By: Trisha Gura
It began, as scientific investigations often do, with a tragedy to someone close. Isaac Chiu, PhD, an undergraduate student in biochemistry at Harvard University, learned that a family friend had developed Lou Gehrig’s disease (also known as amyotrophic lateral sclerosis, or ALS), and was quickly and mysteriously losing muscle strength and control. Devastated, Chiu wanted to know more.
Articles in medical journals gave him the basics: Some 10 percent of ALS cases are inherited; for the rest, the insult that unleashes the disease is unknown. There is no cure, only a handful of supportive treatments. ALS has long been viewed as a neurodegenerative disease, one that exclusively affects motor neurons in the brain and spinal cord.
But as he read more, Chiu saw another possibility. “One of the components, even from the early ALS studies, is inflammation,” he says.
Chiu understood from his undergraduate courses that inflammation is a hallmark of an immunologic reaction. So when the time came for graduate school, Chiu sought out Michael Carroll, PhD, director of the immunology graduate program at Harvard Medical School and a Senior Investigator in the the Program in Cellular and Molecular Medicine and the Immune Disease Institute at Children’s Hospital Boston (PCMM/IDI).
But Carroll was hesitant to take on the project. A consummate immunologist, he was an expert in the mechanisms of lupus, an autoimmune disease in which the immune system mistakenly attacks the body’s own cells as foreign intruders. Lacking intimate knowledge of neurology, Carroll initially thought it a far stretch to mentor a graduate student interested in a disease marked by dying motor neurons.
Still, he had heard of others who were working out a possible role of inflammation in Alzheimer’s disease. Several other conditions, such as Parkinson’s and Huntington’s, once solely in the domain of neurologists, were also showing evidence of an inflammatory component. Carroll had recently read scientific papers about schizophrenia that strongly implicated genes involved in immunity. And in multiple sclerosis, he knew, the immune system unwittingly attacks the fatty layer that sheathes the nerves.
So Carroll decided to give Chiu a shot. They began with a very basic question: could targeting inflammation be a new route to therapy for ALS? The answer turns out to be a definitive yes – but not in the way they expected.
Working the project
The two began their studies with the hypothesis that inflammation was bad for ALS – an idea consistent with reports Chiu read in the literature -- and that anti-inflammatory agents would be good treatments. Their thinking was based on the work of other researchers who showed that, in mice with a form of ALS, certain cells in the spinal cord spew out progressively more pro-inflammatory biochemicals as the disease worsens. Perhaps ALS was an autoimmune disease, in which the immune system was wrongly attacking motor neurons. “I was hoping we would find some key toxic factor that we could block in ALS,” says Chiu.
But over the next five years, Chiu found the complete opposite.
Like his predecessors, Chiu began with mice genetically engineered to develop ALS. These animals make too much of the mutant superoxide dismutase1 (SOD1) protein (in humans, mutation of the SOD1 gene is responsible for 30 percent of genetically inherited cases of ALS). He intended to observe the animals’ spinal cords and brains as they developed ALS symptoms, but from the outset, the experiments were challenging, and finding the right methods to study inflammation in the rodent brain and spinal cord required more effort than Chiu had anticipated.
And then Chiu spotted a strange phenomenon. First, a certain kind of T-cell from the immune system began accumulating in the spinal cord, and to a lesser extent, the brain, as the disease worsened. This was odd because ALS is a considered a “sterile disease,” one that does not involve viruses or bacteria, which T-cells are normally brought in to fight. What’s more, T-cells normally don’t cross the formidable barrier that lies between the body and the brain/spinal cord. More bizarre still, just after the T-cells began appearing, a group of brain cells called microglia activated and started changing to resemble specialized immune cells known as dendritic cells. (Dendritic cells, normally found at the body’s interface with the outside world -- in the nose and lungs, for example -- absorb foreign agents and present them to other cells in the immune system for possible targeting.) In the ALS mice, the activated microglia began swelling, and their thin, arm-like processes began homing in on the injured motor neurons.
“The microglia were acting like immune sensors,” says Chiu. They were surveying the tissue as an immune cell would roam in the blood circulation in search of a virus or bacterium. But there was no microbe. What were these activated immune-like cells doing?
Chiu turned to a technology called microarray analysis, which measures gene activity in cells, to see if he could determine what kinds of proteins the cells were making. He expected to see the microglia in ALS mice, as they got sicker, churn out progressively more toxic, pro-inflammatory agents. This would be a sign that the immune system was attacking motor neurons, as hypothesized. Shockingly, Chiu found the opposite: the activated microglia were damping down production of pro-inflammatory agents, while boosting production of protective growth factors.
“This went against the grain,” Carroll recalls. “The newest thinking at the time was that inflammation is actually causing injury in the central nervous system. But in this case, inflammation is protective.”
The other side of inflammation
Inflammation is a key part of the body’s immune defense. When an infectious agent breaches the body, immune cells are signaled to spew out powerful inflammatory chemicals to take out the threat. But inflammation also has a healing property: after an injury, immune cells are commissioned to deliver pro-healing agents to speed recovery. One of these, insulin-like growth factor 1 (IGF-1), was produced abundantly by activated microglia from Chiu’s ALS mice. Were the microglia actually helping fend off disease?
Chiu went on to prove just that. He genetically engineered his ALS mice to lack the kind of cells, known as alpha-beta T-cells, that he suspected were signaling the microglia to become activated – but left the rest of the animals’ immune systems intact. He reasoned that if the T-cells were helping to prevent neurodegeneration by spurring production of healing growth factors like IGF-1, then ALS mice lacking these cells would do worse than rodents with them. That, in fact, was the outcome: the mice lost more weight, deteriorated in motor function sooner and died earlier than ALS mice still carrying alpha-beta T-cells.
Chiu now suspects that ALS is initiated by some still unknown agent or event. Then, as nerve cells begin to sicken and die, the nervous system tries to right itself by making microglia behave like wound-healers, secreting IGF-1 and other factors in an attempt to preserve motor neurons. “If the immune system has evolved in a way to help heal motor neurons,” Chiu says, “maybe we should start looking at what the body already has tailored to the healing response.”
Into the clinics
People are already trying to tap into this healing – but under the medical radar. In May, the New York Times reported that ALS patients are scrambling to get a drug called Iplex, which was pulled from the market due to a patent dispute. Intriguingly, Iplex contains IGF-1 formulated with an additional binding protein that helps it cross the blood-brain barrier to get into the central nervous system. Scientific studies do indicate that IGF-1 can protect motor neurons, and the Food and Drug Administration is now allowing a few ALS patients access to Iplex under an Investigational New Drug application. But it has not been formally tested in ALS patients.
What has been tested is a drug called minocycline, an antibiotic that suppresses inflammation. Early on, however, the trial was stopped because the drug was actually accelerating ALS patients’ neurodeterioration. Chiu thinks that minocycline, in blocking inflammation, also blocked IGF-1 and other beneficial, neuroprotective effects of the microglia in ALS.
Although many questions remain, what seems clear is that inflammation’s effects can vary depending on the context. It may be that microglia are both protective and harmful in ALS, just as inflammation can be destructive or healing to the body based on whether the trigger is a microbe versus an injury.
“When we think about therapy for ALS, we should not think about blocking the whole inflammatory process,” Chiu says, “rather just enhancing the protective part.”
In order to do that, Chiu wants to gain a better understanding of not just ALS but also other diseases with both immune and neurologic characteristics. He has already learned that the immune and nervous systems actually share cellular and molecular pathways. For example, a researcher on Chiu’s thesis defense committee -- Beth Stevens, PhD, of Children’s Neurobiology Program -- has found that a family of immune-related proteins, called complement proteins, are involved in refining connections between neurons. Chiu graduated this year and is seeking a post-doctoral position in a neuroscience lab so he can gain new insights into the new and burgeoning field dubbed neuroimmunology.
Meanwhile, Carroll is building on Chiu’s work to forge a special training track for neuroimmunology, as head of the Harvard Graduate Program in Immunology. “Very exciting things happen when two fields come together,” Carroll says. “What I’d like to give Isaac most credit for is not just coming in, following around a post-doc, and taking on a project that was ongoing in the lab. ALS was his idea, and he struggled with it pretty much on his own.”
As to Chiu’s family friend with ALS, David Bekker, a 60-year old community pediatrician who used to make rounds at Children’s, is alive and in relatively good health seven years after diagnosis (most patients die within two to five years). Chiu believes Bekker has done so well because of the high-quality clinical care he sought and received, as well as his positive outlook and deep religious faith. There are also the insights Chiu provided. Bekker, for example, had been taking the immune-suppressing minocycline, but stopped after talking to Chiu and learning that the clinical trial had shut down.
Chiu’s journey shows that when science is given the chance to evolve, a fresh perspective coming from a novice researcher can challenge – and sometimes overturn -- old assumptions.
“I’ve always found interesting connections between neurology and immunology,” Chiu says. “Now I know there’s so much more to find out.”
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