Article

Sandra Clifton, former Assistant Director of Genomics

Q&A with the Genome Institute’s Sandra Clifton

After over a decade at The Genome Institute, Dr. Sandra Clifton is retiring. But before she left, she agreed to answer a few questions about her career in genomics.

What got you interested in science in the first place?
When I was in high school I took what was called an ‘Interest Test.’ You answered questions such as: ‘If you had the opportunity, would you type and take shorthand? Would you build a building? Would you wash test tubes?’ I knew that I didn’t want to be a secretary, or a stenographer, or take dictation. So anytime I had the opportunity to put ‘wash a test tube’ or ‘do a lab experiment’ that’s what I put on the test. You have to remember that this was back in the mid-fifties. And when I went to my counselor, he said, ‘It looks like you’re very mechanically inclined.’ And that made sense to me because my dad was, too. He was an MD but he had a shop in the back of our house where he made furniture and rebuilt engines and cars, so I was very familiar with that side of things. So I asked the counselor, ‘What can I do with that ability?’ And he said, ‘Maybe you could repair sewing machines or something like that.’ I just looked at him with utter disbelief. I couldn’t believe that he was telling me that I could only do machine repair, but not a word about science.

But I was just very interested in science and cause and effect and how things worked. I worked in my father’s office when I was in high school during the summers. He had a microscope that I liked to use. Fortunately I ended up in science in a field where I’m trying to discover how genetic material works – how it’s put together and how it affects us.

How did you get involved in the fields of genomics and sequencing?
As an undergraduate, I was working with the director of my microbiology program at the University of Oklahoma. We’d isolated a gene from the bacterium, Haemophilus influenzae, and he wanted to sequence it. So we went over to Bruce Roe’s lab at the Advanced Center for Genome Technology, because he had a sequencing lab. We were talking with him about how to set up to do sequencing in our lab. About halfway through the conversation he looked over at my boss and said, ‘Don’t reinvent the wheel – just send her over here with the DNA, and we’ll show her how to do it.’ So that’s what happened. And during that process, I was doing work and showing Bruce my results and he’d ask me to do experiments for him, too. So I ended up doing a lot of work for him. And finally, he said he would put me on a Research Assistant grant so I could finish my graduate degree. I then did a two-year post doc in his lab, and he promoted me to the position of assistant director in charge of bacterial sequencing.

You decided to start your PhD late in life. What prompted you to go to graduate school?
I went back to school 23 years after I’d obtained my undergraduate degree. My husband was very supportive – he knew I wanted to go back to school. One day we were out to dinner and he said, ‘You know, I think we can swing it now.’ I’d always wanted to do graduate work in microbiology.

I became really interested in molecular biology when I was teaching science labs at a junior college. When I was at school doing undergraduate classes, molecular biology was not even a discipline. I remember one of my professors in microbiology saying during the lecture, ‘By the way, these two guys named Watson and Crick think they’ve figured out what the genetic material is. It’s called deoxyribonucleic acid (DNA).’ And he explained the double helix and base pairing and that was my only exposure. So I had to teach it to myself when I was teaching courses in the seventies. And it was just fascinating to me. I wanted to find how things were put together biologically by looking at this molecule of life. That’s what piqued my interest in the field.

What brought you from the University of Oklahoma to The Genome Institute and Washington University?
One day I received an email from Richard Wilson [the current Genome Institute Director]. At the time he was the co-director of The Genome Institute. I knew Rick because when I was taking undergraduate classes I would come over to the biochemistry building, where he worked. He’d recruited another person I’d worked with so as I was opening the email, I was thinking, ‘Who in the heck is Rick trying to recruit from this lab now?’ The email said: ‘Dear Sandy, You know I’m one to get right to the point. We’ve got this new position that we’ve been talking about. A lot of us around here have small projects that we just don’t have the time to handle and we need somebody to take over that responsibility.’ I knew Washington University’s Genome Institute was a major sequencing lab involved in the human genome project. I wrote back and said, ‘Sure I’d be glad to talk with you.’ So I came to St. Louis, gave a seminar and they essentially made me an offer I couldn’t refuse. My first day at work was July 1, 1998.

What are some of the major projects you’ve been involved with at The Genome Institute?
One of the first projects I worked with had the title, ‘Comparative Genomics in the Enterobacteriaceae,’ the large family of bacteria that includes the normal gut flora in humans and animals. It also includes the widely known Salmonella bacteria. This project actually has been in progress for 12 years, with multiple extensions and additional projects. The administrative group says this is the “grant that will never die.” I eventually took over as Principle Investigator. For our last competitive renewal, we looked at all of the Salmonella pathogens that had already been sequenced, and then we chose certain subtypes that had not been sequenced and that were significant disease-causing organisms. We’re now sequencing those twenty-five Salmonella species.

Another project was the Expressed Sequence Tag project, or EST. In the beginning the ESTs were the only way we had to find genes. Once more genomic sequence became available, the ESTs were used to find and confirm genes within that sequence. At that time we had an independent group that did the sequencing, since we used a different methodology for the ESTs than we did for other sequencing. I eventually took over the project. We contributed over 3.5 million ESTs - over 2.5 million while I was coordinator - to dbEST, the database at the National Center for Biotechnology Information (NCBI). The human ESTs were used for annotation in the human genome project. We also worked with mouse ESTs, soybean, zebra fish, frog and many others. Today ESTs are still very valuable. But when we moved into the more sophisticated sequencing machines, the EST projects were subsumed by the regular production sequencing queue.

Are there certain projects you’ve been involved with that stand out for you?
The maize mitochondrial project was one of which I’m very proud. It was a grant from the National Science Foundation (NSF) to three female researchers. The project director at NSF told us that these mitochondrial genomes were very complicated, and she didn’t think we’d be able to sort them out. But we did it, thanks to Pat Minx, and his great finishing skills.

Another project that stands out is the sequencing of the Pristionchus pacificus nematode genome. It was a difficult genome, and it added information to the free-living C. elegans nematode and parasitic nematode, Brugis malayi, both of which had already been sequenced. The data indicated that Pristionchus was acquiring genes that could eventually lead to parasitism.

Of course, the Enterobacteriaceae project has to be a favorite. It was one of the first with which I worked, and it is still continuing, an indication of the importance of the work that we are doing with that group of organisms.

Finally, being part of Human Microbiome Project is very important to me, since I am a microbiologist. I think it’s really going to increase our knowledge about how microbes affect who we are, what we are and how we respond to the environment.

How would you classify the research you do now?
Now, practically everything I do is comparative genomics that also looks at phylogeny. In other words, we look at where each organism we sequence belongs in the phylogenetic tree of life. It encompasses the analysis and comparison of genomes from different species, to gain a better understanding of how species have evolved, as well as the biochemical, genetic, metabolic and physiological pathways involved.

Does this include studying evolution?
Yes, this gives us a clue to our history and how life has evolved and the many different branches that occur as that evolution takes place. I don’t think that there’s any doubt that life has evolved. It’s just very apparent in the DNA. I go to church and I don’t have any problem with evolution. What’s stated in the Bible is essentially that we have evolved. Interestingly it was my mother who taught me this. She never finished her college education because she was ready for higher education during the depression. But that was her take on things, and it made a lot of sense to me even before I studied science as deeply as I did.

How has the field of sequencing changed over the course of your career?
When I started, it was pretty difficult to do even the smaller projects such as sequencing a bacterial genome. The machines were gel-based fluorescent sequencers and it took us about a year to completely sequence a smaller genome like a bacterium. I was always bumping up against the former director because he was so goal-directed and there was so much time and paperwork involved in these smaller projects. But I sat in front of him and said, ‘You need to get used to this, because this is the way it’s going to work in the future. After the human genome project we’re going to be inundated with what you call small projects.’ And it turned out to be true.

But today we have returned to large projects again. And the small projects are probably now going to be done by people who have one sequencing machine and have the capability to take on smaller genomes more quickly. But I think the problem there might be analysis. They will have to hire or collaborate with people who can take the data they produce and do adequate analysis.

The Genome Institute is providing expertise that those smaller labs would not have access to. We’ve also been very innovative. We have seen a problem most of the time before it arose and determined ways to solve that problem. And the burgeoning informatics group attests to that since we now are experts at producing and analyzing mountains of data. So it’s the analysis that’s going to be crucial – handling the large amount of data that we do produce and analyzing it in a way that is consistent with good science.

Would you change anything about your career?
Not a thing. I’ve been very fortunate in my career. It has been an honor and a privilege to work in Bruce Roe’s lab and at The Genome Institute. Bruce gave me the grounding in research and Rick and Elaine [The Genome Institute directors] have always been very supportive, and that has made the path forward much easier. My family is great, I had a fantastic marriage, and I’ve had a very satisfying career. I don’t think there are a lot of people who could say that, and I know that I am most blessed, both in career and in life.