ARCHIVE. The argument of nature versus nurture is nothing new. And it can be summed up in one question: Why is it that someone can smoke and drink and live long into old age and another person can lead a healthy life, exercise and then die of a heart attack at the age of 40? This question is based on extreme examples, but they are still non-fiction, and they cause people to believe that they have limited control over their health. However, researchers in the broad field of personalized medicine are working to change this mindset by studying the mechanics of diseases at the molecular level so that treatments can be more effective on a case-by-case basis.
One Doha-based project is targeting diabetes - a condition at epidemic levels in Qatar - and how body fluids, or “metabolites,” can provide a more comprehensive picture of what’s happening to the body over its course. The study is particularly exciting because it involves the latest technology available and is thus helping to expand the frontier of research along these lines.
“So my lab uses state-of-the-art molecular profiling tools to understand how biological processes get altered and held in disease,” said Dr. Amrita Cheema, an associate professor at Georgetown University and lead researcher on this research project. “Basically, we use high technology to answer some very pertinent biological and clinical questions.”
Some key metabolites and pathways under investigation.
Three main angles from which to explore disease are genetic, proteomic and metabolomic. They exist in a kind of hierarchy. Genes dictate protein expression, and proteins account for the makeup of all cells as well as their processes. Metabolites - blood, urine and other body fluids termed “biofluids” - give a snapshot of how cells are functioning.
“The advantage of doing metabolomics is that you are weeding through the physiology [body function] because it’s at the very endpoint of the cellular process,” Dr. Cheema said.
The team - which also involves Drs. Nasser Rizk of Qatar University and Mahmoud Zirie of Hamad Medical Corporation - is using ultra performance liquid chromatography, a technique that promotes the separation of biofluids for examination at the molecular level. This technique, paired with a super-sensitive detector system (time of flight mass spectrometer), allows for the instant analysis of fluids. It’s critical that the fluids are processed instantly so that they are observed in their purest state, i.e., their analysis won’t be confused by environmental contaminants.
“So in real time what happens is that you are able to resolve the components contained in blood or urine,” Dr. Cheema explained, “and as the molecules are getting separated they are actually injected on the mass spectrometer instantly, and you are able to identify them. What this enables you to put together is a complete separation and detection system for the analysis of biofluids, and in turn what that enables you to do is to find out the molecular differences between samples that are derived from normal subjects as compared to those who are diseased.”
The testing revealed differences between the diabetic and non-diabetic groups in terms of how they processed key substances in the body.
Another big advantage of using this technology is that it’s extremely high throughput, which means that many samples can be run in short periods of time. “You can really go through hundreds of samples in 12 hours or so. So that really benefits the clinician because now he has the ability to use this technology to really screen patient populations. This is a much faster process than what has been used conventionally,” Dr. Cheema said.
The research, which was funded by a QNRF National Priorities Research Program grant, involves the comparison of metabolites from diabetic vs. non-diabetic patients. Closely inspecting the biofluids based on different metabolites allows Dr. Cheema and her colleagues to trace findings back, from gross-level symptoms and complications of diabetes, to the molecular level. So far, the team has found several significant differences in the metabolites of patients with diabetes, and they have traced these to specific imbalances.
A major finding involved disruption of the glucose metabolism pathway as represented through differences in amino acid levels in metabolites among patients with type 2 diabetes. Glucose is at the heart of metabolism, Dr. Cheema explained. If it is not broken down properly, it continues to circulate through the body in excessive amounts and gets channeled into different processes within the body. This causes stress at the molecular and tissue levels. Other findings highlight not only the impact of the research but also the complicated nature of diabetes.
“We have shown that you can see a deregulation of fatty acid biosynthesis,” Dr. Cheema said. “We also see a huge disruption in vitamin D biosynthesis as well as vitamin D metabolism, and this has been possible because we looked at specific molecules that are participating in those pathways, and characterized them, and found out that these are the pathways that get altered in diabetes. As we gain this knowledge, we can potentially take it back to a medicinal chemist who can then help us to target pathways and develop better interventions.”
This research also contributes to the ability to predict the course of diabetes with all of its complications. Bit by bit, studies are piecing together a complex puzzle that will offer a view of the future for individual patients who might then experience alternatives to suffering with health conditions.
“If you see the levels of a certain compound,” Dr. Cheema explained, “which are some of the proteins that we found at certain levels in sebum or plasma of type 2 diabetes patients, then you can predict that these are the patients who at some point may develop nephropathy. So even before they develop symptoms, you can probably start to intervene therapeutically … that’s the real power of this work.”
Over the long run, Dr. Cheema looks forward to working with other laboratories and researchers in Qatar and worldwide to integrate findings into the advancing field of patient-specific therapeutic approaches.
“In the context of personalized medicine, you want to go back and integrate all of the information you are collecting at the ‘omics’ level, be it genomics, proteomics or metabolomics,” Dr. Cheema said. “What we are doing right now is integrating our analysis and metabolomics screening findings with what is known about genomic alterations. The goal of that project is to find out what are the commonalities at the three levels of expression and those probably are going to be most significant as far as the disease process is concerned.”
Dr. Cheema is grateful to QNRF not only for the direct support she has received to conduct this vital work, but also for the opportunity to participate in an emerging global research hub.
“The effort that QNRF puts into research is commendable. And I think that the way that they are inviting the very best scientists to come and collaborate with researchers in Qatar and invest in the leading edge of technology … I think this is going to make them leaders in science in the next decade or so. So I’m very happy to be collaborating with scientists in Qatar and I look forward to continuing my collaborations.”
Systems approach towards diabetes research using molecular profiling tools