Kirby - Tom Insel (IACC chair) interview - whole version transcript

[Guest guest]

INTERVIEW WITH TOM INSEL

December 18, 2009

DK: I would like to get your interpretation of the new autism numbers out

today. Even the CDC said that ³We cannot rule out² an actual increase in the

risk for autism. So if better reporting, awareness and diagnosis cannot

account for all the increase, what else do you think might explain it?

TI: It¹s the question that everybody¹s asking. I would point you to three

sources for information on questions of prevalence. There is HRSA, which has

done phone surveys. There is CDC, which has been using basically the same

methodology across all of these different cohorts focusing just on 8 year

olds and using secondary data sources. And the third source is the

California registry, the DDS data, which goes back to 1987 and has data from

every year on children who were referred in for services. In which case,

because it is a disability services registry, you are talking about children

who are on the more severe end of the autism spectrum. And as far as we

know, they are not actually seeing the kids who might be called Aspergers,

or on the more functional end.

So the interesting thing about this is, from the California data we actually

have a chance to investigate this question of how much of this is a real

increase, and how much of it can be explained away by ascertainment, by

changes in diagnosis, and by all of these other issues. And I think right

now, based on what we are seeing from the California data, is that it¹s not

really a question about whether this increase is real or not. The question

is, how much of it can be attributed to each of the many factors that one

might be interested in.

So how much of the doubling or - in this case tenfold increase over a decade

- how much of it is related to change in diagnosis, how much to

ascertainment? It looks like about 24 percent of the California increase can

be attributed to something like a change in diagnosis criteria. They are

beginning to use multiple diagnoses. So that children before, who were

listed simply as mentally retarded rather than autism - but they had both -

are now logged in with both. But that really caps out at around 24 percent.

There¹s probably another piece of this, which globally could be attributed

to ascertainment. But that caps out at around 16 percent, or something like

that. And when you put all of that together, you are still well below

explaining 50 percent of the increase.

So what does that mean? It means that, as far as I can tell, the burden of

proof is upon anybody who feels that there is NOT a real increase here in

the number of kids affected. Because all of the evidence we have up until

now says that, well there are what we could call ­ I wouldn¹t call them

Œtrivial¹ factors ­ but they are factors that are not related to incidence,

but would be simply related to prevalence, like ascertainment. But they

don¹t really explain away this huge increase.

This tells you that, you really have to take this very seriously. From

everything they are looking at, this is not something that can be explained

away by methodology, by diagnosis. Some piece of it can, but the whole thing

can¹t.

DK: So that leads to the 64 million dollar question: If there is an actual

increase in incidence year to year, wouldn¹t there necessarily also have to

be an environmental component to at least some cases of autism? In other

words, if it was 100-percent genetic, wouldn¹t you see relative stability?

TI: Yes. I don¹t think anybody is arguing that it is 100-percent genetic. I

mean, I think that there are just a lot of questions that this raises. And I

don¹t think in those terms, exactly, that it¹s either genetic or it¹s

environmental. From my perspective, it¹s almost always going to be both. And

the only question is: How do you nail down this interaction, how do you go

after it?

DK: If there is a true increase, wouldn¹t that be due to environmental

factors rather than genetic factors?

TI: I don¹t know that anybody would argue that, or that anybody has argued

that. There is no question that there has got to be an environmental

component here. The problem for us has been trying to find the right way to

get our hands around it, and to identify what that is most likely related

to.

I think, if you look at whatever that factor is, the way we tend to do this

in medicine is that you look for geographic clusters or temporal clusters.

And I don¹t think we haveŠ we have a few, but there are not very many good

geographic clusters. It could be that the Somali story in Minneapolis is an

important geographic cluster. It could be that there are clusters that have

actually been indentified in California. It¹s a little too early - and I

don¹t think the data are published ­ but I have seen some data in

unpublished form that would suggest that that may turn out to be the case.

These are new data, from work by Bierman, who is an NIH Pioneer

Awardee. He¹s at Columbia.

DK: Can you tell me where those clusters are in California?

TI: I don¹t actually know enough of the details. He presented his work here

about two months ago. So I can¹t tell you exactly where they are, but I can

tell you that they exist. And again, the explanation for that is not clear.

DK: Are you familiar with the Minnesota study of the Superfund sites and the

increased rate of ASDs in proximity to those sites?

TI: I don¹t know that. Where were those data published?

DK: I can get it for you, it was definitely peer reviewed. I don¹t have it

right at my fingertips, but it was a fairly recent study.

TI: You know, we have this stuff - I think it is from the CHARGE study -

that looked at organophosphate fertilizers in California and exposures in

the second trimester. I don¹t know if you¹ve seen that.

DK: I¹ve seen the pesticide study from the Central Valley.

TI: Yes, the pesticide study. And, I mean, it¹s pretty clear there¹s a

signal there. So, again, I don¹t think anyone argues the fact that there¹s

an environmental component here. The question is ­ there may be many, and

how do we get at these, and how do we identify them? Because the real goal

here is to think about prevention ­ what we are really after at this point

is driving the numbers in the opposite direction, so instead of a tenfold

increase, you can we see a tenfold decrease.

DK: And you think that is possible?

TI: I think that, if you could identify the factors that are really pushing

this, then I think you can begin to bend the curve. Here¹s the issue for me,

and I think I am arguing, probably, against the wave of the people that are

in this field. But I think that we¹re approaching autism as if it is a

single thing, as if it is a syndrome that will have one cause, one

treatment, and one explanation. I tend to think of it more in the way we

think of fever. I think this is a collection of many, many different

disorders. And part of the reason why you see so much polarization in the

community is because there is a tendency for people to think that their

experience is the same as everybody else with a child with autism.

It¹s quite believable to me that there are many children who develop autism

in the context of having severe gut pathology, of having autoimmune

problems, of having lots of other problems. And some of these kids really do

recover. And that is quite different from the autism that was originally

described in the 1940s and 50s - where it looks like you have it and you are

going to have it for the rest of your life. And at that point, it¹s a

disorder that is mostly manifest by these huge social deficits.

So I don¹t know if what we have here are 10 different disorders or 20

different disorders. What I think hangs up this field is the inability to

indentify all these different autisms ­ and it¹s very much where we were

with infectious disease 100 years ago, before we knew how to break this down

into multiple different disorders, different causes, different treatments.

That¹s why fever seems like the right analogy. In this context, I don¹t

think anyone would be able to argue very strongly that there is not some

subgroup that¹s going to be unrelated to genetics -- like those kids who

have Fragile X -- and some subgroups that may be much cleaner on the genetic

side, but will have some environmental exposure that triggers the disorder.

DK: And probably a genetic susceptibility?

TI: That hasn¹t been tracked down yet. But this is the cool thing and, I

think, something that many in the community don¹t understand. And that is,

in the last few months, or maybe year, we¹ve begun to develop the tools that

will allow us to get at this. And these tools are from this whole emerging

field of epigenetics, or epigenomics. And in this case you are not looking

at genetic sequence - which is what we¹ve been doing for the last decade -

but you¹re looking at how the DNA is bound up with all kinds of proteins.

That is largely affected by experience, or by environment. Some of it is

probably hardwired, but a lot of it has to do with exposures, particularly

early in development but even, as we are learning, even after birth

So what we are really excited about here, I think, is to be able to use

these new tools. And what has only happened in the last month or two is the

first whole genome epigenetics effort, where we have been able to say, ŒWe

can map this entire aspect of genomic biology, and it tells us what

someone¹s exposure history might have been.¹ It shows you effectively, or we

are hoping it will show us, where the scars might be from early exposures.

DK: Like a footprint?

TI: Precisely. And if that works, that would be a way in which, finally, we

would have the technology that says, ŒAh, this is somebody who was exposed

to organophosphates, or perhaps to some infection, or some autoimmune

process, or something like that, that could really make a difference in the

way the brain is developing.¹ And now they are signaling that I have to get

off this call.

DK: That¹s wonderful news. Let me ask you just a few quick questions more,

because I want to make sure I am clear. Let me ask you your personal

opinion: Is there an actual increase and is there an environmental component

to it?

TI: My personal sense, just from my clinical experienceŠ when I was in

training, I never saw a child with autism. So I went through four years of

training as a psychiatrist, including a rotation ­ a long one ­ through a

year of child psychiatry, and never saw a case. I got interested in autism

through work I was doing in basic science research, and I wanted to see

children with autism. I couldn¹t find them. This was in the mid-1980s, and I

had to find a specialty clinic at Children¹s Hospital in Washington, and I

got to see my first case there. And now I wouldn¹t have to go any further

than the block where I live to see kids with autism today. So if that¹s not

a change, I don¹t know what is. On a personal experience basis, I don¹t

think that¹s unusual. Most people who I¹ve trained with would say much the

same thing. So, of course, I think all of us are much more aware of autism

than we would have been 20 years ago. And again, I want to stress, I don¹t

think it¹s just a difference in awareness, I think that there is something

that we need to get our hands around here.

DK: Have you looked into the XMRV connection at all?

TI: Yeah, last thing. We are hot on that, and I wish I could tell you more.

All I can tell you is that we have an intramural program here which is kind

of our home team, which has seen about 400 kid with autism over the last

couple of years. And they have been looking at regression; they¹ve been

looking at recovery. They are very interested in a lot of the exciting parts

of this story ­ they jumped on the XMRV thing even before it was published.

I don¹t know how they got news about this, but they had already found

someone who could start to look into this.

DK: Dr. Mikovits?

TI: No, they were working with someone through the National Institute of

Allergy and Infectious Disease, who apparently had antibodies. And they sent

off serum, and I think they sent off CSF, cerebral-spinal fluid, one day

after the presentation. And I haven¹t seen the results, but they are really

hot on the trail here to see if there is any story. I¹ve heard that there is

something coming out from the group in Nevada, but I haven¹t seen the data.

Have you seen it?

DK: No. She announced on television that, in a small sample of ASD kids,

they found it in 40 percent.

TI: Yeah, that¹s the number I got. I have been trying to track that. There

is a paper that has been submitted, but I haven¹t been able to get it, and I

don¹t know what the data look like. But I think this is really interesting.

DK: I also understand a number of the Vaccine Court Omnibus cases are now

vigorously testing and finding it to be quite common. And there are rumors

that the parents are testing negative. Now, that¹s just a rumor, I can¹t

confirm it, but that would be an interesting development.

TI: So, of course, if we could just find a small group, and the opportunity

to begin an antiretroviral treatment regime, that could be terrific,

wouldn¹t it? I mean, that would be the kind of thing we¹re really looking

for in this field, is finding the subgroups that might have specific

therapies that would make a difference. And that¹s what we¹re missing. I

mean, frankly, we¹re just not where we want to be yet, and we¹ve got to be

able to break apart this spectrum disorder into its component parts and

identify who¹s going to respond to which interventions.

DK Finally, I know you have to go, will IACC reconsider vaccine research and

-- given this new data -- in particular Hepatitis B coverage? Because that

is something that changed significantly between 94 and 98.

TI: I don¹t know what they will do. You know, I chair the committee, but I

let them bring issues up. I am open to whatever they want. As you know, what

happened with the whole idea of having vaccine studies earlier in the year

was a majority vote. And, I think what you are going to see with this update

is that there is a recognition that we need to look at subgroups who might

be particularly responsive to environmental factors. And, you know, at the

end of the day, the IACC will have some sort of guide on what they hope to

have funded. But it¹s going to be up to the institutes, and the CDC, to

actually do the funding.

DK: Well, what is your opinion, or your response to the fact that in 1994

the Hep B birth dose was around 27 percent coverage, and by 1998 it was

above 90, I believe?

TI: Yeah, I don¹t know what to do with that, but I have to sign off here.

Maybe we can start there with our next conversation?

DK: OK great. I look forward to it in the New Year.

TI: Great. I look forward to talking with you then.

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