TEDMED and Alzheimer’s: Gregory Petsko, Reisa Sperling, and the next Al Gore
Gregory Petsko knows why he came to TEDMED. "I'm looking for Al Gore," he told me flat-out over lunch. Folks who know Petskoknow the former Brandeis University biochemistry department chair isn't one to mince words. And he's nailed the reason why an academic might want to look outside traditional conferences and soak up some of the TEDMED aura. He's looking for a charismatic champion to take up a biomedical cause: in Petsko's case, it's support for research in Alzheimer's disease.
Petsko and Reisa Sperling, director of the Center for Alzheimer's Research and Treatment at Brigham and Women’s Hospital, talked about Alzheimer's at TEDMED on Wednesday. Both talks were cast as calls to action. Just consider the introduction Petsko got from TEDMED chair and Priceline.com founder Jay S. Walker: "This is a man who hears a bomb ticking."
Alzheimer's statistics are sobering and Petsko used them to dramatic effect. People who will reach 80 by the year 2050 have a 1 in 3 chance of developing the disease if nothing is done, he told the audience. "And yet I hear no clamor," he said. "I hear no sense of urgency."
Petsko shared some not-yet-published work with TEDMED's audience. His team is looking at a less-trod path of Alzheimer's biology-- the role protein sorting defects might play in the development of the disease. Their focus is on a protein complex called the retromer, which Petsko likened to a truck driver, because its job is to sort and send proteins either to the golgi--the cell's recycling center, or to the lysosome for snipping. For Alzheimer's, the thought is that improper sorting can make the difference between normalcy and an accumulation of amyloid-beta, the protein thought to be a key player in developing the disease. Petsko told me that his collaborator, Scott Small of Columbia University Medical School, discovered that retromer played a role in Alzheimer's (Neuron, DOI: 10.1016/j.neuron.2006.09.001).
Petsko's truck analogy (Courtesy of G. Petsko)
Petsko's team has developed small molecules that increase the level of active retromer complex in the cell. So far, their agents have been evaluated in cultured cells. Tests in mice are ongoing.
It's important for the Alzheimer's field to look beyond amyloid-beta, says Kevin Sweeney, a TEDMED attendee who teaches at the University of California, Berkeley's Haas School of Business and is part of the Rosenberg Alzheimer's Project, a nascent organization that supports alternative avenues in Alzheimer's research. "For a while, at least, the Alzheimer's space looks like so many of the [clinical] trials have pursued a relatively narrow range of theories," he says. Even though those theories aren't fully played out, "we still think it's useful to start looking for other strands," he says.
"We can look for more of the same. Or we can look for things that are different in fundamental ways," he adds.
After Petsko spoke, Sperling set out to convince the audience that the timing of Alzheimer's clinical trials leaves something to be desired, and that early detection is a strategy worth pursuing.
By the time a patient reaches the medically and scientifically agreed-upon standard for Alzheimer's disease, they've already notched many years of brain degeneration, Sperling notes. "And this is the stage of disease where we're doing our clinical trials," she says. Even mild cognitive impairment, an intermediate stage on the way to Alzheimer's, "may already by too late" for intervention, since 50 to 70% of nerve cells have been lost from key memory networks by that point, Sperling says.
Retromer's role in Alzheimer's (Courtesy of G. Petsko)
Barbara Tate, a neurobiologist and Vice President at Satori Pharmaceuticals, a firm working to develop its own Alzheimer's therapies, told C&EN that the agreed-upon clinical criteria for Alzheimer's disease are blunt diagnostic tools. (Sperling is on Satori's scientific advisory board).
"Spouses have diagnosed the disease a decade before" their loved one meets the criteria, Tate said. "We call it mild or moderate Alzheimer's disease but there's nothing mild about it."
It's expensive to run Alzheimer's clinical trials in their current incarnations, Tate says. However, she notes, "it's been hard to make an economic argument for treating earlier."
Patients at the earliest stages of cognitive decline can often still work, and still care for themselves, so their burden on society isn't anywhere near that of a more advanced Alzheimer's patient. And any therapy that would be designed for such early-stage interventions would have to be both very safe and very cheap, something that's not easy to accomplish, she adds.
As for the TEDMED calls for action on Alzheimer's, Tate is concerned that "there's starting to be an exhaustion" among the public, researchers, and investors alike.
"People get tired of failed clinical trials," such as the high-profile failures of Dimebon and semagacestat in the Alzheimer's realm. Specifics about why a drug failed "don't resonate," she says. "All people hear is that a drug failed."
Though there might be more clinical trial failures to come, Tate says "the data to hold out for" will come from what's called the A4 trial, or Anti-Amyloid Treatment in Asymptomatic AD, which Sperling co-leads. This trial is aimed at treating people who have several Alzheimer's risk factors but who have not developed the full-blown disease. It complements the Dominantly Inherited Alzheimer Network (DIAN) trial, which is looking at patients who have a mutation that are certain to develop the disease.
No word on whether Petsko has met his Al Gore yet. But what's both good and bad about TEDMED is that he's far from only person there who's looking.
UPDATED 3:15PM 4/12: corrected Petsko's chair status and odds of person of 80 developing Alzheimer's by 2050.