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America: How one woman’s quest to understand chronic fatigue sparked a scientific breakthrough

The red flags that Amanda had an unrecognised chronic illness began after her suspected case of mononucleosis in high school. She says she feels she never fully recovered. One big clue: In college, after exercising, Amanda would not experience an endorphin rush. Instead, she told her friends she “felt like garbage.”

By Brian Vastag, The Independent

Article Extracts

In 2016, she was intrigued by a journal article about Li-Fraumeni syndrome written by Hwang [who runs a laboratory at the National Heart, Lung and Blood Institute]. The article described problems with mitochondria – the famous powerhouses of cellular biology, small tubelike structures inside cells that produce the energy we need to live. In people with this cancer syndrome, Hwang’s lab had found that mitochondria produce too much energy, which cancer cells gobble up as they metastasise. Amanda wondered whether her specific version of Li-Fraumeni Syndrome could lead to the opposite problem, too little energy…

Hwang brought Amanda to Bethesda in 2017. During a battery of tests, a curious result popped up. Amanda’s calf muscle took a long time to replenish an energy-carrying molecule after a short exercise session. In other patients with Li-Fraumeni syndrome, this molecule regenerates in an average of 35 seconds. In Amanda, it took 80 seconds. “We never see it that delayed,” Hwang says.

Puzzled, Hwang flew Amanda’s brother and father to Maryland, as they both also carried a gene for Li-Fraumeni. But on the energy-production test, the two men showed quick energy rebound, unlike Amanda. Neither of them had ever complained of serious fatigue, either. Amanda was the outlier. Hwang now had strong evidence that Amanda’s energy problems – both at the cellular and the human level – were caused by something other than Li-Fraumeni. But what?


Around the same time, in 2017, Hwang received another serendipitous correspondence. NIH researcher Brian Walitt had heard Hwang was studying energy production inside mitochondria. Walitt was interested because he was orchestrating an intensive study on a small number of inpatients at NIH’s research hospital who were diagnosed with chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME)…

This contact sparked Hwang’s curiosity: What if this unusual cancer syndrome patient also had an illness, such as ME/CFS, that causes chronic fatigue? Hwang began a detailed biochemical search. He found that skin cells taken from Amanda appeared to be churning out an excess of a protein called WASF3. Zooming inside Amanda’s mitochondria, Hwang and colleagues eventually saw something stunning: like a stick jammed into bicycle spokes, the overabundant protein was literally gumming up the gears of energy production.

Extensive lab work confirmed and extended the findings. In dishes of cells, amping up WASF3 turned down cellular energy production. Tamping it down led to more energy. Mice bred to make too much of the protein got tired quickly, as Amanda does, and will walk on a treadmill for about half as long as normal mice.

A final serendipity broadened Hwang’s research from a single patient to an entire population of sick people. He obtained muscle tissue from Walitt’s ME/CFS patients. Nine out of 14 had a similar overabundance of WASF3 as Amanda, and, on average, the group’s levels of this protein were higher than that of healthy volunteers. Although the sample size is small, the finding suggests that this energy-squashing problem is widespread in ME/CFS.

For Hwang, developing a treatment for the illness is now “what keeps me going.” His small laboratory, just four scientists, is planning a clinical trial with a drug that recently came onto the market for another disease. “Amazing findings in medicine are sometimes based on one patient,” he says.

As for Amanda, after decades of feeling ill with no diagnosis that ever made sense, she believes her own story has finally been legitimised and in a major scientific journal at that. “There’s this difference between cancer and chronic fatigue syndrome,” a diagnosis her rheumatologist has finally added to her file, she says. “Everybody believes you when you have cancer. You joke about having a ‘cancer card’ to get off from doing things. No one is handing out CFS cards. “I can finally say, ‘It’s not psychological. I’m not a malingerer.’ We now have a scientific explanation.”

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