In 2015, after further testing, Twinam, now 44, was found to be a carrier of a cancerous genetic disorder, Li-Fraumeni syndrome. Soon after she was diagnosed with a second breast cancer and Twinam underwent another mastectomy. But Twinam knew something else was wrong.
As he entered his 40s, he had more and more trouble standing and walking. The Albany, New York, attorney reduced her work to part-time, as she could not keep up with her legal cases while she was raising a young daughter.
“I was a less and less functional human being and I didn’t have much of an explanation for it, which made me feel crazy,” she says. “The doctors didn’t know what to do with me.” So Twinam set out on a years-long journey to understand her ongoing fatigue, neuropathy, muscle weakness and other problems.
Their dogged efforts led to a new scientific discovery at the National Institutes of Health and a promising new line of research that may end up helping many other people with chronically fatiguing diseases, possibly including long Covid.
“We are very excited to test” drugs to treat the problem identified in Twinam, said Paul Hwang, an NIH researcher who led the work.
The warning signs that Twinam had an unrecognized chronic illness began after his suspected case of mononucleosis in high school. She says that she feels like she never fully recovered. A big sign: In college, after working out, Twinam didn’t experience a rush of endorphins. Instead, she told her friends that she “felt like trash.”
Between her two breast cancers, Twinam decided to go back to school to earn a master’s degree in public health. She wanted to understand biostatistics on the path to understanding herself.
“I was actually more excited when I got a 100 on a biology midterm than when I passed the exam,” he says.
In 2016, she was intrigued by a journal article about Li-Fraumeni syndrome written by Hwang. The article described problems with mitochondria, the famous powerhouses of cell biology, small tube-like structures inside cells that produce the energy we need to live.
In people with this cancer syndrome, Hwang’s lab found that mitochondria produce too much energy, which cancer cells devour as they metastasize. Twinam wondered if his specific version of Li-Fraumeni syndrome might cause the opposite problem: too little energy?
Twinam began a message to Hwang that proved pivotal: “I read with interest your recent article on the inhibition of mitochondrial respiration in a mouse model of Li-Fraumeni syndrome.”
“I didn’t have any expectations,” Twinam says. “Here I am sending an email to this sophisticated scientific researcher who won’t give me the time of day.”
Hwang, who runs a lab at the National Heart, Lung, and Blood Institute, responded the next day. He wrote: “Yes, I agree with you, it is possible that (your version of Li Fraumeni syndrome) is messing with your metabolism and causing your fatigue symptoms.”
Hwang was wrong: Twinam’s energy problems had nothing to do with Li-Fraumeni syndrome. But it would take Hwang and his colleagues years of laboratory work, including making genetically modified “Amanda mice,” to understand this.
“Amanda showed up and challenged us,” Hwang says during an interview in his office. “So we dig.”
Hwang brought Twinam to Bethesda in 2017. During a series of tests, a curious result appeared. Twinam’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. At Twinam, it took 80 seconds.
“We never see it that far behind,” Hwang says.
Puzzled, Hwang took Twinam’s brother and father to Maryland, as they both also carried a gene for Li-Fraumeni. But in the energy production test, both men showed a rapid rebound of energy, unlike Amanda. Neither of them had ever complained of serious fatigue.
Hwang now had solid evidence that Twinam’s energetic problems (both on a cellular and human level) were caused by something other than Li-Fraumeni. But what?
Around the same time, in 2017, Hwang received another chance correspondence. NIH researcher Brian Walitt had heard that Hwang was studying energy production within mitochondria.
Walitt was interested because he was orchestrating an intensive study on a small number of hospitalized patients at the NIH research hospital who were diagnosed with chronic fatigue syndrome, also known as myalgic encephalomyelitis or ME/CFS. (I was a patient in this study and Hwang also used my data in his research.)
This contact sparked Hwang’s curiosity: What if this patient with unusual cancer syndrome also had an illness, like ME/CFS, that causes chronic fatigue?
Hwang began a detailed biochemical search. He discovered that skin cells taken from Twinam appeared to produce an excess of a protein called WASF3. Getting closer to the inside of Twinam’s mitochondria, Hwang and his colleagues finally saw something surprising: Like a stick wedged into the spokes of a bicycle, the overabundant protein was literally jamming the gears of energy production.
“It’s really surprising,” Hwang says.
Mitochondria produce energy through a process called respiration, transforming oxygen and glucose into energy-carrying molecules. At the center of this chemical chain reaction is an 800-pound biochemical gorilla called a supercomplex.
The protein Twinam overproduced? This grossly clogs the super complex. “It’s bringing this whole thing down,” Hwang says. “It’s literally falling apart.”
Extensive laboratory work confirmed and expanded on the finding. In cell dishes, amplification of WASF3 reduced cellular energy production. Suppressing it generated more energy. Mice bred to produce too much protein defecate quickly, as Twinam does, and walk on a treadmill about half as long as normal mice.
A final serendipity expanded 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 of 14 had a similar excess of WASF3 as Twinam and, on average, the group’s levels of this protein were higher than those of the healthy volunteers. Although the sample size is small, the finding suggests that this energy crushing problem is widespread in ME/CFS.
The investigation initiated by Twinam culminated in August with a publication by Hwang and colleagues in the journal PNAS. Scientists in the small field of ME/CFS research are excited about the discovery, which points to a potential (and much-needed) treatment strategy.
“It was done very elegantly,” says Mady Hornig, who also studies ME/CFS as a physician-researcher at Columbia University’s Mailman School of Public Health. “It’s not very often that we go through all of these… steps, having doctors who are really persistent about what’s going on with an individual and applying a scientific lens.”
ME/CFS is common: Up to 2.5 million Americans suffer from it, according to a 2015 Institute of Medicine report. – but also commonly misunderstood.
Funding for research has been scarce. The diagnosis is often delayed or never arrives. The pandemic has dramatically swelled the ranks of people with ME/CFS, as studies find that up to half of people with long Covid qualify for that diagnosis. There are no blood tests to identify the disorder, no Food and Drug Administration-approved treatments, much less a cure. Up to a quarter of all ME/CFS patients are bedridden.
For Hwang, developing a treatment for the disease is now “what keeps me going.” His small lab, of just four scientists, is planning a clinical trial with a drug that recently came on the market for another disease.
“Surprising discoveries in medicine are sometimes based on a single patient,” he says.
As for Twinam, after decades of feeling sick without a diagnosis that ever made sense, she believes her own story has finally been legitimized, and in a major scientific journal, too.
“There’s a difference between cancer and chronic fatigue syndrome,” a diagnosis his rheumatologist eventually added to his record, he says. “Everyone believes you when you have cancer. You joke about having a ‘cancer card’ to stop doing things. Nobody hands out CFS cards. I can finally say, ‘It’s not psychological.’ I’m not a fake. “Now we have a scientific explanation.”