When baseball great Lou Gehrig was stricken with amyotrophic lateral sclerosis in 1939, his name became synonymous with this terrible disease. Since then, Lou Gehrig's disease has hit hundreds of thousands of victims worldwide, among them the famous physicist Stephen Hawking. Now a Canadian researcher has found evidence that some cases of this affliction, along with such other neurological diseases as Parkinson's, may have been caused by one of the most innocent foods imaginable: white bread.
Amyotrophic lateral sclerosis (ALS) is characterized by the progressive death of specialized nerve cells in the brain and spinal cord. These cells, known as motor neurons, control muscle movement and their loss leads to progressive paralysis and death. Many people suffer from ALS; around 300 new cases appear every day worldwide and three Canadians die daily from it. Some cases, less than one in 10, seem to be inherited, but the main cause of ALS has remained a mystery.
This week, researchers at the University of California and in Lyon, France, isolated a virus they believe might be responsible for ALS. Fifteen of 17 victims of ALS they studied showed evidence of a virus in the motor nerve cells of their spinal cords, while the virus was found in only one of 29 people who died of other causes.
But Christopher Shaw, a neuroscientist and associate professor at the University of British Columbia, says he believes at least some cases can be traced back to a common process once used to bleach flour.
In the early 1900s, bleached or white flour came into vogue in Western industrialized countries including Britain, the United States and Canada. There were several reasons for its popularity, but the main ones were that bleached flour seemed to rise better and more consistently and could also be spread out further. That is, more bread could be produced with the same amount of flour after bleaching. The whitening process of choice was called the agene method and used nitrogen trichloride gas for bleaching. In Britain, and probably North America as well, this method was used to process about 80 per cent of all flour.
Health authorities eventually became suspicious about the agene process when reports about sick dogs started to turn up. Over the years, people had noticed that dogs who ate large amounts of agenized flour came down with a bizarre disorder known as aecanine hysteria.
Researchers began studying bleached flour and, in the late 1940s, found that the agene process produced a toxic byproduct, methionine sulfoximine (MSO), which stayed in the flour during baking and was eventually ingested. MSO is not only toxic, it has very unpleasant effects on the central nervous system; tests at the time showed MSO could induce epilepsy in animals. Fortunately, the agene process was discontinued around 1950 in Britain and the United States, and also seems to have gradually dwindled away in Canada around the same time. It's not clear when or if the agene process was ever officially banned here, although Health Canada outlawed similar methods in 1968.
This episode was more or less forgotten for many years until recently, when Dr. Shaw began to investigate a very different subject.
"It was a true case of serendipity that we found out about it," he says. "We were studying the role of glutathione depletion in neurological disease."
Glutathione, he says, is a very useful substance that occurs naturally in the body. It works to mop up free radicals; reactive molecules that can easily damage cells. Glutathione also works to keep the nervous system functioning properly.
Dr. Shaw considered using a chemotherapy drug, buthionine sulfoximine (BSO), to control glutathione levels in lab animals. BSO is given to some cancer patients during chemotherapy because it inhibits the body's ability to make glutathione. Although glutathione is normally a good thing, cancer cells use it to shield themselves from attack during therapy. The rationale is that using BSO can temporarily cut down on glutathione levels and make cancer treatment more effective.
While looking into BSO, he stumbled on 50-year-old literature documenting the bleaching of white bread and recognized that MSO, the bread toxin, was almost identical to the chemotherapy agent he was studying. Here was a toxin, cousin to a powerful chemotherapy drug, which millions of people had eaten for decades.
"I thought, 'If this substance was in bread, what could that have meant?' " recalls Dr. Shaw. "There is an intriguing correlation between the increase in neurological diseases and the period during which people were eating this bread." If MSO really is poisonous to nerve cells, it could easily explain at least some cases of ALS and related disorders.
Dr. Shaw believes he has evidence that MSO is actually extremely good at killing brain cells. "MSO has several effects in the nervous system," he says, "all of them damaging."
First, MSO knocks out at least some of the body's glutathione, just as BSO does. This means that nerve cells don't have their normal protection against free radicals. Second, MSO also prevents the synthesis of glutamine, an important amino acid, which could lead to a buildup of toxic ammonia.
Perhaps more importantly, Dr. Shaw has shown that MSO also tends to kill nerve cells by jamming their calcium channels open so they become overloaded with the mineral. Based on the synergy between all these effects, MSO would seem to be a very potent neurotoxin.
Although Dr. Shaw has made some intriguing in-vitro connections so far, he stresses that the link between white bread and ALS is not complete. There are still many questions that need to be answered, such as why not everyone who has eaten the toxic bread has come down with ALS. Dr. Shaw believes that some people could be hit harder than others because they are also exposed to co-factors in their diet, such as certain metals, or have a genetic predisposition.
In the meantime, Dr. Shaw is about to begin an important second round of testing to examine how these substances perform in vivo, or in tissue. "We are trying to duplicate our toxicity findings in animals."
His team will test the MSO and BSO, probably on live mice, to find out if these substances are, in fact, neurotoxic in living systems. He is also working in collaboration with other researchers trying to find a bioassay that will allow testing of subjects to see whether they have been exposed to the various neurotoxins.
The research has drawn attention from experts in the field.
Dr. Leonard Kurland of the Mayo Clinic in Rochester, Minn., who is an authority on neurotoxicology, says the causes of ALS are probably multifaceted. "It's most likely a combination of genes and unknown environmental factors."
Dr. Peter St. George-Hyslop specializes in neurological diseases at the University of Toronto and sees some validity in the MSO hypothesis. "There has been a lot of speculation about environmental toxins as a cause of neurodegenerative disease," he says. "Particularly with Parkinson's and ALS."
He points out that ingesting a toxin could have effects that show up years later since symptoms don't become evident until the number of healthy brain cells falls below a certain level.
"When you have an acute insult, such as exposure to a toxin, it brings you closer to that threshold. The effect clearly doesn't have to take place immediately," says Dr. St. George-Hyslop.
Dr. Shaw is convinced there are many other undiscovered toxins still lurking in our environment.
"I would be surprised if we didn't find more man-made neurotoxins," he maintains. "Substances are screened for carcinogenic and mutagenic properties but rarely for neurotoxicity."
And not all the poisons we eat have to be man-made. As a case in point, Dr. Shaw's research group is now investigating a natural neurotoxin on the Pacific island of Guam, whose inhabitants have shown a high incidence of ALS. The condition was once so prevalent, in fact, that the celebrated science writer Oliver Sacks visited Guam and wrote of it in his book Island of the Color Blind. Previous studies had looked for poisons in cycad seeds, once a staple food on the island, but came up with inconclusive results.
"We decided to re-examine the issue," he says. His group has isolated a new compound from cycad, a plant steroid. Dr. Shaw believes the compound to be "very neurotoxic" in lab tests so far, although its chemical makeup is not at all like MSO.
"But they do share some features," he says. The cycad toxin seems to kill cells by one of the same mechanisms as MSO.
But Dr. Heather Durham, a researcher at the Montreal Neurological Institute, cautions that we have to keep the proper perspective.
"Eating a varied diet, and not overeating is probably the best advice to follow to minimize risk," she says.
Still, amidst the current debate over the safety of food inspection in Canada, Dr. Shaw's research seems to show that we need to be vigilant.
"Many people who talk to me are offended that something as fundamental as bread contained a poison," he says. "The MSO story points to a situation that got away from the people who should have been monitoring." Michael Judge is a Winnipeg science writer.
A NOTABLE CORRELATION
Christopher Shaw, a neuroscientist at the University of British Columbia, stumbled on methionine sulphoximine by accident. Seeing the correlation between a former abundance of MSO in the food chain and high occurrence of neurological diseases in humans, he began to look further. One such disease is amyotrophic lateral sclerosis, also known as Lou Gehrig's disease. It causes the progressive death of nerve cells in the brain and spinal cord. Dr. Shaw began to look at the ways MSO affected neurons in the outer part of the brain.