S2 E11: Physician-Scientist Herb Lachman, MD, Talks about Recent Genetic Observations in PANS: DNA Damage Response Genes

Dr Herb Lachman is a physician, behavioral geneticist, and professor at the Albert Einstein College of Medicine in New York City.  In his 44 years on the faculty, he has studied the molecular basis of schizophrenia, autism, and the broad category of neurodevelopmental disorders. More recently, a serendipitous inquiry about a major DNA Damage Response Gene, PPMD1, prompted Dr. Lachman to shift his focus to PANS (Pediatric Acute-Onset Neuropsychiatric Syndrome).

In the 11th episode of “Untangling PANDAS and PANS,” we discuss some basic information about genetics so that laypersons with an interest in this subject are able to assimilate his findings about DNA damage repair genes and their potentially significant role in neuropsychiatric conditions. These genes not only underscore the complexity of PANS and PANDAS but also point to the multifaceted interplay between genetics and the immune system at the intersection of the brain.

Genes are surely Dr. Lachman’s muse. He is quick to acknowledge that his sample sizes are small and biased, but they are nonetheless generating hypotheses to study more fully with larger data sets.

The simple question of why, given the ubiquity of Group A Strep, does only a small subset of patients develop PANDAS? Genetic mutations will very likely help to provide answers in the future.

To learn more about Dr. Herb Lachman's recent genetics findings on PANS, please refer to these two articles: 

https://karger.com/dne/article/doi/10.1159/000541908/914745/Ultrarare-Variants-in-DNA-Damage-Repair-Genes-in

https://pubmed.ncbi.nlm.nih.gov/35773312/

Disclaimer: The views and opinions expressed in this program are those of the speakers and do not necessarily reflect the views or positions of any entities they represent.

Credits: Music by Kingsley Durant from his "Convertible" album

To learn more about PANDAS and PANS and The Alex Manfull Fund, visit our website: TheAlexManfullFund.org

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Episode Transcript

Susan Manfull, PhD (00:07):
Untangling Pandas and Pans is a podcast
about two little-known medicaldisorders characterized by the
sudden and dramatic onset ofsymptoms such as obsessions and
compulsions, vocal or motor ticsand restricted eating behaviors
, and a whole host of othersymptoms following a strep or
other bacterial or viralinfection.

(00:29):
I have the privilege ofinterviewing some of the top
researchers and clinicians inthis rapidly growing area, known
by various names such asimmune-mediated neuropsychiatric
disorders, infection-associatedneuroimmune disorders and
autoimmune encephalitis, orsimply PANDAS and PANS.
My name is Dr Susan Manfull.

(00:49):
I am a social psychologist, theexecutive director of the Alex
Manfull Fund and the mother ofAlex Manfull, who died at 26
years old due to PANDAS, adisorder my husband and I knew
next to nothing about, certainlynot that our daughter could die
from it.

William Manfull (01:19):
This is episode 11 of Untangling Pandas and
Pans, recorded February 19th2025.

Susan Manfull, PhD (01:27):
Welcome everyone to the 11th episode of
Untangling Pandas and Panshosted by The Alex Manfull Fund.
I am Susan Manfull and I amhere with Dr Herb Lachman.
He is a physician, a behavioralgeneticist and a professor in
several different departments inAlbert Einstein College of

(01:48):
Medicine in New York City.
If you happen to find yourselfon campus, you may find him in
the Department of Psychiatry orMedicine, Genetics or
Neuroscience, and althoughpodcast listeners cannot see his
young appearance in spirit, Ican tell you unequivocally that

(02:09):
they belie the length of histenure at Albert Einstein.
He's been on the faculty for 44years.
That's a lot of time to doresearch.

(02:38):
He has long had an interest inthe molecular basis of
schizophrenia, as well as autismand neurodevelopment disorders,
studying pluripotent stem celltechnology, which is either
generated from patients or byengineering control lines using
CRISPR-Cas9 gene editing.
I will let him elaborate on that, but his work currently now is

(03:04):
devoted to and, thankfully forus, PANS, Pediatric Acute Onset
Neuropsychiatric Syndrome, whichis the broad category in which
PANDAS falls.

(03:50):
So I had the pleasure of meetingHerb through Rene Blanchard,
the chair of EXPAND, theEuropean Immuno-Neuropsychiatric
Association, where Herb serveson the scientific and medical
advisory board.
He was working on a paperabout ultra rare genetic
variants in PANS.
When I first met him, and helater presented that with Peter
van der Spek at our secondsymposium here in Portsmouth,
New Hampshire I was verygrateful to make his
acquaintance for many reasons,but not the least of which is
his very patient tutorials thathe has given me and I know many
others about his geneticresearch.

(04:11):
He keeps long hours.
I met with him Sunday morningat seven o'clock in the morning
because I think he genuinely andpassionately loves his research
and, as I alluded to above, hedoes generously give his time to

(04:31):
others like me to help usunderstand what I feel is a very
complicated subject.
However, he does manage to findtime to travel.
He's an avid traveler and Ibelieve that he is heading to
someplace in Mexico soon, that'sright.

(04:53):
And when not in his lab, he maybe out riding his bicycle.
I asked him where he rides andhe mentioned the rail trails
near his house in upstate NewYork.
When he's in the city, youmight find him in Central Park
or riding along the Hudson River.

(05:13):
He did confess that he nolonger rides in the 100 mile
races through New York City.
I have a feeling he could if hewanted to.
Anyway, he's a very interestingman and I'm very grateful for
the fact that he's here with ustoday.

Dr. Herb Lachman (05:36):
I'm impressed with myself.
That was a great, great intro.
Who is it?
Who is this guy?

Susan Manfull, PhD (05:52):
All right, well, we have a lot to talk
about.
The uh, the title that we cameup with is something to the
effect of making sense of ofrecent genetic findings in PANS
patients, and Dr.
Lachman will be talkingespecially about DNA damage
response genes.
But before we get started onany of that, I'm always curious

(06:17):
how researchers find their wayto the particular area of
research that they're in.
So how did you get interestedin the genetics of PANS?

Dr. Herb Lachman (06:30):
Well, it was really quite a set of
coincidences.
I was working on a condition.
I am working on a conditioncalled Janssen-DeVries syndrome,
which is due to mutations inthis gene called PPM1D, and
that's a gene that's reallyimportant for repairing DNA,
which I guess I'll talk aboutlater on.
And.
I got interested in that becauseI have a cancer genetics

(06:51):
background and the control ofDNA repair is a critical cancer
mechanism.
So I was always interested inDNA repair and when I found out
about Janssen-DeVries syndrome Igot some money to start
studying this problem by makingstem cells from patients' blood.
And those stem cells can beturned into neurons and the

(07:15):
brain the immune cells calledmicroglia and we studied the
molecular basis of what effectPPO1D mutations have on neuronal
and microglia function.
So that was the background.

Susan Manfull, PhD (07:32):
Before we go on, just so the listeners know,
could you just tell us how themanifests itself?

Dr. Herb Lachman (07:41):
So this is manifested by an intellectual
disability and severe anxietyand gastrointestinal problems.
They have very severelyrestricted eating, which is one
of the pans of symptoms, andthey generally don't have OCD.
And they're very, very nicekids.

(08:01):
They have a very nicedisposition like kids with
Williams syndrome.
But every now and then some ofthese kids have very severe
neuropsychiatric decompensationresembling pants.
That's in a very small subgroupof patients.
Most of the kids don't havethat, but a few do when looking
at the genetics of that.

(08:21):
But that part came later on howprevalent is that disorder?
well, just degrees is very rare.
Uh, I think they're about acouple hundred case reports.
So, uh, but it's underdiagnosed because not
everybody's getting dnasequencing done.
Uh and um, you know, theprevalence will will go up as we

(08:45):
do more sequencing.
Right now there are, you know,a couple hundred cases in the
Janssen-DeVries Foundationwebsite.

Susan Manfull, PhD (08:53):
Okay, so you found yourself interested in
that disorder because you wereinterested in the gene.

Dr. Herb Lachman (09:01):
Yes, because it's a DNA repair gene and I
have a very strong cancergenetics background and that
pathway is really critical formany, many cancers.

Susan Manfull, PhD (09:12):
Interesting.
Okay, so there you were,studying that.
How did you find your way overto PANS?
Well, renee emailed me.
Well, Rene emailed me.
Renee knew a family that hadtwo kids with PANS who had
mutations in the PPM1D gene andthey were found by Peter Peter

(09:33):
Van Der Spek from theNetherlands.
And she said what do we do next?
And he said, well, find theworld's expert on PPM1D and
that's not me, that's somebodyelse.
And if she had gone to thatother person he would have
dismissed the whole thing mostlikely.

Dr. Herb Lachman (09:55):
and I was open to hearing about the condition
and she told me about PANSpatients and how the families
were suffering because diagnosisis not in the DSM-5.
So it's largely dismissed bymost of the psychiatric
community.
And I heard these stories,these terrible stories of what
the families were going through,and I was really, really I hate

(10:18):
to sound Pollyannic I wasreally moved by these stories
and I felt that it was a socialjustice situation.
Some of these families werehaving nightmarish connections,
interactions with lawenforcement, with the education
system, and even if the parentswere being dismissed, the

(10:42):
parents know a lot about theseconditions.
They know much more thandoctors do and when a lay person
goes to a doctor armed withdata that they don't know, the
short reaction is to dismissthat and I thought that was
really unprofessional andanti-intellectual.

(11:02):
And I'm very open to hearingwhat parents and patients have
to say and I'm very happy toadmit that I don't know what's
going on and I'll find out moreabout it when I explore the
literature.
So I found that attitude to bereally, really dismissive and
even if you don't believe it,you don't have to dismiss what

(11:23):
the parents are telling you.

Susan Manfull, PhD (11:24):
Right, aren't you curious?
Yeah, yeah.

Dr. Herb Lachman (11:28):
Right, yeah, absolutely, you have to be
curious.
It's a fascinating conditionand even but even if it's not
true, it is true, but even ifit's not true, the parents need
to have some respect.
Now, 90% of the families, who,90% of the parents who are
dealing with PANS, who arelearning about it, who are

(11:48):
communicating with doctors andfinding healthcare professionals
and talking to each other,they're mothers.
And so you have this situationNot only do we have a layman or
layperson seeing a doctor, it'sa woman seeing the doctor.
So you have this patriarchalmentality which increases the
dismissiveness even more.

(12:09):
The doctors are more inclinedto dismiss a woman than they are
a man, although both sexes doget dismissed.
But I felt that was really aninjustice as well.
And Peter had sequenced a fewother families, a few few of the
kids with pans, and he told mewhat those findings were.
And immediately, uh, it becamepretty clear that we were

(12:32):
dealing with a very geneticallyheterogeneous condition, meaning
that there were many, manydifferent genes that could be
involved.
And that explains, or itexplained to me, my novice state
at that time.
That was like four or fiveyears ago.
I knew nothing about immunology, nothing about
neuroinflammatory disorders.
I knew nothing except for myown field.
But it became clear that thereason why there have been so

(12:53):
many problems in proving theeffectiveness of certain
medications like antibiotics andIVIG and so on, is because of
genetic heterogeneity.
That one patient might respondvery well because he or she has
an underlying genetic matrixthat is conducive to being
responsive to these medicationsand others do not.

(13:15):
They have different causes anddifferent responses to treatment
that could all have a geneticbasis.
And that makes it much morechallenging to prove that
certain medications work, but itexplains why, at least
theoretically, why you mighthave run into problems in
proving a particular medicationis effective.
So that launched me into thatand then I contacted a PANS

(13:42):
clinician in the US who had beensequencing a lot of his
patients, that's Dr Cifraletti,and we put together his cases
and other cases that Peter hadsequenced and a couple of cases
that I sequenced and we came upwith this story that was
published a couple of years agoand the most important

(14:02):
revelation in that study wasthat there were a couple of
years ago and the most importantrevelation in that study was
that there were a couple ofgenes that were involved in DNA
repair.
Ppmd was one of them and theother one was another gene
that's involved in that reactionin that response.

(14:24):
So my brain was focusing on onDNA repair, the first um
conference that I attended, uh,with you in 2022 that story to
tell and I asked her whether ornot her daughter had had had

(14:50):
genetic analysis done and shesaid yes.
I said what was the gene?
And she said ATM.
And ATM is connected to PPO andD and the other DNA repair gene
that we found in the firststudy.
When I heard that, my headexploded.
Wow so that's what, that's how,that's what that's meant to be

(15:14):
the DNA repair story.
That was your first, the firstconference that I attended, you
know, in New Hampshire back in2022.

Susan Manfull, PhD (15:22):
Wow, I'm so glad that we played a small role
at least in seven.

Dr. Herb Lachman (15:26):
I mean it was a big role For you to learn more
.
Well, you get people togetherand that's what happens.
That's the whole point ofhaving a conference, I agree.
It worked really well.
It worked very well for me.

Susan Manfull, PhD (15:37):
Yeah, I completely agree.
So it was at first the PPM1D.
The light bulbs went off.

Dr. Herb Lachman (15:48):
That was the initial little flicker.

Susan Manfull, PhD (15:50):
Yeah.

Dr. Herb Lachman (15:51):
And then ATM was the full blast furnace.

Susan Manfull, PhD (15:56):
All right, so we're going to get into talk
about those things, but Ithought maybe we should hear a
little bit about how genemutations are identified, so
that when you go on to talkabout this, we can follow you.

Dr. Herb Lachman (16:12):
Yeah, okay.
So the first thing is, when wesay we have a gene for an
abnormality, for a condition,it's not the gene per se.
Everybody has the same genes.
It's a mutation in those genesthat are affecting gene function
.
So if I say that the PPOMD geneis involved in Janssen-DeVries
syndrome and a small subgroup ofPANS, it's not the gene per se.

(16:34):
It's a very unique mutation inthat gene that's doing that so
when we say genes we meanmutations in those genes.
And the way we analyze genomesnow is through something called
next generation sequencing.
Now the first human genome.
The human genome is gigantic.
It's got 6 billion DNA letters6 billion compared to bacterial

(17:01):
species or small microbes,viruses and bacteria, which
contain a million or so.
So the human genome is reallygigantic and sequencing is a
real challenge.
And the first sequence, thefirst DNA sequence, was
published in 1990 or so.
That was the culmination of theHuman Genome Project.
It cost $10 billion for the beefor that first sequence and it

(17:27):
took 10 years.
The insurance company will notpay $10 billion for a DNA
sequence that was carried outusing the classic technique of
DNA sequencing which wasdiscovered by Fred Sanger back
in the 1970s, which earned him aNobel Prize.
So that's a sequencing strength.

(17:47):
It's really elegant.
I'm not going to go intodetails.
I mean it's only poetry toscientists, but it is a really
beautiful technique.
Next-generation sequencing usedthat technology, at least at
the beginning, and really rampedit up to the point where you
can sequence the entire humangenome in a couple of weeks for

(18:08):
a few thousand volts whoa sowith next generation sequencing.
We people have been sequencingtens of thousands, hundreds,
hundreds of thousands of genomesand we get this gigantic
database of dna variation acrossthe human genome.

Susan Manfull, PhD (18:22):
So so when you order DNA, yeah.
Well, what year did that beginwhere the price went down so
much?

Dr. Herb Lachman (18:30):
That's been going down steadily over the
past decade and the cost hasbeen halved every couple of
years for the last decade.
Now, I would say that startedback in about 2012 or so.
Give or take a couple of years.
For the last decade.
Now you know it's.
I would say that started backin about 2012 or so.
Give or take a couple of years.
Okay, and some very cleverscientists figured out other

(18:52):
ways to sequence dna rapidlythat doesn't rely on the sanger
technique.
So there are many, manydifferent techniques, but uh,
that one, uh, they're allcollectively called
next-generation sequencing.
The bottom line is that it'scheap and relatively easy to
sequence the DNA.
So when a kid comes to a doctorwith, let's say, autism or some

(19:13):
neurodevelopmental disorder,they get some basic DNA analysis
done.
They don't get the fulltreatment.
They don't get the full, wholeexome, what we call whole exome
sequencing or whole genomesequencing.
They usually get a panel.
If a doctor writes down on areport this kid has autism,
they'll analyze a panel of genes, only a fraction of the 25,000

(19:38):
or so genes in the genome.
That's what insurance companieswill pay for.
Basically they use the samekind of technique, but they only
analyze a small fragment of thepossible genetic variations.
It is really really hard to dothat, to analyze the entire
genome.
It's very hard on my end tolook at the mutation to say you

(20:01):
know what's going on over here,is this relevant or not?
So the companies to cut backcosts?
What's going on over here?
Is this relevant or not?
So the companies to cut backcosts?
They only analyze panels ofgenes.
Generally, when we sequence itfor research we do a much more
extensive analysis and somecompanies will do it also.

(20:21):
Patients pay out of pocket.
Some insurance companies willpay for the more extensive
genetic analysis but by andlarge most families will get
back some kind of panel of genesrelevant to the kid's disease.
And unfortunately the geneticsof PANS is complicated.
It doesn't exist yet.
It only exists in my two papersand in my brain.

(20:41):
So the company is not sayingwell, we need to analyze her
blackened jeans.
It's not.
It's not there yet.
So that's why the typical panelanalyses that are done are
suboptimal.
It's the best you can do rightnow.
But it is suboptimal.
It doesn't tell you the wholepan genetics story as I think it

(21:02):
exists.

Susan Manfull, PhD (21:04):
Okay, so last, I forgot, I thought I
would do this at the end.
But since we're on this subject, if a parent does want to have
some genetic testing maybe notthe whole genome sequencing, but
something that would bevaluable in understanding the
genetic picture of their childor the young adult of his or her

(21:28):
James what would you recommend?

Dr. Herb Lachman (21:34):
Oh, that's really hard to say.
I recommend the full analysisbut you can't get that insurance
to pay for that Right now.
In the US, standard care of anykid who has either autism, a
neurodevelopmental disorder oran immune deficiency they'll get

(21:54):
the panel for immunedeficiencies.
If they have autism they'll getthe autism panel and that's
standard care plus separateanalysis for the fragile X,
which can only be analyzed usinga separate technique, and they
can have a chromosomal studyalso done to look for what we
call copybearance.
So it's a whole slew ofdifferent genetic studies but

(22:20):
most kids will have a copyvariation analysis study and a
panel analysis and analysis forfragile X, which is the most
common cause of autism andintellectual disability, and if
the doctor is savvy enough theycan argue for doing a more

(22:41):
extensive analysis.

Susan Manfull, PhD (22:42):
Okay, so is there.
Maybe I misunderstood.
Is there a particular name forthat panel?

Dr. Herb Lachman (22:50):
Well, it depends on the company that the
doctors are familiar with.
So if you go to Invitae or youknow, they have their own
different names for the panelsand because the costs are coming
down.
Uh, it's much, much easier toget, uh, it's cheaper to get
what we call exome sequencingdone, which is an analysis of
the genes that code for proteinsabout 25 000.

(23:13):
Of those, the panels typicallyanalyze 500,000, which is only a
small fraction of the 25,000that exist in the genome.
But with costs coming down,it'll become very cost-effective
to do a much more extensiveanalysis.

Susan Manfull, PhD (23:28):
And we can talk about this later, but of
course you would need someone toread that panel, correct?

Dr. Herb Lachman (23:35):
Well, the companies analyze the data.
So what they do is, if youwrite down on the patient
summary what the kid has autism,learning problems, dyslexia,
adhd they will analyze the genesthat are known likely to be
involved in those conditions.

(23:56):
There are a thousand differentautism genes that have been
published, so they have a wholepanel of genes that they known
likely to be involved in thoseconditions.
There are a thousand differentautism genes that have been
published, so they have a wholepanel of genes that they can
analyze.
And what they do is they lookfor variants that are
potentially pathogenic and theyhave different algorithms that
are used to try and figure outwhat variants should be looked

(24:18):
at.
One of the major filters is tolook for variants that are very,
very rare.
So in human genetics, incomplex traits, which is all
psychiatric disorders, you havecommon variants and rare
variants, and the rare variantsare the ones we go after because
those are the ones that aremore likely to have a strong

(24:40):
effect on biology.
So one of the first filters isthey're only going to look at
mutations where the frequency ofthe mutation is present in less
than one in a thousand kids.
So you'll miss the other ones.
But it's very hard since, let'ssay, you have a mutation that's
found in one in every hundredpeople.
Well, that far exceeds thenumber of cases.

(25:02):
So the significance of thatclinically really can't be
figured out from a single case.
Those studies to look forcommon variants are really
research studies.
It's a whole different type ofanalysis but for patients, for
the whole exome sequencing, thewhole genome sequencing, the
first filter is to only look formutations that are present in

(25:23):
less than one in a thousandcases.
And then there are differentalgorithms that the companies
use to determine thepathogenicity of those mutations
and that's.
You know, you can't test, youcan't do biological tests on
every variant to say, oh, thisvariant is doing X, y and Z.
It's impossible, it's notpossible to do that.

(25:45):
So you have these computeralgorithms to say, okay, this
mutation exists and it lookslike it's pathogenic or likely
pathogenic or benign.
So that's the next filter.
It goes through all those andit'll report to the doctors who
order the tests.
You'll get a list of variantsand it'll say either a variant

(26:08):
of unknown significance, a VUS,it'll say pathogenic or likely
pathogenic and it will notreport benign variants,
pathogenic or likely pathogenic,and it will not report benign
variants as predicted by thedifferent tools that are used to
assess functionality.
And again, this is a predictedfunctionality and not a true
biological functionality.
That can only be done in thelab and that cannot be done on

(26:37):
all the variants that are found.
A very small minority ofvariants are scrutinized on the
biological level because it'stoo hard, too expensive.

Susan Manfull, PhD (26:45):
This is very complicated.
So that's what you essentiallydid in that first paper with Dr
Trifiletti and a whole slew ofother people the identification
of ultra-rare genetic variantsin PANS using exome and whole

(27:15):
genome sequencing the.
You found two classes.

Dr. Herb Lachman (27:21):
That's right right.

Susan Manfull, PhD (27:22):
And one you labeled synaptic function and
the other the immune system.

William Manfull (27:29):
Right.

Susan Manfull, PhD (27:30):
Can you elaborate a little bit on that?

Dr. Herb Lachman (27:32):
and then we can do the DNA repair we can get
the DNA repair.
So a lot of kids with PANS haveunderlying autism or
neurodevelopmental problems andor immune deficiencies a very,
very large fraction.
And what we're finding in someof those genes may not be

(27:55):
actually PANS genes per se orautism regression genes per se.
They're genes that these kidshappen to have and they have as
one of the manifestations of theillness they have PANS.
Some of the genes that we foundlikely are in that category.
So the immune genes are theones that affect the immune

(28:15):
system.
I mean, I can't go into.
The immune system is like thesecond brain.
It is amazingly complicated.
The most important, the mostcomplicated structure on the
planet is the human brain andthe second is the human immune
system and of course both areinvolved in PANS, which makes it
an ultra complicated disorder.
And the immune system is just athing of beauty, and again I'm

(28:42):
going to go down this nervetrack if you let me, so don't
let me.
It is a thing of great, greatbeauty and I wish people could
appreciate how that's how itworks.
I'll say one thing about theimmune system.
We have the ability to producetens of millions of different
antibodies to pathogens thatexisted in the past, to

(29:04):
pathogens that will come to usin the future.
We have the ability to producetens of millions of different
antibodies.

Susan Manfull, PhD (29:11):
We only have 25,000 genes.

Dr. Herb Lachman (29:14):
How is that possible?
What happens is that you havethe, the the genes that make
antibodies are modules andbasically you have recombination
occurring.
You have these modules uh,being expressed randomly in in
immune cells during development.
Uh, that will tell this b cell,this immune cell, this antibody

(29:37):
immune cell, thisantibody-producing cell, you are
only going to produce thisantibody and that antibody is
due to the fact that thesemodules got rearranged during
development.
So you might have a small set ofmodules, a handful of modules,
but you have a near infinitenumber of possible combinations,
and those combinations aretotally random.

(29:59):
So we're born with thisrepertoire of B cells, the
antibody-producing cells thatcan respond to literally any
foreign substance.
So it's this modular formatthat allows us and other animals
to make antibodies toeverything, even though we only
have a small number of genes.

(30:19):
So that was a Nobel Prize inthe 1970s.
And the same thing is true forthe other part of the immune
system, the T cells, which haveT cell receptors.
That also, you can make tens ofmillions of different T cell
receptors from a small handfulof genes through this random
recombination that occurs duringdevelopment.

Susan Manfull, PhD (30:40):
So we have that situation Anyway yes, so
that helps me understand whenpeople say they simply haven't
perhaps haven't identified theantibody for this particular
disorder.
I mean, if there's so many outthere antibody for this

(31:00):
particular disorder.

Dr. Herb Lachman (31:00):
I mean, if there's so many out there?
Well, not exactly.
So the antibodies that areproduced are produced to respond
to a pathogen, theautoantibodies that are produced
autoimmune disorders are due toa during development.
You have these cells that turnoff, that knock out those T
cells and B cells, thoseantibody-conducing cells and

(31:21):
those T cells.
It knocks out those thatrecognize self-antigens, the
proteins that we have in our ownbodies and in autoimmune
disorders that process escapes.
So you lose the ability tocontrol the attack against your

(31:42):
own body.
So those antibodies and thereason why those antibodies are
hard to find is not because ofthat process that I mentioned
earlier, it's due to you know,it's very hard to find
antibodies that are specific fora particular protein or antigen
.
So, it's a somewhat differentway of looking at it.

(32:02):
That's a tech issue Findingantibodies or not.
Finding antibodies, which isvery, very important in
diagnosing these conditions, isdue to how much autoantibody
somebody is producing.
How good are the tests.
A whole slew of differentfactors go into why, or why not,

(32:25):
you might find an antibody.

Susan Manfull, PhD (32:29):
Okay, interesting, all right.
So you identified the twodifferent classes of genes and
your curiosity was piqued,especially, I think I'm
gathering, from the DNA damage.

Dr. Herb Lachman (32:47):
Right right.

Susan Manfull, PhD (32:48):
So do you want to tell?

Dr. Herb Lachman (32:49):
us.
Yeah, before I get to that, letme just mention one thing about
the neuronal genes.
A lot of the kids in the firststudy had underlying autism and
it turns out that some of thegenes that we found the first
study had had underlying autism.
And it turns out that some ofthe genes that we found really
they're really autism genes, butthose genes, for some reason,
reasons we don't, we don't knowyet those genes, uh that cause
autism are.
Those kids are more prone tohaving some kind of immune

(33:13):
attack that leads to pans orregression in autism, attack
that leads to PANS or regressionin autism.
One of them was SHANK3.
Shank3 is a very commonlymutated gene in autism and
patients with SHANK3 mutations,for many, many studies, are much

(33:34):
more prone to aneuropsychiatric decompensation
following infection or somenon-infectious stressor, and I
mean a physical stressor, not anemotional one.
So some of those genes thatcause autism are more prone to
an acute breakdown mediated byimmune cells, and Shank 3 is the
best example of that.
So what we found?
There were kids with Shank 3mutations that had autism, that

(33:58):
also had autism, uh, that alsohad it and had pants okay, so so
so dna repair dna repair right

Susan Manfull, PhD (34:08):
okay, so we had these two and I guess the
reason I want to focus on onsomething like that.
As you said at the verybeginning, this is such a
complex, heterogeneous kind ofdisorder that I think it would
it behooves us to focus on onepart now and then maybe you'll
come back and talk about anotherclass of genes that are-.

Dr. Herb Lachman (34:35):
Other classes now.
Other classes, okay, moreclasses now.

Susan Manfull, PhD (34:37):
Other classes Okay.

Dr. Herb Lachman (34:39):
More than one?
Yeah, more than one, okay.
So, so my brain is tuned intoDNA repair.
Okay, I went to your conferenceI met the parent of a child who
had an ATM mutation and then Istarted.
Then I started to do my ownsequencing and After the
conference A lot of familieswere sending me their DNA
reports, started to do my ownsequencing and after the
conference a lot of familieswere sending me their DNA

(35:00):
reports and they, the doctors,really couldn't make any sense
of it.
So I was looking at the reportsand I was sequencing my own, my
own samples now and doing amuch more extensive analysis of
the other, of the genetics, thanwhat the drug companies, what
the genetics companies, wereproducing for the families.

(35:22):
I was really diving deep intothe genomes.
I spent, I would say, every oneof these genomes that I look at
.
It takes me roughly 10 to 20hours to analyze them.

Susan Manfull, PhD (35:39):
Oh.

Dr. Herb Lachman (35:40):
Yeah, so I do it almost one by one because I'm
all time.
I can't just rely oncomputation.
I need to see the genes and geta feel for it, and I only get a
feel for it when I look at thelist of genes and something hits
in my brain.
I do the bioinformatics too.

(36:02):
I do the computations.
You have to do that, but I needto feel the genes.
So that's why it takes me avery long time and I dig deep
into the potential functionalityof these genes using tools that
are not used yet by thesegenetic companies, and those
tools help to inform whether ornot these mutations that I'm

(36:23):
finding are relevant.
So it takes me a long time tolook at this Again.
I'm going to go down the nerdtrail here.
The most fun I have in life, oneof the most fun things I do, is
getting these DNA sequencingdata and looking at the thousand
genes that come back after wedo our filtering and looking at

(36:44):
them and trying to figure stuffout.
And I drop everything.
When I have a sequence on mycomputer, I drop everything to
look at it, because to me it'sfun.
Believe it or not, it's reallyfun.
So I really like doing that.
That's why it takes me a longtime.
I really look at it and reallytry to get a feel for the genes

(37:06):
that you can't get when you plugin the genes into some kind of
database.
I do that too.
You have to do that.
But I have to feel the genes.

Susan Manfull, PhD (37:18):
Feel the genes I have to feel.

Dr. Herb Lachman (37:19):
the genes Feel the genes I have to feel the
genes.
That's right.
So, doing that, we ended upfinding a bunch of other genes
where we had pathogenicmutations or likely pathogenic
mutations in other DNA repairgenes, and that led to our
second paper, second paper andthat resulted in the

(37:41):
identification of nine or 10other genes that separated into
two different DNA repairpathways.
One of them clustered aroundthe process that PPMD and ATM
work at, which is the so-calledP53 pathway, and the other one
revolved around what's calledthe Fanconi anemia complex
pathway.
All DNA repair genes and I have, I would say, another dozen

(38:04):
waiting in the wings.

Susan Manfull, PhD (38:05):
Another how many?

Dr. Herb Lachman (38:07):
Another dozen genes that I haven't published
yet.
So we have that second paper,we have these two families of
DNA repair genes and one reallyimportant caveat in all this is
that many of the mutations wefind, you find them at very low
frequencies in the population.
They do exist and it's reallyimportant to do an analysis

(38:31):
where you compare the number ofcases you have that have these
mutations with what's found inthe general population and when
we do that we give us some kindof significant number to satisfy
the statisticians and thegeneticists.
Only the ATM gene comes backsignificant.

(38:54):
The other ones don't, and thereason for that is that our
sample size is too small.

Susan Manfull, PhD (39:00):
Okay, so the PPM1D, doesn't come back.

Dr. Herb Lachman (39:04):
significant no it does not, it is.
It clearly is.

William Manfull (39:10):
This is why what I mean.

Dr. Herb Lachman (39:12):
I feel the genes.
The significance value is greatto have and it is important to
have to convince otherscientists, but for me I need to
.
There's no question that thisis a DNA repair gene and there's
no question that a smallsubgroup of patients with
Janssen-DeVries syndrome have anacute neuropsychiatric

(39:33):
decompensation.
There's no question about that.
But I don't have the actualnumbers to prove that yet.
That will require a very, very,very large and expensive study
to accomplish.

Susan Manfull, PhD (39:48):
Which, of course, would be difficult with
this population, since it'srelatively small.

Dr. Herb Lachman (39:53):
Yeah, Well, PANS is not in DSM-5.
So it's a clinical diagnosis.
Those of us in the PANScommunity believe in it, but
those who fund us may not.

Susan Manfull, PhD (40:08):
So you said that these genes occur in those
who have cancer or some types ofcancer?

Dr. Herb Lachman (40:18):
So the P53 pathway this goes back to.
I was an early researcher onP53, it turns out P53 is the
most commonly mutated gene incancer by far.
When you have a defect in DNArepair in a cell, that cell
doesn't fix DNA breaks, whichoccur naturally as cells divide.

(40:39):
And the more DNA breaks youhave, the less able you are to
repair those breaks, the morecancerous the cell becomes.
The cell loses its control overgrowth and becomes cancerous.
And p53 is the number one genethat is mutated in cancer.
Now those mutations occur afterfertilization.

(40:59):
They occur in our bodies.
They're called somaticmutations.
They're mutations that occur bychance in our bodies as we age,
as we expose ourselves tocancer-causing DNA breakage.
So everybody alive hasthousands of mutations that

(41:19):
we've accumulated in ourselvesrandomly because of mistakes
that happen when cells divide,when we go out into the sun too
long, when we eat carcinogenicor smoke carcinogenic agents.
Those agents increase thenumber of DNA mutations that
occur.
So DNA mutations occurring afterfertilization, so-called

(41:42):
somatic mutations, are the majorpathway involved in cancer.
Cells lose the capacity tocontrol cell growth because of
mutations in genes that regulatethat process and regulate P53
DNA repair.
That's one of the major cancerpathways.
Now, these kids that we havewith PANS, they're born with

(42:03):
these mutations and thosemutations.
When they happen duringdevelopment, when they happen at
fertilization or fromtransmission from a parent, or
de novo during ergo spermformation, those mutations lead
to neurodevelopmental problems.
Some kids who have thesegermline mutations in those

(42:26):
genes that cause autism or otherneurodevelopmental problems end
up having a higher risk forhaving cancer.

Susan Manfull, PhD (42:33):
Oh, interesting.

Dr. Herb Lachman (42:35):
And we don't know yet about the PPM1D in
these kids with and we don'tknow whether the cancer risk has
increased in those kids.
There may be somethingdifferent about being born with
these mutations having thatmutation existing at
fertilization as opposed tohaving it as part of this
stepwise conversion of a normalcell into a cancer cell when
these mutations occur afterdevelopment.

(42:56):
Stepwise conversion of a normalcell into a cancer cell when
these mutations occur afterdevelopment.
So there may be somedifferences there.
We don't know yet.

Susan Manfull, PhD (43:08):
Maybe this is a silly question, but how do
you know that the children wereborn with those genes?

Dr. Herb Lachman (43:17):
Well, because they have them in every cell in
the body.

Susan Manfull, PhD (43:20):
Okay, okay.

Dr. Herb Lachman (43:22):
That's one.
So in 95% of the kids have ade novo mutation, meaning that
the parents don't have it andyou can analyze parents, they
don't have it, the kids have itand they have it in every cell.
Some kids have mosaicism forthat, so half the cells might
have the mutation and half thatdon't.

(43:42):
And that happens.
That happens, uh uh.
That mutation occurs afterfertilization, but typically the
normal mutations occur duringegg or sperm formation and it
leads to that mutation happeningin every cell in the body.
But if it happens afterfertilization, in the first or
second cell division afterfertilization, then the kid

(44:03):
becomes a mosaic for thatmutation and every now and then
the parent, who's relativelyasymptomatic, will transmit one
of these genes to theiroffspring.

Susan Manfull, PhD (44:17):
Okay, so you've discovered the DNA Right.
Genes are culpable, perhaps.
Right right In this disorder.
So what else do we need to knowabout how this leads to the

(44:37):
symptoms?

Dr. Herb Lachman (44:39):
Okay, well, that's the key question now.
So we postulate that mutationsin DNA repair can activate the
part of the immune system that'salso activated by viruses and
bacterial infections, and thisoccurs in many auto inflammatory

(45:02):
disorders.
It's lupus.
These pathways are activatedwhen DNA repair is damaged and
it activates the immune pathwaythat leads to to interferon
production, which is anantiviral cytokine, and it leads
to the activation of severalother cytokines.

(45:22):
We think that's happening andwhat we're doing now is we're
studying cells with the PPODmutation to see how it's
affecting those immune pathways.
How it's affecting those immunepathways and I think that our

(45:44):
initial hypothesis might nothold true for PPOD.
There are other parts of thecell that are damaged as a
result of abnormal DNA repair,but the common theory is that
abnormal DNA repair, either inthe nucleus of the cell or in
the mitochondria mitochondrialDNA, abnormal DNA repair will
lead to the leakage of DNA fromthe nucleus and the mitochondria

(46:10):
into the fabric of the cell,the cytosol, and that will act
as if the cells are fooled intothinking that they're being
exposed to a virus, so it'llactivate that pathway.
So if you already have thatgoing on innately because of DNA
repair problems and then youget hit with, let's say,
sars-cov-2, which causesCOVID-19, the combination of the

(46:32):
two of them might trigger aninflammatory response.
That's the hypothesis.

Susan Manfull, PhD (46:38):
Because it's sort of overloaded, if you will
.

Dr. Herb Lachman (46:40):
Yeah, exactly yeah so you have the natural
immune pathway activated byviruses, then you have this
unnatural one, activated by,caused by abnormal DNA repair,
and the two of them togethermight cause kind of an avalanche
of activation, of theover-activation of the immune
system.

(47:01):
That's one possibility.
It's much more complicated thanthat.
I mean, this is just one ideaand we're doing that in the lab
now to try to find out whetherthose immune pathways are
activated.
But other things can happen inthe cell as a result of abnormal
DNA repair, Many but otherthings can happen in the cell as
a result of abnormal DNA repair.
Many, many other things canhappen, which I mentioned in the

(47:24):
second paper, thanks to JanetCunningham, one of the
co-authors, who pointed out thatother things can happen when
you have an abnormal repair ofDNA.

Susan Manfull, PhD (47:38):
Do you want to talk about any of that?

Dr. Herb Lachman (47:44):
about what?

Susan Manfull, PhD (47:45):
Some of the other things that might happen.

Dr. Herb Lachman (47:47):
Oh yeah, yeah, so one of the things that can
happen when DNA damage.
First of all, DNA damage occursall the time In everybody's
cell.
Every time a cell divides,every time we go out in the sun,
every time we get exposed to aninfection, DNA damage occurs
and the DNA repair pathway fixesthat DNA.
It's not perfect.

(48:08):
It's very good.
If it wasn't very good, we'dall have cancer by the time we
were 10.
We have a very good way ofabout 100 genes that repair DNA.
It's really an importantprocess.
We fix the DNA.
When we can't fix it, the cellsget damaged.
They can get damaged andproduce an overactive immune
system.
They get damaged and becomesenescent, meaning they can't

(48:30):
divide anymore.
They become damaged and causemitochondrial dysfunction.
And also they can cause adefect in the ability of genes
to make proteins.
The purpose of genes is thatthey code for proteins.
The purpose of genes is to theycode for proteins, so DNA
damage can cause a problem inthe ability of cells to produce

(48:56):
proteins.
DNA expression is the term andthere are several other pathways
also, and these are allpossibilities and we're
exploring all those phenomena inthe context of PPM and DG.
It's really challenging.
It's a very, very hard set ofexperiments to do, really,

(49:17):
really hard.

Susan Manfull, PhD (49:19):
So what are the implications in terms of
treatment or prevention?

Dr. Herb Lachman (49:25):
Okay, that's a great question.
That is the key question.
I'm primarily a researcher, butI'm also an MD, very interested
in patient care and translation, and right now the treatments
for PANS are really suboptimal.
Some kids respond toantibiotics, non-steroidal
anti-inflammatories, ivig.

(49:46):
Some kids could put on potentimmune suppressors like
Rituximab, and they may have agood response.
They may not.
What our studies are showing is, if it's true that the pathways
that are being activated arethe same immune pathways that

(50:07):
are activated by viruses andcertain bacteria and it's all
leading to interferondysregulation or dysregulation
of several other cytokines, thenit's possible that those
cytokines can be targeted bysome of the great medications

(50:28):
that are being used now to treatautoimmune disorders.
This is a very, very tough roadthat we're on for many, many
reasons.
One is that this disease occursin kids and you can't just give
these potent immune modulatorsto kids without having very,
very solid evidence that it'sgoing to do any good.

(50:49):
And that's only going to happenwhen we go beyond the basic
science stuff that I'm doing andactually do clinical studies uh
, maybe even in animal models toshow that these immune
modulators can can interrupt animmune medimediated behavioral
problem.
It's a very, very long haul.
No doctor is.

(51:10):
One of the possibilities is aninterferon inhibitor, for
example, that's being used inlupus.
It's a new treatment for lupusand people with lupus don't
respond to more conventionaltreatment.
Nobody is going to prescribethat potent interferon inhibitor
to a kid without really reallystrong proof that it's going to

(51:36):
do any kind of good.
So the burden of proof is on usto show that these pathways are
being activated, and thenthere'll be a burden to show
that it works in animal modelsand clinical trials.
I mean, we're talking about avery long haul and I wish I had
an easy answer to the parents.
I really don't.
There's no easy answer.
Some of the genes we're findingare saying you know something?

(51:59):
Yes, this kid could respond to,let's say, an interferon
inhibitor, or they could respondto another inhibitor of the
immune system.
There's so many different drugsmonoclonal antibodies that are
being developed.
I feel my bones that some ofthese kids might respond, but we
can't do it right now.

(52:20):
It's not ethical because thesekids they're kids and they're
unproven medications and theseare drugs that have really
potentially dangerous sideeffects.

Susan Manfull, PhD (52:29):
So we're a ways away from finding some
treatments, but it sounds likeyou're collecting data.
That's promising.

Dr. Herb Lachman (52:42):
Well, which I think is very promising, and
there are some doctors out therewho are really really brave and
parents who are very, verybrave, and they're actually
trying some of these medications, some of these immune
modulators.
I couldn't do it.
Maybe that's why I'm on thebench and not with patients.
I just can't do it.

(53:04):
I'm a half-less-empty kind ofperson and I'm always't do it.
I'm a half less empty kind ofperson and I'm always thinking
about complications.
You give this kid something andhe or she is going to come down
with a fatal fungal illness.
That is my thought process.
But then you have doctors whoare much more aggressive and
parents who are willing to trythese treatments experimentally,

(53:24):
and maybe the answer will comewith them, as opposed to a very
conservative therapeuticnihilist like me who really
follows the do-no-harm rule ofmedicine.

Susan Manfull, PhD (53:37):
Well, I think so much depends on the
severity of the disorder too,and how many other approaches
they've tried that have not beensuccessful.

Dr. Herb Lachman (53:47):
There will be some cases where the kids are
really in bad shape, theyhaven't responded to IVIG, they
haven't responded to rituximab,and then you say what do we do
next?
And that might be the next stepand you might have kids there
might be some kids who actuallyhave an autoimmune,
autoinflammatory disease thatyou would treat with these

(54:09):
medications.
That is a strong possibility.
So they have the indication totry these medications like an
interferon inhibitor becausethey have lupus or something
else or severe inflammatorybowel disease and they have PANS
too, and then you can study thephysical disease and see what

(54:30):
effect that has on theneuropsychiatric bubble.
That, I think, is going to bethe fastest route to showing
that these things work.
They're going to be tested inthese kids for the inflammatory
disorder and as a bystanderwe're going to study the effect

(54:52):
it has on behavior.
So to do this kind of work in akid you need approval by the RV
and you would not be able toget approval for these drugs to
treat PANS or regression inautism, which is kind of the

(55:14):
same family of PANS,neuroinflammatory disorder at
the effect of these medicationson refractory Crohn's disease,
refractory lupus, and if the kidhappens to have and that's how
you get the IV approval and thenyou piggyback the observations

(55:38):
you'd make on the effect it hason the neuropsychiatric problems
.
And this actually came out atthe last conference, at the last
Alex Manfull conference.
We had this little get togetherand I you know I'm blocking his
name, but he actually is tryingto do that in you know he's
piggybacking theneuroinflammatory problem on

(56:00):
back, on the back of a somaticor systemic inflammatory
disorder, which is a reallybrilliant strategy.

Susan Manfull, PhD (56:09):
So there is the research that Kyle is doing.
There was a man in his 50s whohad refractory OCD for years I
mean 30 years, over 30 years,and he also had psoriasis.

Dr. Herb Lachman (56:30):
Yes, right.

Susan Manfull, PhD (56:32):
And he took Cosentix for the psoriasis and
it was very successful.
But it was also very successfulin completely removing his OCD
symptoms.

Dr. Herb Lachman (56:44):
Right.
So that's another brilliantobservation.
And it turns out that theimmune pathways that are
overactive in psoriasis also areoveractivated in the mouse
model appendix.
That's interleukin-17.
And we're studying IL-17 andinterleukin-17 in my lab, thanks

(57:05):
to those pioneering studies.
So yeah that kind of thing.
Those are really really greatstudies and that is going to be
the way we're going to crackinto using these medications in
kids who have refractory PANS.
That'll happen much faster thandoing studies on the PANS
itself they're doing studies onthe pants itself.

Susan Manfull, PhD (57:32):
So um there are other studies that show a
connection to dna repair and andregression.
Uh like down syndromeregression.
Can you talk a little bit aboutthat?

Dr. Herb Lachman (57:42):
yeah, so down syndrome regression is is the uh
, I think it is the paradigm foran immune-mediated
decompensation About 15%, that's1.5%, of kids with Down
syndrome.
Adolescents with Down syndromewill have a severe regression.
These kids are usually verysocial.
Some of them have achieved ahigh level of independence and

(58:05):
regression causes them to revertback to a much more
underdeveloped state and theycan develop psychiatric problems
that they didn't have before.
They have cognitive decline.
That's down syndrome regressionand there's evidence that this
is immune-mediated because thesekids do respond, or these
adolescents do respond, toimmune modulators like

(58:26):
prednisone or IVIG.
And a study came out a fewmonths ago looking at genes that
might separate thoseindividuals with Down syndrome
who regress from the other majorpopulation of people who don't
regress.
And Down syndrome is due tothree copies of chromosome 21,

(58:48):
which actually has some immunegenes on it.
But they found eight genes thatwere not linked to separate
chromosomes.
They found eight genes that hadmutations that were associated
with regression.
And among those eight genes werefour that affected same

(59:14):
pathways.
We predict to be affectedwithout DNA repair genes.
That's the interferon pathway.

Susan Manfull, PhD (59:21):
And three of those genes.

Dr. Herb Lachman (59:22):
Three of those four genes are DNA repair genes
themselves.

Susan Manfull, PhD (59:25):
It's fascinating.

Dr. Herb Lachman (59:26):
So when I read that study I I you know I
always have my doubts that I'mnot.
I've made so many mistakes inmy life.
Anytime I have a greatdiscovery.
Only a couple have reallypanned out.
So most of the time I make Ihave a finding and it doesn't.
It doesn't pan out.
And when I saw that study Irealized that I was on the right

(59:46):
track.
And one of the reasons why I'mstill a little bit cautious is
that most of these mutationsthat we have, that we found, are
found in disease, but only whentwo copies of the gene are
mutated.
So, when two copies of ATM aremutated, it causes a disease

(01:00:08):
called ataxia telangiectasia,which is very rare.
Having one mutation does notcause that.
So we have a burden of proof toshow that having one mutation
is enough to be a contributor toPANS or regression in autism.

(01:00:29):
That's something that worriesme.
I have lots of theories to getaround that.
I really do and I think that'sprobably going to end up being
right.
But the bottom line is thatunless when you have a end up
being right.
But the bottom line is thatwhen a gene mutation is flagged

(01:00:51):
as what we call autosomalrecessive meaning you need two
copies.
A geneticist sees that and saysthis is meaningless, it's a
parent carrier, they're not sick.
And it turns out that if youhave one copy of ATM, actually
there's an increased risk ofcancer.
So having one copy actually cancause problems.

(01:01:14):
What I'm seeing in my studies,when I dive deep into my
analysis, when I feel the genes,what I'm finding is that I have
genes, I have mutations thatare likely pathogenic in five or
10 genes, in these kids, inthese patients, and I'm thinking

(01:01:39):
okay, so one, okay, one you candismiss, maybe two you can
dismiss, but maybe three or fouror five interacting on the same
pathway in the cell.
The combination of having asmall defect that by itself is
meaningless, as opposed tohaving five or six of these that

(01:01:59):
are individually meaninglessbut together they're coalescing
to form to cause problems in thecell.
That's my thinking right now.

Susan Manfull, PhD (01:02:08):
That makes sense.

Dr. Herb Lachman (01:02:09):
Yeah, you have to have a lot of mutations.

Susan Manfull, PhD (01:02:11):
Uh, and that's how I'm getting around
this, this problem of explaininghow a recessive disorder is
causing a problem in a carrierso, herb, I think we probably
have time for for one morequestion, and in our earlier
talks you talked about some gutgenes that you had identified.

(01:02:35):
Can you talk a little bit about?

Dr. Herb Lachman (01:02:38):
yeah, okay so I mentioned earlier that the
brain is the most complicatedstructure of the planet.
The immune system is second andthe gut is the third.
And the connection between theplanet.
The immune system is second andthe gut is the third and the
connection between the gut andthe brain, which I was very late
to appreciate, is reallysomething that is a real entity

(01:02:59):
and there's this back and forthcrosstalk between the brain and
the gut and the gut actually hasa ton of immune cells and the
brain, through the vagus nerve,controls how the gut immune
system functions and what Ifound I noticed a couple of
patients had mutations in genesthat are only expressed in the

(01:03:21):
gut and I have one gene that Ifound.
I found it in three cases andthey're all pathogenic mutations
and it's primarily expressed inthe gut and it turns out those
genes affect how the gut reactsto our load of bacteria that we

(01:03:43):
have in our guts bacteria thatwe have in our guts In Crohn's
disease, the breakdown in how weregulate the bacterial growth
in our intestines.
There's this incrediblerelationship between the gut
microbiome and us.
We have two pounds of bacteriain our guts.

(01:04:06):
It's an amazing process, it's aco-evolutionary process.
And how does the gut allow thesemicrobes to exist?
We need those microbes.
We need them for digestion, weneed them to produce vitamin K.
They're part of the humansystem but every now and then

(01:04:29):
there's a breakdown.
The cells in the gut begin torecognize these bacteria as
being enemies and it causes abreakdown of the gut mucosa and
that leads to Crohn's disease.
And some of the genes we'refinding are actually Crohn's
disease candidates and some ofthe families that I'm seeing

(01:04:51):
with these other genes have ahigh prevalence of Crohn's
disease, even though those genesthemselves have not been found
to be associated with Crohn's.
So I have about five to 60genes that are primarily
expressed in the gut that Ithink might be causing
neuroinflammation because of thebreakdown in the gut-brain

(01:05:13):
connection, a breakdown in thepermeability of microbial
products getting into thecirculation and causing an
immune response or inflammatoryresponse.
I really think that I'm on theright track there.
Not published.

Susan Manfull, PhD (01:05:27):
And that's with PANS patients.

Dr. Herb Lachman (01:05:32):
Well, I'm combining PANS and regression in
autism under the same generalcategory.
There's maybe no time todescribe why I came to that
conclusion, but these arepatients both with PANS or
regression.

Susan Manfull, PhD (01:05:48):
So we have Talk a little bit about that,
please.

William Manfull (01:05:52):
Regression and PANS.

Dr. Herb Lachman (01:05:53):
Mm-hmm.
So I don't see these patientsclinically but I talk to the
parents and I get the histories.
Everything I know about theclinical aspects of PANS I get
either from Jennifer Frankovich,renee Aker and families and my
reading.
I noticed that in some of thecases we had, you had one kid

(01:06:16):
with PANS and the other kid wasdiagnosed with autism and
seronegative autoimmuneencephalitis or regression.
They had a regressive episodefollowing infections that did
not meet PAN's criteria.
They regressed in math, theyregressed in cognitive function.

William Manfull (01:06:36):
They didn't have.

Dr. Herb Lachman (01:06:37):
OCD.
Necessarily, they didn't haverestricted eating, but they had
other symptoms and they were inthe same family.

William Manfull (01:06:43):
And when I analyzed their genes.

Dr. Herb Lachman (01:06:44):
Pardon me.

Susan Manfull, PhD (01:06:45):
Not as many um psychiatric symptoms.

Dr. Herb Lachman (01:06:48):
It sounds like oh plenty plenty but not, but
they overlap, and most of themhad anxiety, but they overlap.
Uh, and kids with pans havehave cognitive dysfunction too.
Uh, it's just that the theclinical criteria for pans
weren't met.
They didn't have ocd orrestricted eating.
And they're in the same family.
And some of these kids had onefamily of four kids that had

(01:07:11):
pathogenic mutations in ATM.
All four kids had that mutationplus others.
Some of them had PANS, some ofthem had regression.
And then it really dawned on methat this was that, this is
that they're connected.
This is they're connected andin Shang-3 mutations, the gene
that causes autism.
When these kids develop, whenthey become, when they regress,

(01:07:41):
they either regress in cognitivefunction with some
neuropsychiatric manifestationsand some of them regress with a
PANS-like clinical state.
They have the PANS criteria,ocd and or restrictive eating
plus the other symptoms.
So I really look at it as allpart of the spectrum of some
immune-based decompensation thathas fundamentally a similar

(01:08:04):
genetic background.

Susan Manfull, PhD (01:08:05):
Well, do you think that we're going to find
that there's a whole lot moreoverlap than we know right now
in many of these disorders?
I think so.

Dr. Herb Lachman (01:08:19):
I know that some autism doctors don't
believe that you can have panson top of autism.
That's a nut to crack.
If you have that belief system,then yeah, it's being
undiagnosed.
Actually, for those familiesthat have kids with autism who
regress, it's much better tocommunicate with the doctors

(01:08:44):
from the point of view of thesekids are having some acute
regression, leaving pans out ofthe picture.
They're regressing.
And I have patients who havemajor, major regressions in my
studies.
They become catatonic, theybecome mute, they stop, they
refuse to walk, they havecognitive decline.

(01:09:07):
They really do resemble uhseronegative autoimmune syphilis
and it's easy to approach uhthese doctors who are pan
skeptics from that point of view.
My kid has autism and they areregressing so, herb, what are
you working on?

Susan Manfull, PhD (01:09:29):
I know you're working on quite a few
things, but what's captured yourgreatest attention right now?

Dr. Herb Lachman (01:09:37):
Well, like I said, the most fun I have is
looking at these genes.
So I'm doing two things.
One of them is I'm doing my ownsequencing at Einstein and
looking at those genomes.
I have very little funding todo this.
This is really being done withvery little funding.

(01:09:58):
So we're doing that analysis.
So I'm accumulating a wholelist of genes that will
hopefully come out in the nextyear in a series of papers New
genes involved in DNA repair,these gut genes that I found,
other genes involved in theimmune system and mitochondrial
genes.

(01:10:19):
That's another thing that wehaven't talked about, that we're
finding mutations in genes thataffect mitochondrial function.
So we're working on the geneticpart and then on the other side
is doing what we call molecularstudies.
How do these genes affect thefunction of neurons and the
brain's immune cells, which aremicroglia?
So in the lab we're doing thosestudies.

(01:10:41):
We're trying to see when youhave these mutations, what is
that doing to the cell?
How is it affecting the abilityof microglia to produce
cytokines?
How is it affecting neuronalfunction?
So we're doing the geneticstudy to find the genes and
we're doing the molecularstudies to find out what those
genes are doing to those cells.
Wow, well, we look forward to togetting an update sometime soon

(01:11:08):
yes, I think that we needscience updates in this current
anti-science climate, to say theleast.
This is why I retreat intoscience.
The more I get exposed to theworld, the more I retreat into
science.
The more I get exposed to theworld, the more I retreat into

(01:11:31):
science, which is beautiful.
Scientists may not be beautiful, but science is very beautiful.

Susan Manfull, PhD (01:11:39):
Well, we hope you emerge to come to our
brunch in DC in April to talkabout it.

Dr. Herb Lachman (01:11:46):
I'll rearrange my schedule to be there.

Susan Manfull, PhD (01:11:48):
Excellent, because we'll be looking forward
to seeing you All.
Right, well, is there anythingthat you'd like to add that we
didn't cover before we?

Dr. Herb Lachman (01:11:58):
I'm going to leave mitochondria for the next
webinar.

Susan Manfull, PhD (01:12:01):
Excellent, and maybe microglia.

Dr. Herb Lachman (01:12:04):
Oh, yeah, yeah .

Susan Manfull, PhD (01:12:06):
All right.
Thank you so very much.

Dr. Herb Lachman (01:12:10):
Well, thank you, we can't do this stuff
without you.
The parents are so important inthis process I can't tell you
how important it is and I reallyview us, I view my parents, the
parents I deal with, as reallygreat amateur scientists.
Some of them know a lot andthey send me papers and they

(01:12:33):
challenge me and I say you know,I didn't know that, I didn't
see that paper.
They send me stuff.
I learn from them.
So we are a partnership.
Now we need a third arm of thatpartnership, which is somebody
with a billion dollars who candonate money for this research.
We need a Michael J Fox.

Susan Manfull, PhD (01:12:51):
Yeah, we do, Herb.
Thank you so very much.
I look forward to seeing youand talking to you later.

William Manfull (01:12:58):
This concludes Episode 11 of Untangling Pandas
in Pans.
Thank you for listening.
For more information aboutPandas and Pans and the Alex

(01:13:19):
Manful Fund, please visitthealexmanfulfundorg.
The content in this podcast isnot a substitute for
professional medical advice,diagnosis or treatment.
No-transcript.