• I can't give you brains but I can give you a diploma.

Posted: September 14th, 2011

"I can't give you brains but I can give you a diploma."

(the wizard of Oz to the scarecrow)

A wry but all to often prescient comment on how we measure intelligence.  When my children were young, a wonderful animated movie was released called the Secret of NIMH.  The main characters were rats that had been the subjects of an experimental drug. They became very smart and escaped from an NIH lab.  Two films this summer; Limitless and Rise of the Planet of the Apes are different takes on a similar theme. Both films are about drugs that make those who take them smarter.  Not just a little smarter, but orders of magnitude smarter.

In Limitless, there is a bit of information, though sketchily given, about the drug clearly implicating neurogenesis and neural stem cells in the adult brain.  In Rise, we are briefly exposed to the term neurogenesis.  Neuralstem of course is a company with the first of a new class of neurogenic drugs (NSI-189) in human trials.  So it is no surprise that I have been fascinated by this new focus in the entertainment culture.  Clearly, the idea of such a drug is ready for prime time, but is the science?

To answer that question we must first address the question Mr. Baum so artfully skewers; what is intelligence?  If we can’t agree on what it is, how do we know if we have increased it?  There are of course a number of ways to measure (what society calls) intelligence, but we are after what is “behind” the test scores.  We are after what powers intelligence.

Societies often analogize concepts using the dominant technology of the time.  For example in Isaac Newton’s time the intricate mechanics of a clock was the most advanced technology.  Everything from gravity and the workings of the Universe to the workings of the human body was thought of in terms of the winding and unwinding of a clock.  We were all part of one giant machine, and each movement was the inevitable result of some cog or wheel turning to make it so.  When Darwin’s theory of evolution became widely accepted, “survival of the fittest” seeped into how society explained everything from countries making war against each other to social policy.  When biology exploded on the scene, people even began to speak of corporations and other institutions as “organic” things and today we still speak of “pruning” and growth in institutions as though they are living things.

The dominant technology of our time is the computer.  So not surprisingly we tend to think of memory as a process of storage and retrieval; and we tend now to think of intelligence as processing power.  Certainly memory is a key component of intelligence in every day life.  And the ability to retrieve information equates to “higher” scores on most tests.  But we should not confuse the process of storage and retrieval with processing power.  The ability to learn, new things, is perhaps the true measure of intelligence?

Once, people thought that “larger” brains must mean more intelligence.  When it became clear that was not the case a theory came into vogue that we only use a tiny percent of our brain, equally untrue.  While different regions of the brain have some sort of “primary” responsibility for different types of thought/activity, it is becoming clear that there is a tremendous interconnectivity in the brain, and a complexity involved in “thought” that we have barely glimpsed.

In both movies, ‘intelligence” is defined by the ability to learn.  To learn a lot, to learn complex things, and to learn them quickly. The “mechanism” that allows for this increase in intelligence can be thought of as an increase in processing power.  Under this view, intelligence, or processing power, is linked most closely with the density and number of synaptic connections in the brain; the “wires” in your brain.   Neurogenesis can be thought of as the ability to repair and increase the number of synaptic connections in the brain.  That’s what the mysterious drugs of the movies are said to do.   Interestingly enough, that is just what we believe  NSI-189 does.  Both in vitro and in vivo (in dishes and in animals) we have seen a robust effect.

We are just now concluding our first in-human healthy volunteer safety trial of NS-189 to treat major depression.  Later this fall we expect to start a trial in actual depressed patients. There is good evidence that endogenous neural stem cells in the adult hippocampus are killed off in depressed patients, and the hippocampus actually shrinks over time because of that.  The theory is to see if repairing and/or rebuilding the hippocampus can help depressed patients.  The animal studies are encouraging, but the animals don’t really have human depression.  If we are right, this will be a unique approach to treating depression by actually repairing the structural damage which may be causing it…..but will it make people smarter?

That is a very different question.  We are currently looking into whether or not our drug can increase cognitive scores in an animal model of Alzheimer’s disease.  If the evidence is there (and there is good reason to believe it will be) then in about a year we may also be ready to start a phase two trial for some form of cognitive impairment indication.  It could be Alzheimer’s or it could be some simpler form of dementia.   Then, we will have to decide exactly what “smarter” really does mean, so that we can answer the question posed at the movies this summer.  In the meantime, if you haven’t seen the movies, they are entertaining in their way, and summer is almost over..