Complex paradigm may explain elusive illnesses

“It has been suggested by many researchers that these chronic illnesses — with overlapping signs and symptoms — may share a common causal mechanism.”
— Martin Pall

The dragging feeling had come on slowly. For weeks he brushed it away with easy rationalizations, but now he had to admit something was definitely wrong. An insidious “brain fog” had overtaken him — a nightmare for someone who makes a living with his mind. In 1997, Martin Pall was diagnosed with chronic fatigue syndrome.

Nearly paralyzed mentally and physically for the first six months, Pall eventually began to surface and, in moments of clarity, tried to sort out what was happening. Three doctors agreed the condition had been triggered by a bout with varicella zoster — a herpes virus that also causes shingles. But they could offer little more in explanation or treatment: “We really don’t know,” was the standard reply.

Defying the odds, Pall, professor of biochemistry and basic medical sciences in the School of Molecular Biosciences, completely recovered within 1 1/2 years from what is often a lifelong illness. The ordeal triggered his personal investigation into the biochemical aspects of chronic fatigue syndrome. That led to the publication, due next month, of his controversial book, “Explaining Unexplained Illnesses.” 

Paradigm compelling
In it Pall proposes a complex new mechanism for understanding the cause of debilitating diseases like multiple chemical sensitivity, fibromyalgia, post-traumatic stress disorder, chronic fatigue syndrome (CFS), Gulf War syndrome and others. Though he invites “critical scrutiny” to prove or disprove his theory, his ideas offer a potential new paradigm for framing these mysterious multisystem diseases, which severely affect about 7.4 percent of the U.S. population.

“His work is very compelling,” said Mick Smerdon, Regents Professor of biochemistry and biophysics in the School of Molecular Biosciences. “It’s a new direction and, any time you publish something that goes against the dogma of the field, it meets some — or a lot — of resistance.

“If his hypothesis turns out to be correct, it will lead to further testing in these areas. The accuracy of the theory awaits the data,” he said.

Nitric oxide cycle
Pall’s theory has been boiled down to five basic principles describing a self-perpetuating “vicious cycle.” In essence, he states that CFS and similar illnesses may be set in motion by short-term stressors such as viral or bacterial infection, chemical exposure, physical trauma or severe psychological stress. These stressors are all known to raise levels of the compound nitric oxide — and its oxidant product, peroxynitrite — in the body.

In high concentrations, peroxynitrite damages mitochondrial proteins in the cell, leading to the release of other breakdown products which, in turn, stimulate further increase in nitric oxide levels.

This becomes a vicious cycle involving an array of chemicals (see diagram) — including inflammatory hormones and neurological receptors — all capable of causing the wide range of symptoms associated with these diseases. Pall calls this the NO/ONOO cycle (pronounced No! Oh no!). 

Localized disease process
This complex biochemical cycle involves 22 known mechanisms that have been documented or reported on in various studies. Pall said there is extensive evidence supporting the individual mechanisms of the NO/ONOO cycle, but the question lies in its relevance to multisystem chronic diseases.

One of the puzzling aspects of diseases such as fibromyalgia, CFS or Gulf War syndrome is that the signs and symptoms vary so widely between patients. Pall explained that nitric oxide and peroxynitrite have short half-lives and cannot easily diffuse through tissues. Also, the NO/ONOO cycle works primarily at the cellular level. These observations suggest that the disease acts locally rather than systemically (body-wide) as with an infection or deficiency. Depending on the specific tissues involved in each individual, there could be “an infinite number of variations” in the presentation of the disease, said Pall.

Treating the biochemistry
Though he offers no “magic bullet” for curing any of these diseases, Pall discusses therapy protocols that have shown promise in a limited number of clinical trials.

“Therapy should first focus on down-regulating the NO/ONOO cycle,” he said. “We need to stop doing things that aggravate this cycle — avoid known stressors such as certain chemicals or situations, for example. Also, since the cycle is very difficult to down-regulate, it is likely we will have to use multiple agents to be effective.” 

In his book, Pall lists 30 agents or classes of agents which, in combination, are predicted to down-regulate the cycle. Among them are antioxidants, vitamins, minerals, fatty acids and a few pharmaceutical drugs. These also are detailed on one of his research websites ONLINE @

“We may be on the verge of a new era of effective therapy for this group of diseases, focusing on treatment of the underlying biochemistry, rather than on symptomatic relief,” Pall said.

Pall has been invited to speak about his findings at major meetings in Europe, including the Royal Society of Medicine in London on May 12. 

“The most important thing is how well does this paradigm hold up as an explanatory model?” he said. “I think the potential for understanding the illnesses that afflict mankind is stunning, and the potential for therapy could be stunning as well.”

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