Report Cards that Shine
From the Center’s Third Annual Symposium: Real Gains

The audience at the recent Packard Center symposium— postponed from September, courtesy of hurricane Isabel— looked like any gathering of scientists: a Norman Rockwell of nationalities, women and men, earnest young postdocs and more assured heads of labs, the tie-wearers and the slightly rumpled. But several things, other than the high level of the research, gave clues the meeting wasn’t ordinary.

One was Director Jeff Rothstein’s reminder of the ground rules. “We insist that you critique each other and that you offer your expertise,” he said. “But remember, you can’t say anything outside about what you hear in this room. All I ask is that you share your newest data. If you don’t feel you can do that, please leave.”

Another was the evaluation form placed in the symposium binder: Packard Center scientists are reviewed each year, shortly after the sessions, by the Center’s scientific advisory board. The researchers, in other words, are getting report cards.

It all may seem harsh, but then, ALS is no gentle disease. By asking scientists to share both the sandbox and their toys before they accept grants, the Center’s founders sidestep the rule that research results must appear in a journal before they’re shared. This can only speed insights—if the researchers are good ones—leading to a cure. So will making sure work is high quality and that everyone stays “on target.”

“So far,” Rothstein says,“we have every sign the approach is working.” In this third year of the Packard Center’s full operation, scientists are sharing lab mice and cultures. They’re suggesting ways to tighten each other’s research. They’re apparently proud of the Center’s rigor. And, most important, their studies are making headway.

Here’s a sampling of this year’s presentations. Because patients with familial ALS due to mutations in the SOD1 gene are similar to those with sporadic ALS, much of the Center’s work turns on figuring out what goes wrong in animal models carrying mutant SOD1. It’s a sensible approach.

Screen’s Top Hits Looking Good

Rothstein: Progress on the drug front

After last year’s NIH-sponsored screening of 3,000 existing drugs for potential use against ALS and some other diseases, laboratories nationwide— including the Packard Center— produced a short list. Beta-lactam antibiotics made the top four. Since then, Center Director Jeff Rothstein and his team have explored the drugs’ nature and behavior. The ordinary antibiotics have the useful ability, in brain and spinal cord, to spark creation of glutamate transporters—the selfsame molecules that clear toxic glutamate from sensitive synapses. The drugs may also help resist damaging effects of mutant proteins that accumulate in ALS.

So far, the scientists have checked the antibiotics’ activity in spinal cord models and in normal mice and rats. It’s just fine. More important, the drugs have proved highly neuroprotective in models of neural injury, including ALS mice. As for patients? Plans for human trials are under way, awaiting NIH approval and funding.

The Molecular Silver Lining

Andreasson: "We were surprised."

“You find COX-2 throughout the brain and, normally, it assumes a useful role,” says neurologist Kati Andreasson, who spends her laboratory hours clarifying the enzyme’s activity. COX-2, biologists have recently found, somehow assists learning and memory.

“But in greater amounts, there’s a different story,” she says. COX-2 is an “inducible” enzyme; it’s called forth by the neurotransmitter glutamate. And, in acute situations, as in stroke, or in more gradual disease like ALS, neurons experience a glutamate surge. That’s followed by a wash of COX-2 which, in excess, is toxic to motor neurons. Yet when Andreasson set out to discover why that’s the case—a first step to blocking the toxicity—what she unexpectedly found may lead more directly to therapy.

Andreasson has focused on prostaglandins, molecules slightly farther down the pathway that COX-2 triggers, to see how they confer the toxic effect. But working with sections of mouse spinal cord made to mimic ALS injury, she found the opposite is true: certain prostaglandins—not all—protect motor neurons from harm. Andreasson may have hit on a natural neuroprotective system, tripped when COX-2 goes into overdrive. She’s exploring drugs that could enhance this effect, with an eye on therapy.

Feeding the Masses

Borchelt gives SOD1 a wary eye.

Dave Borchelt’s studies elegantly support the idea that, in ALS, abnormal buildup of SOD1 protein—or possibly pieces of it—are at the heart of motor neuron death. He’s systematically sorting through the different mutations that appear in SOD1 genes, noting how each mutation relates to the clumps of misshapen, proteinaceous stuff that clutters motor neuron cells. In the past, Borchelt’s shown that some of the mutations create proteins especially quick to aggregate, and that the more “aggregates” motor neurons have, the worse the animal’s disease.

Yet some death-bound cells appear to lack the protein masses. Borchelt suspects smaller, mutant SOD1 protein fragments or even trace amounts of whole, especially aggregation-loving forms of the protein could be at work there. Even though the latter may be fewer in number—a seeding phase that reflects the disease’s slow start—once they begin to aggregate, the dynamics of the process shift and newly made SOD1 proteins get pulled into the aggregate at a furious rate. Then a critical mass for disease is reached, Borchelt suspects. That the course of aggregate forming parallels the onset of symptoms in mice gives strength to the idea that aggregates power a lion’s share of ALS’s damage.

Immunity Gone Awry?

Inflammation is no friend, says Julien

“We have this idea,” says Jean-Pierre Julien, “that some process outside of motor neurons, some sort of damage, is a prerequisite for their decline.” And a potential culprit, he says, could be inflammation. Julien’s work with the Center has been dedicated to seeing if this basic reaction of the immune system—in this case, a built-in response to invading bacteria and other microorganisms—pushes cells toward ALS.

Julien’s team has focused on microglia, the nervous system’s specialized immune cells. When active, microglia trigger the release of possibly cell-destroying agents. Scientists have long noted a spike in microglia at the time symptoms appear. And Julien’s recent study showing that the anti-inflammatory antibiotic minocycline lengthens life in ALS mouse models feeds his hypothesis. This year, he showed that model mice whose immune response shot up with a gradual challenge of a highly provocative bit of bacterial coat succumbed to disease more quickly.

Now Julien’s trying to engineer a new mouse model that will let him eliminate microglia, via a drug injection, at various steps in the ALS process. He’ll see how the animals fare. “Even if the immune cells don’t directly trigger ALS,” he says, “finding they add to the disease gives us a ready target. We could, perhaps, slow the disease down or make it manageable.”

Other Symposium Highlights
Positive, nerve-protective results have come from knocking out a natural “death gene” in animal models of ALS. There’s also far greater understanding of the “excitotoxic” pathways that kill motor neurons in ALS, and progress in seeing what goes wrong in the newly discovered ALS2 form of inherited ALS. More evidence points to non-motor neuron cells as key players in encouraging ALS’s destruction of motor neurons. And a variety of stem cell studies still show that approach to replenishing the nervous system is well worth looking into.

Next > Join Tony Bennett
Enjoy Bennett’s imaginative style at a performance to benefit The Johns Hopkins Robert Packard Center for ALS Research.