When Jerry DeZutter first came to the ALS Therapy Development Institute in 2005, meetings focused on “frank and open discussions about the life of the institute — whether it would survive,” he says.
DeZutter, now head of the in vitro (test tube) validation group at this MDA-supported institute in Cambridge, Mass., says it’s been gratifying to move from being “stressed out about the survival of the company” to being “stressed about the science” as the institute matures.
MDA, which has pledged $18 million to ALS TDI through its Augie’s Quest research initiative, has put the institution on solid footing. “We’ll be solvent at least for the next several years,” DeZutter says.
Tuning out noise
|Jerry DeZutter checks to see that compounds do what they’re expected to do in a simple system before they’re studied in mice.
When DeZutter first came to the TDI, the focus was on high-throughput screening of drugs in mice. Now, though, “instead of going blindly into the mouse” with drugs, the TDI has moved to what DeZutter says is the industry standard: putting an experimental compound into cells in a culture dish first “to see if the compound is behaving as they say it does” before moving it into an animal (in vivo) model, such as a mouse.
“There’s too much noise” in an in vivo model, he notes, referring to the almost infinite number of biochemical events taking place in an animal, and the difficulty of determining which ones are related to the experimental substance.
Testing compounds in vitro first is more economical, he says. For instance, some of the short hairpin RNA molecules purported to dampen activity from genes with ALS-causing mutations have not worked well in vitro, he notes, and need to be perfected in these simpler systems first.
Some high-profile compounds do skip the in vitro step and go straight to animal trials, DeZutter concedes. One recent example is lithium, which showed great promise in slowing ALS progression in a small human study in Italy and moved directly into mouse testing at the TDI, as well as an MDA-supported human clinical trial. But for most compounds, the in vitro step is a crucial saver of resources.
Information management provides ‘brain extension’
|Fernando Vieira says the ALS TDI’s laboratory information management system is like an extension of one’s brain.
Down the hall from DeZutter are hundreds of mouse cages, all overseen by Fernando Vieira, the director of animal studies.
TDI’s mouse studies are exquisitely controlled. Not even the technicians know which mice are receiving an experimental drug and which are receiving a placebo (fake drug), eliminating bias from assessments. TDI can test far more mice in any given experiment than academic laboratories, Vieira says, because of its industrial-scale mouse program.
Vieira is particularly proud of the institute’s laboratory information management system (LIMS), designed for the TDI by Sean Scott, the institute’s president, with software experts.
“It’s like an extension of your brain,” he says, pointing to the widescreen display on the wall. “You can search for a gene and see what it does in brain, muscle and spinal cord. It also has everyone’s tasks for the day laid out, and it prints out bar-coded labels for every sample.”
Noting that the TDI has tested almost every compound that other groups have found promising (and found little to get excited about), the institute now is developing its own targets and validating them with its strict experimental methods.
“Every step we take gets us a little closer,” Vieira says. “It’s a little more light in a dark room. I’m confident in our process. If we plug away, we will find something.”
|Annette Ferrari specializes in extracting pure cell samples using laser capture microdissection.
Monitoring how cells change as ALS progresses
Annette Ferrari specializes in “laser capture microdissection” (LCM), using specialized equipment purchased with MDA funding.
This equipment allows a skilled technician to select a specific cell type — like motor neurons, which die in ALS — from a tiny sample projected on a large screen and dissect them out for further examination.
TDI now is looking at motor neurons in spinal cord tissue from day 60 and 90 of the disease in a mouse model of ALS. “We want to see what changes in the motor neurons over the course of the disease,” Ferrari explains. Next TDI will be examining the neuromuscular junction, the area where nerve and muscle fibers meet, which has become a new focus of attention in ALS research.
Bridging the academia-industry gap
John Lincecum, associate director of research biology, is philosophical about where scientific research is heading. He thinks the TDI has the right research model for challenges like ALS.
“It’s an expensive endeavor to work on intractable diseases like ALS,” he says. “And when the marketplace doesn’t see dollars, they don’t do the work. Before the Bill Gates Foundation started working on malaria, no one was working on it. Gates made it possible by putting money into it.”
For the last 60 years, Lincecum notes, basic biomedical research has been funded mostly by the National Institutes of Health. “That worked well for a long time, until scale [size] began to overwhelm the system.” Academics don’t have the resources for challenges like ALS, he says; the pharmaceutical industry does, but generally isn’t interested.
|John Lincecum, shown here with a device for homogenizing tissue, says equipment for high-tech lab work is improving.
“Big pharma can do it but won’t. They’re risk-averse,” he says, noting pharmaceutical companies are more comfortable tweaking a drug for erectile dysfunction than sinking resources into uncharted territory that might never provide a return on investment.
That’s where ALS TDI comes in. “The ALS TDI is a hybrid. It can lower the risk for pharma,” he says, describing the institute’s capabilities to provide large drug companies with the data they need to decide whether to invest $35 to $40 million into drug development.
Lincecum says the institute hires people who’ve worked in an industrial setting and applies industrial laboratory techniques, while keeping its “eyes on therapeutics” and expenses low. “We got these off the street, literally,” he says, pointing to conference room chairs covered in faded, brown fabric.
But the institute has spared no expense in purchasing equipment that speeds the research process. “What used to take three minutes now takes 10 seconds because of this machine,” he says, indicating a device that resembles a large food processor.
“We’re a bridge between two worlds.”