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Applied Biosystems and Dr. Scott R. Diehl

A partnership for the advancement of science

Dr. Scott R. Diehl is the director of a state-of-the-art laboratory in New Jersey studying pharmacogenomics and the genetics of disease risk. His research focuses on understanding the genetic basis of diseases that have complex etiologies involving both environmental and genetic factors, and the differences among individuals in response to drugs and other therapies.

We recently caught up with Dr. Diehl at the grand opening of the new Applied Biosystems Application Support Center in Foster City, California. We asked him to share his thoughts about his current research, his experience working with Applied Biosystems over the past 20+ years, and how continued collaboration with Applied Biosystems is helping his team advance their science as they strive to unravel the mysteries of complex diseases.

First off, tell us a little about your area of expertise and the type of research you do.

My focus is in the fields of genetic epidemiology, statistical genetics, human gene mapping, and pharmacogenetics. I have studied both early onset and chronic forms of periodontitis, cleft lip and palate, oral cancer, nasopharyngeal carcinoma, hereditary deafness, mental illness, neurofibromatosis, and neuropathic pain.

The ultimate aim of my work is to find the particular genes and genetic variation that will cause one person to have a higher risk of disease and another person to have a lower risk, and to identify the individual differences that affect how people respond to medications. We also look at environmental factors—by combining the study of genetics with a focus on the environment we can learn a lot about the environment that we might not have been able to see had we not brought genetics into the picture.

What research is your lab currently focusing on?

We're conducting a major NIH-funded research study on chronic periodontitis, a serious disease that affects over 20% of adults age 40 and above. It is the major cause of tooth loss in older Americans and recent findings suggest that periodontitis may also significantly increase risk of cardiovascular disease (myocardial infarction and stroke). In women of childbearing age, it may be associated with pre-term delivery and low birth weight.

I've also been developing a number of new research studies that focus on the genetic basis of individual differences in drug response, which is the pharmacogenomics part of my work. For example, we are evaluating individual differences in response to opioid drugs used for treatment of severe pain, focusing both on susceptibility to severe side effects and analgesic efficacy.

And you're using Applied Biosystems tools in your research?

Yes, my research center is largely centered around Applied Biosystems technologies. We do a lot of our work on the 3730 DNA Analyzer using the SNPlex™ system for genetic polymorphism research. We also use TaqMan® SNP assays, which are analyzed on the AB 7900 instrument. And we use a customized version of the Applied Biosystems Laboratory Information Management System (LIMS) to keep track of our data.

Can you tell us more about the Applied Biosystems LIMS and how you customized it for your lab?

When I established the laboratory, we acquired the Applied Biosystems LIMS for tracking millions of genetic assays and thousands of DNA samples and chemical reagents stored in our freezers. Over a period of several years, we worked extensively with the bioinformatics and computational staff at Applied Biosystems to customize the system for the specific needs of my laboratory.

We were very fortunate to have some of the top Applied Biosystems application specialists and R&D scientists come and spend extensive time in our lab. They worked side-by-side with my staff to help us get the protocols and robotics systems up and running. Because the work we do is very specific to our lab and our platforms, it was very important that we could build the integrated system and develop protocols for running it right here on site.

What results have you achieved to date, and what impact do you expect your findings to have on the diagnosis and treatment of periodontal disease?

During the past year we completed a whole genome linkage and association analysis using the SNPlex system. We assayed more than 4,000 genetic polymorphisms on a collection of approximately 1,100 DNA samples. That research work was based on a juvenile form of periodontal disease that affects teenagers, and we're currently deep in the midst of statistical analysis of the data. After analyzing a set of about 4.5 million SNPs, we're very optimistic about the early findings regarding specific genes and their involvement in susceptibility to juvenile onset of periodontitis.

Our new work is turning to research studies of the same disorder in adults. In addition to finding genetic factors that cause periodontal disease, a number of lines of evidence have indicated that risk of periodontal disease is associated with risk of cardiovascular disease. We believe that some of the same inflammatory processes that show genetic variation among individuals may influence risk for both of these diseases. Our goal is to find the genes and how they interact with environmental risk factors so we can predict who is at especially high risk of disease and ultimately move toward improved strategies for diagnosis, treatment and prevention.

You mentioned that you have worked with Applied Biosystems for many years. How has that long-standing collaborative relationship evolved?

I've enjoyed collaborating with the company since the late 1980s, when I worked with several R&D scientists in the Foster City lab to develop fluorescent-based analysis of the genetic polymorphism system of the time, called microsatellites. I continued testing subsequent Applied Biosystems polymorphism systems during my nine years as an intramural Senior Investigator at the NIH. And as I mentioned, I have recently worked with Applied Biosystems to establish optimized TaqMan and SNPlex kit workflows in my current lab.

Can you give us an example or two of how collaboration with Applied Biosystems has benefited your research?

In general, it's very beneficial to interact with some very smart people who are well educated through their experience working with other customers and with the global community of scientists. With access to Applied Biosystems experts and tools, I can not only improve strategies for my research and get data faster than I would without them, but I can also bolster the reputation of my lab—utilizing the most advanced technologies available is helpful in getting grants, which is absolutely essential in what I do.

A more specific example of the benefits of working closely with Applied Biosystems scientists is in the development of two sets of genetic polymorphism assays—the LMS and the MALD. The Linkage Mapping Set (LMS) assay is a collection of 4,000 SNPs that are distributed throughout the genome. This panel was highly optimized by the scientists at Applied Biosystems, and it works terrifically right out of the box with very few customizations or tweaking of parameters. It's a very informative system, meaning the genetic polymorphisms are high frequency in both Caucasian families and African-American families.

The Mapping by Admixture Linkage Disequilibrium (MALD) map is a subset of a highly specialized panel of SNP markers that is also invaluable for my research. We have used it to conduct some smaller-scale studies looking at markers for mixes of different ethnicities. This may lead to some important insights into the etiology of the disease, particularly the juvenile form, which occurs approximately 10 times more often in the African American population compared to the Caucasian population in the United States.

What capabilities do you hope to have in your lab three years or five years from now?

I'm hoping that in the not-too-distant future the cost of sequencing will come down. The recently announced Watson genome cost a million dollars. In the kind of work I do, I need to analyze hundreds if not thousands of human DNA samples. Obviously, a million-dollar cost for each of these DNA samples isn't going to work for small labs like mine, but once the costs come down this will open up many exciting new avenues for advancing our research.

You're here for the opening of the new Applied Biosystems Application Support Center in Foster City. How do you think you might utilize this facility?

This beautiful facility with the state-of-the-art equipment and informatics capabilities will be a really excellent way to bring my staff up to speed as new technologies are introduced. Sure, we could try to learn things ourselves with limited onsite application support, but I believe that the intensive experience of training at the Application Support Center will allow us to come to Foster City for a week, make rapid progress, and then take that progress and expertise home where we can use it in our own research.

One last question: What are you most excited about as you move forward in your research and in your collaborations with Applied Biosystems?

Wow. How much time do you have? There are a lot of things to be excited about. For example, a number of major publications have recently reported that the human genome has a very large number of previously unrecognized copy number changes in addition to the single nucleotide polymorphisms that genetic researchers have been focusing on up until now. These changes often have functional effects on the performance of genes, which in turn may increase or decrease risk of a disease or affect the way a person metabolizes a drug. For the future, I'm very interested in investigating opportunities for using both the TaqMan and SNPlex systems for copy number assays. I believe these technologies will be very useful for my research program because we already have the basic TaqMan and SNPlex assays up and running in a highly optimized way.

In addition, like most members of the human genetics community, I'm extremely excited about the next generation of high-throughput DNA sequencing capabilities such as those embodied in the new SOLiD™ system from Applied Biosystems. People often talk about a technology that is revolutionizing a particular science or field, and that word is probably overused—it seems like we're having a revolution about every six weeks! But I don't think it's an exaggeration to say that this new technology from Applied Biosystems has the potential to revolutionize not only biomedical research, but also clinical practice in the area of genetics. I believe that over the long term of the next two decades, whole genome sequencing has very real potential for enabling us to develop greatly improved methods for diagnosis, treatment and prevention of a wide range of high-impact diseases. It's going to be a very exciting and rewarding time to be working in the field of human genetics.

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