A research team at Stanford gave an update yesterday on some of the breakthroughs its team has made in understanding the metabolic cycles that are not working properly in people with ME/CFS that might be at the heart of the disease.
Ronald W. Davis, PhD, made the announcement via YouTube. Davis directs the CFS Research Center team at the Stanford Genome Technology Center (SGTC).
Problems with metabolic cycles
The team’s metabolomics tests on severely-ill patients revealed problems with the citric acid cycle. Participants’ blood work showed that some of the chemicals involved in the citric acid cycle are very low, making it difficult for the patient to generate the chemicals we use for energy. Several chemicals were found to be two standard deviations away from those of healthy controls, which is serious, according to Davis. The problems found in the citric acid cycle of ME/CFS patients does not look like the result of a typical genetic defect in the mitochondrial metabolism, Davis noted.
Recent research by Fluge and Mella has also suggested that pyruvate dehydrogenase, the enzyme that helps glycolysis transition into the citric acid cycle, may be blocked.
“We have not investigated that, but it is consistent with glycolysis being shut down,” Davis said. “We also think that pyruvate kinase might be shut down. Those are not inconsistent and it is possible there are blocks in both of them.”
The problem with NIH
Davis and his team applied for federal funding from the National Institute of Health (NIH) for the research that led to the data showing the dysfunctional citric acid cycle in people with ME/CFS. The NIH turned down both of his grants “because we were trying to do discovery, and they wanted us to only do hypothesis testing,” Davis said.
“I said to them: the scientific method is first observation, then hypothesis. And if you have virtually no observations you can’t generate a good hypothesis. I think one of the big problems we have is that we do not know enough at the molecular level to generate hypotheses.”
Technology to screen drugs without using patients
Davis also announced a device that the Stanford team has developed to test metabolic functions, which will enable them to do mass screenings of drugs without the time and cost restraints of using patients.
The device is about the size of a computer chip. It has a small channel in it to accommodate a tenth-of-a-drop of blood, all that is needed for this assay. It has 2500 electrodes in it, and each electrode is sampled 200 times a second. This generates a massive amount of data.
Davis explains how the device works:
“What we have noticed from this device is that if we put bacterial population into this, we will get a certain electrical impedance signal. If we then add an antibiotic that kills the bacteria, the electrical impedance will rapidly increase. If the bacteria are resistant to the antibiotic, we see no change.
“So, if we put healthy cells and their serum into the device, it is pretty stable and does not change. If we put in ME/CFS cells and their serum, it doesn’t change. However, if we put a demand on the cells, we require them to consume energy, and that demand is seen in this graph where there is a slight dip in the healthy controls – but they handle that demand quite well and don’t change after that – however the cells from the ME/CFS patient shows a rapid increase in impedance. And that has been shown for every patient we have looked at, and also every healthy control is the same.”
Most importantly, the device provides a way for Davis and his team to test drugs on ME/CFS cells and serum to see the effect.
Davis noted that the rapid rise in impedance is caused by the serum, not the cell, which means that there is something being released into the serum that may be causing or contributing to symptoms.
“If it is in the serum, we probably can find it,” Davis said. “And that is what we’re trying to do now, which is find the component or components – most likely plural – that is causing this effect… Now this a good hypothesis, and we are now testing it.”
Davis said that the next step is to use the device to test the effects of various drugs on the cells and serum of ME/CFS patients. For example, Davis’ team found that adding ATP to unhealthy ME/CFS cells and serum made the cells respond normally. The team also plans to test drugs that many ME/CFS patients have reported helpful using this device, such as Valcyte and Rituximab.
If the device turns out to be a good diagnostic test for ME/CFS, Davis said his team will disseminate information to doctors’ offices.
This device may be applicable to other diseases as well, including Lyme and Fibromyalgia.
The magnetic levitation device
Davis and his team have also developed a magnetic levitation device which separates cells based on their magnetic properties. The device is small and can fit onto an iPhone. This device can be used to separate and examine cells with differing properties, which has broad applications, including examining specific cell types in ME/CFS patients. The magnetic levitation device costs 5 cents per assay.
“We’re accumulating a list of things that we are trying with this device,” Davis said.
“One of our focuses is on developing engineered biosensors and devices. We also have a synthetic biology core that is used to develop new ways to do production of drugs and test drugs… So we have a heavy focus on how to reduce cost of tests and simplicity of those tests and portability,” Davis said.
Listen to Davis speak about the team’s research here, or read the full transcript.
The Open Medicine Foundation (OMF) is helping fund the work of Dr. Davis’ CFS Research Center team at SGTC. So far, their breakthroughs have been achieved by doing one experiment at a time, week-by-week. At this point, the team is ready to ramp up the project in order to carry out multiple parallel investigations to get answers as fast as possible. However, substantially more funding is needed for this to happen. Please donate to OMF here.
Some edits were made to this article by Jaime Seltzer.