Gunning for fats
Targeting body fats finds disease markers, moving closer to individualized medicine
When medical diagnosis catches up to the abilities of shotgun lipidomics, the technology could vastly expand the information available from a simple blood test.
“If we can find the right indicator, we can identify what is malfunctioning and fix it. We're giving doctors and scientists a way of finding biomarkers that they've never been able to see before.”
RICHARD W. GROSS, MD, PHD
SPARE TIRES, DOUBLE CHINS, THUNDER THIGHS.
A common misconception about fat is that it’s found only in these fatty masses so many of us would like to be rid of.
But in fact, fats, fatty acids and their derivatives (collectively called lipids) are everywhere in the body, and they are vital to a myriad of bodily processes. Lipids form barriers and scaffolds in cells to facilitate biochemical reactions. Some are burned for energy. Others are used to create signaling molecules that regulate the body’s systems.
And while most of us weigh fat in pounds on our bathroom scales, researchers in the School of Medicine’s Division of Bioorganic Chemistry and Molecular Pharmacology measure amounts millions of times smaller. For this they use a new technology called shotgun lipidomics.
The procedure takes the measure of the body’s lipids with the speed and coverage of a shotgun blast. In a matter of minutes, shotgun lipidomics can quantify and identify nearly all of the hundreds of lipids in a complex biological sample, even those present in minute amounts.
“ With shotgun lipidomics we can compare the lipid profile of various tissues during the healthy state to that of the disease state with amazing accuracy,” says Richard W. Gross, MD, PhD, the division’s director and a professor of medicine, chemistry and of molecular biology and pharmacology. “That’s very powerful. It allows us to find key changes in body chemistry and identify lipid profiles associated with specific diseases, so it’s very useful for diagnosis and treatment.”
Because of their importance in the scheme of living organisms, researchers and physicians have always needed to measure the lipids in biological samples. Unfortunately, previous technologies had major shortcomings.
Shotgun lipidomics overcomes those problems. It’s fast, it’s highly sensitive, and it can identify hundreds of lipids missed by other methods — all with a much smaller tissue sample so that specific cells or minute biopsy samples can be examined.
The instrument that makes this possible is a state-of-the-art mass spectrometer, which transforms a biological sample into a cloud of ions, flings the ions through an electric field and measures them when they reach the other side. An integrated computer processor produces a serious of narrow peaks on a screen to represent the amount and identity of each lipid, making the sample’s lipid profile visible within seconds in graphic form.
But the heart of shotgun lipidomics is a set of chemical techniques that ensure each lipid will appear on the instrument’s screen in a unique and predictable location, and this is where innovative thinking was needed. Gross developed the techniques alongside Xianlin Han, PhD, assistant professor of medicine, formerly Gross’ graduate student and now an independent researcher in the division.
“ Han is an artist with lipid analysis,” Gross says. “He did wonderful things with the instruments, which made it possible for us to bring this technology to its current level.”
According to Han, the technology is very precise.
“ I can immediately tell the difference between the lipid profiles of two samples, even when there is only a single change,” he says, lining up the peaks on two printouts from the mass spectrometer. “This is so new that we’ve only scratched the surface of what can be accomplished with it.”
While today doctors routinely test blood for levels of high- and low-density lipoproteins (HDL and LDL), shotgun lipidomics can identify dozens of constituents within these categories. When medical diagnosis catches up to the abilities of shotgun lipidomics, the technology could vastly expand the medical information available from a simple blood test.
“ Consider a car,” Gross says. “If a car usually gets 32 mpg and then suddenly starts getting 20 mpg and smoke comes out of the exhaust pipe, you know there’s a problem. By looking at the smoke, a good mechanic could deduce what part of the car is broken.”
“ The same is true of the body,” Gross continues. “If we can find the right indicator, or biomarker, we can identify what is malfunctioning and fix it. We’re giving doctors and scientists a way of finding biomarkers they’ve never been able to see before.”
As the technology is used to analyze more kinds of samples, a whole panoply of biomarkers will emerge to provide an accurate predictor of a person’s health and health outlook, according to Gross. The technology will yield clues to enzymes that are malfunctioning, help identify new targets for drugs, and allow doctors to evaluate the effectiveness of treatments.
With the backing of David M. Kipnis, MD, Distinguished University Professor of medicine and of molecular biology and pharmacology, Gross founded the division in 1987 after completing a PhD in chemistry on the Hilltop campus. Before that, he was an MD specializing in cardiology. “I studied chemistry so I could understand medical processes at the molecular level,” Gross says.
Gross’ career exemplifies the blending of disciplines that so often leads to original discoveries. “Richard is broadly trained,” Kipnis says, “and he’s creative. I knew that when I was chief of medicine and he was an intern. He’s done remarkable research since then and draws a lot of graduate students to his division — graduate students can sense where the action is.”
Gross would like to convince more students and faculty that chemistry and medicine are complementary. “I really consider our division a gateway for all the departments in the university to integrate new science and technologies,” he says.
Along with collaborators in the Department of Medicine, Gross altered the predominant view of the cause of heart disease in diabetics using shotgun lipidomics. They found that diabetics’ heart muscles underwent changes in fatty constituents, some of which could not be corrected by insulin treatments. This led to new insights into the diabetic state and the importance of saturated and non-saturated fats. Moreover, it showed that changes in heart cell metabolism were at the root of diabetic heart disease.
Han and collaborators in the Department of Neurology showed that patients in the early stages of Alzheimer’s disease lacked a specific lipid in their brains. The decrease could be detected in cerebrospinal fluid as well. The discovery may allow development of new diagnostics for early-stage Alzheimer’s and suggest new research avenues for researchers seeking the cause of the disease.
Daniel P. Kelly, MD, professor of medicine and of molecular biology and pharmacology, who has worked with Gross on several research projects, says, “The only way to determine the effect on lipids during disease is to profile the lipids. So the advanced technology developed by the division will figure prominently in several large research efforts at Washington University that aim to translate research in animal models to humans.”
Right now, the division has only one instrument devoted to shotgun lipidomics, but Gross would like to gear up to do thousands of samples at a time. He envisions a room full of mass spectrometers fed samples by robotic equipment and linked to computers using advanced analysis programs. “If we could automate, it would become routine for doctors to make use of the sophisticated information about lipid chemistry that we can provide,” Gross says.
Shotgun lipidomics can supply clues to each patient’s unique metabolism and can play a significant role as medicine moves further toward truly individualized treatments. Pairing the capabilities of the division with Washington University’s extensive research programs in human genetics would facilitate matching patients’ body chemistries to their genetic profiles, adding to the strength of the medical school’s BioMed 21 initiative to utilize genetic information for patient treatment.