Researchers at Stanford Medicine have shown they can measure thousands of molecules — some of which are signals of health — from a single drop of blood.
The new approach combines a microsampling device — a tool used to self-administer a finger prick — with “multiomics” technologies that simultaneously analyze a vast array of proteins, fats, metabolic byproducts and inflammatory markers.
“More importantly, we showed that you can take the drop of blood at home and mail it to the lab,” said Dr. Michael Snyder, director of the Center for Genomics and Personalized Medicine and senior author of the study, which was published in Nature Biomedical Engineering on January 19.
Want more breaking news?
Subscribe to Technological networks‘ daily newsletter delivering breaking science news straight to your inbox every day.
Subscribe for FREE
Unlike the diabetes finger-prick test, which measures a single type of molecule (glucose), multi-omics microsampling provides data on thousands of different molecules at once.
The research sounds similar to a well-known approach promoted in the past for testing a single drop of blood, but there are important differences: While the earlier approach was based on replicating existing diagnostic tests, multi-omic microsampling uses a different type of data analysis based on technology called mass spectrometry, which sorts molecules based on their mass and electronic charge. Also, the data analysis is done in a lab, not in a portable box.
Less blood, more insight
Rather than focusing on any single protein, metabolite or inflammatory marker, the growing field of ‘omics’ research takes a broader, systems-biology approach: analyzing the entire spectrum of proteins (proteome), fats (lipidome) or by-products of metabolism (metabolome). Although recent advances have made this data analysis more robust and efficient, the utility of multiomic studies in the real world is limited by sample collection difficulties, among other challenges. To measure someone’s response to a food or drug, many samples may be needed in a short period of time; currently, sampling requires a trip to a clinic for an intravenous blood draw of 10 to 50 milliliters.
“For the study, we asked participants to take blood samples five times in just four hours,” said Snyder, the Stanford W. Asherman, MD, FACS Professor of Genetics. “Traditionally, this would mean inserting a catheter and drawing a lot of blood each time. By the fifth draw, your participants will have less iron and less red blood cells.
The researchers wanted to know if they could drastically reduce the volume of blood used for multiomics analysis, but still profile thousands of molecules. After testing various microsampling devices, they chose one called the Mitra, a portable finger device that draws 10 microliters of blood into a gel matrix. They then tested multiple extraction techniques to separate the proteins, lipids and metabolites. A second separate microprobe was used to measure inflammatory markers.
“It was totally unexpected that we would be able to do this kind of analysis on such a small sample,” said Dr. Ryan Kellogg, a postdoctoral fellow in genetics and one of the paper’s four co-lead authors. The other three co-authors are Stanford postdoctoral fellows Xiaotao Shen, PhD, Daniel Panyard, PhD, and Nasim Bararpour, PhD.
In a pilot study of two test subjects, the researchers were able to measure the levels of 128 proteins, 1,461 metabolites and 776 lipids from each microsample. They then monitored the samples for stability when stored at different temperatures.
“In general, very few proteins are unstable regardless of temperature,” Snyder said. Some of the lipids and metabolites degrade during storage at certain temperatures, but the majority are stable, he said.
When the researchers compared the multiomics results obtained by microsampling with those from a traditional blood draw, they found that the results from the two types of collection were similar for the vast majority of molecules. Confident that their multi-ohm microprobes were reliable, the scientists then tested applications for the new technique.
Tracking individual metabolic responses to food
Researchers conducted a study that looked at the molecular impact of a nutritional shake, analyzing data from 28 participants over four hours after they consumed a specified amount of carbohydrates, fat, protein and micronutrients from a meal replacement shake.
“What we found is that people reacted very, very differently to this mixture,” Snyder said.
Different people can have dramatically different metabolic responses to the same food, but standard blood tests don’t provide enough data to know why.
Almost 50% of the compounds in the shake were eventually detectable in the participants’ blood, and the researchers were able to separate the participants into two large groups based on how quickly the molecules in their blood changed, with one group responding more quickly to the shake from the other. Participants with known insulin resistance were more likely to fall into the “fast responder” group.
Some participants also had an inflammatory response, with molecules involved in their immune response peaking about 30 minutes after consuming the shake.
“The ultimate goal of doing these detailed profiles is to give people information,” Snyder said. “If you learn that you have an immune response to a certain food, you may be quite motivated to change your diet.”
24/7 monitoring with wearable sensors
In the second experiment, the researchers took molecular monitoring a step further by taking samples of Snyder’s blood every one to two hours while he was awake for a week.
“After 98 samples, I’ll admit my fingers were pretty sore.” He also wore four different smartwatches and a constant glucose monitor to track his heart rate, activity level, sleep and food intake.
By the end of the week, the research team had taken a total of 214,661 biochemical measurements, including levels of proteins, fats and hormones such as cortisol, which they compared with physiological data from the wearable sensors. In addition to discovering many molecules that exhibit previously unidentified 24-hour rhythms (meaning that certain molecules follow a daily, cyclical ebb and flow), the researchers noted that glucose and cortisol levels varied significantly throughout the day, contrary to , which they expected.
“Textbooks describe how these molecules should behave,” Snyder said. For example, cortisol is expected to be high in the morning and fall during the day. But when the researchers analyzed the data, they found that this was true for Snyder on some days but not on others, underscoring the importance of frequent sampling.
Because these data represent the molecules of one participant, they cannot be used to draw conclusions about anyone else. But according to Snyder, this is one of the important takeaways from this research: Individuals have different molecular profiles that can change based on their personalized patterns of behavior.
“The most exciting thing about microsampling is the ability to collect denser time points and more comprehensive data,” Kellogg said. “With traditional venipuncture, your doctor gets a sample every six months or maybe even every few years. A lot of biology happens between these samples.
In the middle of the week, for example, multiomics monitoring detected an immune event Snyder himself was unaware of—he suspected his body was fighting an infection. Snyder was also able to track his own personal metabolism of salicylic acid (a byproduct of the baby aspirin he takes every morning), suggesting that the multiomics microprobe could be useful for tracking an individual’s response to the drug.
Bringing health care into the home
The next step for Snyder’s lab will be to expand the pilot studies and offer multi-omic microsampling to a wider range of patients. “Several ongoing projects are evaluating whether this method can be used for early disease detection,” said Shen, who was in charge of data analysis for the project. “Through longitudinal observation, we’re very hopeful that this can be used for diagnostics.” Additionally, Kellogg founded a startup that uses multi-omic microsampling to better define the molecular effects of long-term COVID and develop new diagnostics.
Snyder envisions a future in which healthy people will perform multi-omic microsampling at home at regular intervals—monthly, weekly, or perhaps even once a day—to gain insight into their personal molecular fingerprint. Subtle changes in this fingerprint can signal the onset of disease long before an abnormality is detected by standard laboratory tests.
“The bottom line,” Snyder said, “is that we can get a really in-depth profile of a person’s metabolic and immune health, all through the convenience of a home test.”
He added that many people experience a “white coat effect” that causes their heart rate and blood pressure to skyrocket the moment they enter a healthcare facility. “It will change your physiology and affect your results. It’s better to do as much of this as possible from home.
Reference: Shen X, Kellogg R, Panyard DJ, et al. Multiomic microsampling for profiling lifestyle-related health changes. Nat Biomed Eng. Published online January 19, 2023. doi: 10.1038/s41551-022-00999-8
This article has been republished from the following materials. Note: Material may have been edited for length and content. For additional information, please contact the cited source.
Add Comment