“When do you pull the trigger?”  Evan Snyder of the Burnham Institute asked this pivotal question of panelists at Cambridge Healthtech Institute (CHI)’s Molecular Medicine Tri-Conference last week. But the trigger in this case doesn’t fire a weapon, rather, it launches a potential cure.

Snyder was challenging his fellow panelists to determine when, and in what cases, stem cells can be considered ripe for clinical application. 

Tremendous anticipation has built up around stem cells as possible treatments for a variety of conditions, including heart disease, a slew of inherited diseases, and central nervous system disorders such as Parkinson’s Disease and paralysis. The CHI panel included renowned neuroscientists, a venture capitalist, a biotech lawyer, a regulatory issues specialist, and a representative from Stem Cells Inc., a biotech company currently running a clinical trial using stem cells for Batten Disease -- a rare inherited condition.

It is critical that scientists not jump the gun and try stem cell therapy too soon, the panelists agreed. Not only would that be a disservice to patients, but high profile failures could tarnish the field.  Figuring out the right time to launch a trial is still extremely difficult though.

The basic scientist will say, “We never have enough knowledge,” said Snyder.  On the other hand, “The clinician has patients in front of him and knows not making a decision is a decision in itself.”  Snyder suggested “pulling the trigger” when the preclinical data supports the decision and when patients in such a trial would not be denied effective, established therapy in order to test something that may not work.

Currently, Snyder considers brain tumors the “low hanging fruit” in the field. “If stem cells could be used to deliver a tumor-cell killing payload, that would not be “expecting too much” of the therapy.

But much of the hope around stem cells derives from their plasticity.  Plopping these cells into a new environment can change their destiny. So, just using them as delivery vehicles seems insufficient. Unfortunately, “Even the dumbest stem cell is smarter than the smartest neurobiologist,” Snyder said. “The stem cell knows it just doesn’t have to give you one cell, but all the cells around it.” 

Scientists need to know more about how to coax stem cells into exhibiting very specific characteristics.  Otherwise, the therapy won’t just be ineffective, it could be harmful.  Accidentally growing bone or muscle cells in the brain, for example, could have detrimental effects.

“Reconstructing neural circuitry is very very difficult,” Snyder said.  There is little evidence yet that this can be successfully done in many cases.  It will likely take a lot longer to develop treatments that replace cells that are missing or not working properly.  For now, “It will be much easier to try and preserve what already exists,” Snyder said.  As scientists “fill in the gaps” in our knowledge, more complicated types of cures can be tried.

Flawed Studies

During a breakout session where audience members and panelists met at individual tables, neuroscientist Arnold Kriegstein listed many problems he sees with current studies using stem cells. Kriegstein is director of UCSF’s Institute for Regenerative Medicine.

“It’s very annoying to read papers where scientists claim they have derived neurons from stem cells, when they are using only one marker [to make that determination],” he said. “Are those really neurons? If so, what kind are they?”  Scientists, he said, should go further and characterize the cells they generate with multiple markers. “And go beyond markers, look at the physiology of the cell,” he said.

Another “pet peeve” of Kriegstein’s is when scientists label certain stem cells “adult” even if the cells have been derived from a newborn mouse brain.  “If you are modeling a disease you want an animal of the same relative age,” he said.  Showing that something works in a young rodent is not the same as showing it works in a mature animal.

Kriegstein detailed several other flaws that often mar scientific studies. Until a wealth of data is built up using solid scientific technique, he emphasized, the field will continue to be dogged by uncertainty.  “In many studies there is wide variation in response even among the control subjects,” he pointed out.  That makes it even harder to determine whether good responses in a treated group are due to a stem cell therapy or some other factor.

A Surge Ahead?  

While there are clearly still major scientific questions ahead, the steam seems to be building back up for the stem cell field.  According to panelist Greg Bonfiglio of Proteus Venture Partners, “We are in a new cycle.”  After the boom/bust of the late 1990s and 2000, a lot of venture capitalists pulled back from stem cell companies because “The perceived technology risk was high.”  But Bonfiglio thinks that is changing.  

He said the technology has improved, a huge body of research has built up, and the political climate is changing.  “More than 100 new stem cell ventures have formed over the last year,” he said. That puts the number of companies in this field at around 500. “The ecosystem is maturing.”  Venture capitalists, he said, are taking another look at stem cell therapy, and will likely be funding more companies.  

So, is this a mid-course correction? A new, albeit much smaller, boom? Or just another false start? The panelists agreed that to keep the field on course scientists and companies need to exercise great caution.

While steady advances are being made, “We can’t just blithely go from disease to disease conducting trials,” Snyder said.  He urged scientists to clearly characterize the cells they are using and really understand the diseases they hope to treat. “Are you really making the enzyme you need? How are the cells behaving in the milieu you are exposing them to?” he said. “And most importantly, do you really know what needs fixing in the disease?”  

It is telling that while hundreds of Phase I trials of cell therapies are being carried out, very few treatments have made it to Phase II or III.  “People just don’t do their homework,” said Darin Weber, a regulatory specialist with Biologics Consulting Group.  “Once you are going into Phase II, you need to prove the therapy will actually help the patients, and that’s going to require a lot more evidence.”

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