more rewarding career.

Lee D. Gibbs Lee D. Gibbs is a postdoctoral research fellow in the Department of Translational Genomics at the Keck School of Medicine of the University of Southern California.