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Autism Now: Dr. Gerald Fishbach Extended Interview

April 20, 2011 at 12:00 AM EDT

ROBERT MACNEIL: Dr. Fishbach, you are one of the leading researchers in this field.  How close do you think you are to finding the cause of autism?

DR. GERALD FISHBACH: Robert, that’s a difficult question.  I think we’re much closer now than we were five years ago.  There’s been a tremendous amount of new information and discoveries since, I would say, 2006, 2007.  But with any disorder as complicated, as multifaceted as autism — I’m reluctant to say how close.  I hope that in the next decade, we will have treatments, whether they’re behavioral, new medicines or devices for activating the brain that will improve the quality of life of people on the autism spectrum. Whether we can actually eradicate all evidence for autism, I’m skeptical about that. And I think many people on the spectrum would not welcome that.  They want to live better. They want to live within their own personalities. 

And I do think we can make life easier by not only treating the peripheral symptoms, the anxiety, the seizures, the gastrointestinal problems, the aggression, but I think we can begin to approach some of the key symptoms of autism, some of the extreme social isolation and withdrawal, the lack of understanding completely what other people are thinking.

I don’t know any neuro-psychiatric disorder where the process has been totally reversed.  And in this particular case, where autism blends into the normal population, you want to avoid over-medication and turning people into rather robotic individuals. Have to preserve individuality while trying to treat the disabling aspects of autism. In that sense, I’m optimistic, just because we’ve learned so much in the last four or five years about the biological bases of many of these mental phenomena.

ROBERT MACNEIL: Can you find effective treatments without knowing the cause?

DR. GERALD FISHBACH: I think so. In fact, the history of neurology and psychiatry is exactly that. Finding some hint, some clue, but not really having a precise idea of the mechanism. But by one empirical, serendipitous maneuver, advancing the therapy.  You know, Louis Pasteur made the comment that chance favors the prepared mind.  So the great clinicians in the past would learn from their people they were working with, their patients, by understanding what led to an improvement, without understanding the underlying cause. And taking advantage of that.

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And then manipulating the potential therapies in such a way that they optimize them. Many of the medicines now used to treat really profound depression or schizophrenia, we just don’t understand how they work.  But because of serendipitous discoveries of effects on behavior, they’ve been developed.  And new ones with improved distribution in the body and ease of use have been developed.

The hope, of course, is that we can start with mechanism that we understand.  And there are some clues about this now, that we understand what the fundamental defect is. And approach what’s called target-directed therapies.  That’s the dream.  But I certainly wouldn’t put off all attempts at therapy until we understood what the target was.

ROBERT MACNEIL: With a mind as prepared as yours is, what is your scientific hunch that the cause is going to be, when it’s found?

DR. GERALD FISHBACH: Well, I think many people feel that autism and in all its aspects and other neuropsychiatric disorders is a problem in communication between cells in the brain. Now that’s saying an obvious truth.  The brain is a communicating organ. We take in sensory information. We put out motor actions. And in between, there’s the whole phenomena of perception, understanding and digestion of that information.

We don’t know how that happens, but we do know that communication between individual nerve cells at specialized contacts called synapses are key for that orderly communication. It’s the phenomenon of synaptic transmission.  It’s the timing of it that is tremendously important.

Now when I started in neuroscience 45 years ago, we had glimmerings of how synapses were constructed and how they developed, how they matured, how they could change with experience.  What transmitters were being used, what chemicals were at work there. But now we have a much more detailed analysis of how synapses work. And my belief is we will find root causes of our autism at particular synapses in the brain. And I believe the genetics are going to lead us to which changes we should focus on and perhaps even where in the brain these changes are most critical and when they develop during development is the changes evident before birth, after birth or fairly late, after three years of age.

ROBERT MACNEIL: Through this foundation, you’ve invested heavily in genetic research.


ROBERT MACNEIL:  Do you think the answer’s going to be found through the genes?

DR. GERALD  FISHBACH:  I do feel the answer’s going be found through genetic analysis.  It’s not going to be simple.  First, there’s no question that autism is a genetic disorder. The simple fact is that identical twins have almost, in some studies, a 90 percent concordance rate.  Somewhere, different studies, between 70 and 90 percent. If you have an identical twin who is autistic, the chances are somewhere between seven and nine out of ten that you will become autistic. That cannot be ignored. And there are many other clues in the population.

That does not mean the environment is not tremendously important, because it is also clear that the genetics are complex. Autism is not ging to be a one-gene, one-disorder condition, as Huntington’s disease is, or as sickle cell anemia is, or as cystic fibrosis. There may be many genes that enhance the risk for autism, don’t cause it necessarily, but just increase the vulnerability, the risk for autism.

Our own estimates and estimates of others indicate there may be more than 100 genes that can enhance the risk.  We are looking, at the Simons Foundation, for what are called de novo mutations, mutations that arise anew, in the germ cells of one or the other parent, sperm or egg, because it appears that these de novo mutations have a very big effect, a very profound effect.  In the jargon of geneticists, they’re highly penetrant.  If you have that mutation, you have a great risk of developing autism.

ROBERT MACNEIL: Germ cells are the sex cells of the mother or father.

DR. GERALD  FISHBACH: Yes, the sperm cells of the father and the egg cells of the mother.  So whereas these new mutations, and they’re new, because the parents are not on the autism spectrum.  And the siblings of the affected child they’re probing are not clinically on the autism spectrum.  So something  has happened at that union of sperm and egg in that child that has produced the autism phenotype.

And the — it’s turning out that each one of these events is very rare, occurring in one percent or less of the autistic population.  But all together, there may be 100 of them.  And they may add up to account for a large fraction of what we now call idiopathic or unexplained autism.

ROBERT MACNEIL: It’s strange that if there are so many contributing genetic factors that are predisposed, that the symptoms of autism, at least the neurological symptoms, are relatively consistent.  The disabilities you mentioned.

DR. GERALD  FISHBACH: Yes.  It comes back to the synapse as a molecular machine. As I said earlier, the complexity of the synapses really being revealed in our last generation.  And more every day.  So there are many ways to alter a synapse.  One can alter the amount of chemical transmitter that’s released.  One can alter the number or the efficacy of the receptors that receive that transmitter and the target cell.  One can alter the way that synapse learns how it may change its transmission as a result of experience.  And one can understand now how the number of synapses may change during development and in later life.

The brain is not hard-wired.  It’s not a computer.  The broad outlines, the connections between systems, are fixed.  But it’s now clear that there’s really microscopic rearrangement and reorganization of synapses.  My feeling is there may be 100 ways to do that.

And my hope, the faith of people in this area, is the genetics will all give us clues as to how the responsible genes are affecting synaptic transmission.  So the hope is that all the genes will converge.  And point to one or a few processes at the synapse.

: As you’re aware, there are people, researchers in the field, who feel that so much emphasis has been put on genetic research through various funding mechanisms that it has excluded or downgraded efforts to find environmental causes.

DR. GERALD  FISHBACH: I don’t agree with that. I don’t think this is an either/or effort.  There’s been significant amount of funds directed to autism research.  The issue is ideas and hypotheses.  The genetics will facilitate work on the environment.  And once you have a clue about which environmental factors might be at risk or once the epidemiology clearly points to one or more environmental factors, the genetics will help us understand what is going on and make the epidemiology even more convincing.

And so I don’t think it’s either/or.  And I think if there is a perceived lack of funding in– environmental science, epidemiology, that should be fixed.  And we should develop proposals that are realistic and that demand immediate attention. But I wouldn’t say that the lack of advance there is due to overspending in genetics.

: Where is your research directed specifically right now?

DR. GERALD  FISHBACH: Well, there are several areas.  I think right now, I want to mention two areas.  One is in the area of genetics.  We have learned a tremendous amount by screening the whole genome of almost 3000 people, which we have gathered at 13 different universities around the country.  And we are beginning to see consistent, recurrent, genetic alterations.  We want to explore those alterations in more detail by looking with the really fantastic new high-throughput DNA sequencing.

It’s possible now for very few thousand dollars to sequence the entire genome or the part of the genome that is encoding for proteins– in each individual, even 3000 of– and then we will have a more complete picture of the genetic landscape.  That’s where the tough work begins.  That’s where we have to understand which one of these genetic alterations is really of interest.

And we’re going do that by introducing the mutations we find into animal models and into cells growing in culture.  It’s possible now to take cells from affected individuals on the spectrum and convert them in tissue culture into nerve cells.  These are called induced pluripotent stem cells.  And these cells will be very useful for studying the action of particular genes.  They will also be useful for screening for potential therapies.  So we are going to explore the clues we have about genes and narrow down that list, to say, “These are the genes we want to focus on.”  And then we want to use them to begin thinking about therapeutic intervention.

ROBERT MACNEIL: Speaking of possible therapies, you’ve told us that you are studying trans-cranial magnetic stimulation.  Where do you think that may lead towards finding causes?

DR. GERALD  FISHBACH: I am a fan of electrical stimulation. You know, before I came to the Simons Foundation, I was directing the National Institute of Neurological Disorders and Stroke.  And while I was there, the technique, the approach of brain stimulation for Parkinson’s disease really exploded.  In cases where individuals were no longer responsive to medicines, in selected cases, careful placement of electrodes, in this case, deep in the brain, could reverse symptoms on the operating table.

And subsequently, this has been applied to cases of refractory depression, life saving in some cases, in cases of obsessive-compulsive disorder.  And now people are beginning to think maybe we don’t have to implant the electrodes in the brain.  Maybe we can do it with electrodes outside of the skull.

You mentioned trans-cranial magnetic stimulation.  It’s not, and that is really in its infancy for psychiatric disorder.  But the reason I’m optimistic or hopeful, I won’t even say optimistic, about autism is that some people are pointing to a very superficial region of the brain in the temporal lobe called the superior temporal gyrus, right where the temporal parts of the brain are named for the bones and the skull over them.

So the region of the brain between the temporal lobe and the parietal lobe seems to be very involved.  At least that’s what the imaging studies are telling us, seems to be very involved when people are trying to understand other people’s actions.  And that’s very superficial.  It’s right near the outside of the cranium.  And the hope is that trans-cranial magnetic stimulation would give us more clues and perhaps even ways to regulate this cognitive hurdle that people must get over.

ROBERT MACNEIL: Are you at all discouraged that after so much effort, investment, some of the best minds in the world on this, that autism is still so baffling?

DR. GERALD  FISHBACH: I’m not discouraged at all about that.  I think we’re addressing one of the most profound problems in not only all of medicine, but in all of human existence.  You’re talking about the ability to relate to other people, to empathize in a certain way and to comprehend.  And I think it’s the most worthwhile, most challenging effort in science that I’ve ever been involved in.

And I don’t expect immediate results.  I hope we can develop some relief, some improvement in life.  But I understand the magnitude of this problem.  And what’s been deeply gratifying to me, Robert, is the influx of people into this field.  You know, we’re now funding about 100 investigators around the world in addition to this large genetic study I talk to you about.  I’d say more than half of them were not working in the field of autism four years ago.

But they have, and it would not be enough to attract them with money.  I think these are some of the world’s most extraordinary neuroscientists.  And they really have to have an idea that something can be done.  There’s a hypothesis here, that what they’re doing is now relevant.  Our understanding of autism has advanced enough.  And I think that general sense of excitement is in the air.

And our job is just to facilitate it, to encourage it, to promote collaborations.  And the last four years have been deeply gratifying.  So I’m not discouraged at all.  I think publications from work we fund and from the funding of others are beginning to appear, which are qualitatively different than they were five or six years ago.  These are things that are providing real clues.  I don’t want to sound too Pollyannaish or overstate things.  That’s been done too often. There’s still a war on cancer.  But I’d rather be diagnosed with cancer or with Parkinson’s disease or with autism today than I would ten years ago, because I think there are things on the horizon.

You mentioned earlier in our discussion the issues with adults, even not giving up on adults.  Autism is a developmental disorder.  But there’s enough evidence now of reversal of signs and symptoms in animal models and adult animal model to reinforce my notion that the nervous system can adapt, whether it cures itself or whether it has enough redundancy to work around what are perceived as disabilities, I don’t know. But in several models now that are close to what we call autism, it’s been able to reverse them, genetically and medically.  So I’m not discouraged at all.

DR. GERALD FISHBACH: One therapy that’s here that is effective, not 100 percent, but it offers a great deal of hope is early behavioral intervention.  So it’s not entirely without controversy.  But I think the weight of opinion now is that intensive behavioral therapy– when I say behavior I mean there are various approaches.  Some is very rigid.  Some is more play oriented.  But early intervention can change the course of autism, at least for a long period of time.  We don’t have enough follow-up studies but certainly for years — two or three years at a time, early behavioral intervention is key.

And I’m saying early for a reason. The most recent studies indicate that the earlier the better.  If you can do it before age two — very hard to diagnose autism before age two.  But there are tremendous efforts now to make the diagnosis even in the first year of life. I think the genetics are going be enormously helpful here.

If we do pin down a set of genes which are truly predictive, that they may help direct people to early therapy.  But also there are new tests being developed that don’t depend on speaking with a child. One group at Yale has worked very hard on eye movements, what are young infants, six months to a year old, looking at?  And based on that, can you predict a later downhill course to its therapy?  And there’s some hints that that may be true.  That needs a lot more work.  But early detection and early intervention gives me a lot of hope.
ROBERT MACNEIL: How do you define autism?

DR. GERALD FISHBACH: I define autism as having two major core deficits. One is a lack of mutual social interaction, a deficit in understanding other people’s actions, mutual joint play, not knowing what they’re thinking.  Social cognition is the core symptom.  But there’s another related symptom, which involves motor behavior, repetitive actions and another facet of it, insistence on sameness, the inability to change certain patterns of activity.

Now, there are many other things that you can tack onto the broader definition of autism.  Those are two cores in my mind. Other things that can be manifest are language delay, aggressive behaviors — not true in every case — these other components, slightly diminished intellectual capability.

The mean IQ in our study of 3,000 — proband’s is about 85.  It’s not 115, but it’s not 60.  So these children are slightly disabled.  At some ends of the spectrum, though, they’re severely disabled, with IQs of 20.  But I don’t consider that part of the core definition.  It can be associated with autism.  Epilepsy — there can be what the new DSM5 is driving towards; the new diagnostic statistical manual, is to simplify things by defining a category called autism spectrum disorde — based on those two criteria, the movement disorder and the social cognition.

And then there will be autism spectrum disorder … with language delay … with epilepsy … with intellectual disability … with aggressive behavior.  So that’s how I define autism.  The sinequanones those two core symptoms.

ROBERT MACNEIL: I’ll just ask you one more final question. Some people we’ve talked to say, “We are on the verge of big discoveries.” Others say, “We’re just scratching the surface.” Where do you think we are?

DR. GERALD FISHBACH: I think we’re scratching the surface of big discoveries. I think until something happens we can wait with baited breath. I can name you two, three, four, five publications in the last two years that make you step back and say, “Wait a minute. That could be really important.”

But the way science advances is not a linear step forward. I think the discovery of recurrent patterns of genetic vulnerability is a major advance. And I when I say recurrent, I mean the genes that we now know are altered in one to two, to three percent of the autistic population. When you think about that, that’s enormous. And if we have a few more hits like that we will begin to have a good handle. The imaging studies have been very informative. I mentioned when we talked about transcranial magnetic stimulation, of focus on the junction between the parietal and temporal lobes is more and more a consensus that there’s something called the social brain. And the temporal-parietal junction is in the middle of it. There’s some structures deeper and there’s some right in the front of the brain.

But we’re beginning to have an idea where in the brain attention ought to be focused. And we’re beginning to understand that it has something to do with the synchronous coordinate activation. So I think that’s a big plus. One reason Parkinson’s disease advanced as it did is we can point to a region in the brain where this disorder either begins or is most manifest, and can direct therapies there.

ROBERT MACNEIL: It’s the one that’s at the very base in the back of the brain?

DR. GERALD FISHBACH: It’s in the base of the brain, a region in the core of the brain called the substantia nigra, where a lot of cells that use dopamine as a transmitter reside, and that project widely to the rest of the brain. So we can go after that. And knowing where that went led to certain surgical interventions. I’m not using surgical on the bad word of the bad old psychosurgery, but good microsurgery. And I’m not using it in the sense that we have to alter people’s social behavior. But we can make it easier. And my thought is directing attention to particular regions of the brain and to particular synaptic dysfunctions.

There’s been one recent study, for example, that shows that you can reproduce in an animal model most of the symptoms of Rett syndrome, which some people feel is on the autism spectrum by expressing the mutant gene in just one kind of neuron, the kind of neuron that makes an inhibitory transmitter. That’s a very big clue that there’s some imbalance, there’s something malfunctioning in these inhibitory neurons. And we just have to understand that better to tip the balance a little more towards the excitation to change the excitation-inhibition balance in key regions of the brain. It could be done easily for all we know at that ah-ha moment, “Oh, now I know how to do this,” or it may be years and years away. I don’t know.

ROBERT MACNEIL:  That’s great. Thank you very much.