Sitting Down With… Timothy Garrett, Director of Experimental Pathology and Associate Professor, Department of Pathology, Immunology and Laboratory Medicine, University of Florida, USA.
Can you tell us about your current role?
Since 2019, I have been an associate professor at the University of Florida, where I am also Director of high-throughput metabolomics for the Southeast Center for Integrated Metabolomics (SECIM) and Director of Experimental Pathology. My interests cover both research and clinical work in several areas, including cancer, rare diseases, and diabetes. My lab comprises 12 scientists, including graduate students and post-docs grappling with complex problems and new fields of research. I often think my job is just to facilitate their work! We are asking fundamental questions: what drives human metabolism? Why does it sometimes fail? How does it change throughout the course of a disease? And how can we better characterize disease so that we can make a diagnosis earlier – or more accurately? By understanding how health may be disrupted, we will help find better treatments.
Much of your work is focused around MALDI MS. When did you become aware of this technique?
My interest in MALDI MS began as an undergraduate in Jonathan Amster’s lab at the University of Georgia, working on the characterization of bacterial proteins. MALDI fascinated me: such a simple technique, and yet it generates so much information from such tiny samples. Not only did I fall in love with the technique, I also fell in love with the instruments themselves – how to operate them, fix them, and tinker with them to make them better. Right now, we are pushing MALDI to its limits in metabolomics and lipidomics; we are analyzing populations of metabolites and lipids, and applying informatics to determine which ones are important in disease.
How does your research connect with clinical labs?
It may be easiest to demonstrate this with an example. Recently, a clinical pathologist asked for help with a female patient who had symptoms similar to the lysosomal storage disorder, Fabry disease. Interestingly, this is an X-linked condition typically found in males. To investigate her lipid metabolism for defects, we needed to develop a new diagnostic approach, with careful attention to experimental design. It paid off – we found a defect in a non-obvious enzymatic pathway, completely different to those defects typically seen in male Fabry patients. We can’t actually declare the patient to have Fabry disease, because our technique is not yet validated as a diagnostic. Our work does, however, suggest ways of better managing these patients, and, as it is MS-based, it is easy for labs to adopt. Ultimately, it may lead to significant improvements in our ability to diagnose and develop new therapies that target the enzymatic defect we identified.
What most satisfies you about your work?
I’m most proud of having built a resource – the SECIM center – that helps address difficult clinical questions both locally and nationally. And it’s immensely satisfying to see our work fundamentally affecting patient care. For example, our method of assessing the immune system of transplant recipients, specifically pediatric kidney transplant patients, allows us to predict organ rejection before development of clinical symptoms. And that can improve healthcare management of these children after validation studies are completed. We’re always proud to see our systems solving clinical problems.
Is your technology applicable to COVID-19 research?
Yes. We are developing an MS test that both rapidly diagnoses COVID-19 and also identifies the causative strain. This ability to identify multiple variants – or multiple viruses – in a single assay is a real advantage of MS; PCR, by contrast, is designed to detect only single analytes. We are also collaborating with partners on a multi-omics analysis of the effects of different COVID therapies. The aim is to understand how drugs might affect SARS-CoV-2 infections and prevent the spread of this disease.
What impact has the pandemic had on analytical science?
COVID-19 highlighted the importance of analytical science for diagnosing, monitoring, and tracking infections – and reminded us of its critical impact on public health. But it also taught us that large-scale testing is expensive and slow to implement. It crucially exposed our heavy reliance on reagents – for PCR tests, for example – and we should not forget how limitations in reagent supply forced us to be selective regarding which patients we would test. In a pandemic, these resource constraints are not national, but global. The development of MS-based tests, or diversification of analytical systems in general, will help us address reagent constraints in the future. Having the staff and technology to run mass screening programs is of little use if you have run out of reagents! Overall, then, the pandemic has emphasized the need for investment in faster, cheaper, and simpler analytical technology.
What are your plans for the future?
For me, it’s exciting to see how MS can solve problems associated with virus detection – and not just SARS-CoV-2. I want to know how we can harness the power of MS to understand symptoms and to understand when and why one person might be sicker than another. Now, we are looking at how to make testing faster – using techniques like paper spray ionization we could get a diagnosis in 30 seconds, with no sample preparation. And subsequently – by running the same paper sample through MS, we could gain a full metabolite profile. Combining technologies that permit both rapid diagnosis and also deep metabolomics analysis is very promising. For all these reasons, I am very passionate about continuing virus research in my group – but seeing MS reach its full potential will take time!