Saturday, 16 October 2010


Institute of Medicine of the National Academies Webcast
A Workshop on the Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-borne Diseases: the Short-Term and Long-Term Outcomes

Spectrum of Lyme Disease: Approaches to Understanding Multi-factorial and Multidimensional Diseases
Benjamin J. Luft, M.D. (confirmed)
Edmund D. Pellegrino Professor
Division of Infectious Diseases
State University of New York at Stony Brook

here about 54 mins in.

Below is a phonetic translation, sorry about the mistakes but as I am not sure how long the videocam will be available I wanted to save something of this important event.

(Ben Luft's presentation in my opinion was the most important and significant part of this two day workshop.)

Good morning.

I tried to put this together. I was invited only about a week and a half ago and only decided to come about a week ago so it's a
little bit of a last second type of job and I'll apologize in advance

What I wanted to do, I've been working in Lyme Disease for the past 25 years.

I worked on a number of other infectious and noninfectious diseases.

I consider myself to be an academic physician.

I see patients when I find them to be important to my overall
research activity and so my gamut has ranged from working initially about HIV/AIDS and toxoplasmosis to the World Trade Center where I follow 5,500 responders to the World Trade Center disaster for their neuro,psychiatric problems and using epigenetics to try to understand that.

What I would like to do is talk a little bit about Lyme Disease today and part of it comes from my own understanding of this disease from seeing patients over a long period of time and part of it comes from my understanding of other disease entities which I think gives us insight into what is occurring here.

As you heard today by both the previous presenters, you know, Lyme
Disease continues to be an emerging and diverging disease.

What I mean by diverging disease is that it is not purely confined to Borrelia burgdorferi, or at least the original species of Borrelia burgdorferi that we originally heard of.

As we go on and as our knowledge continually expands we realize that
there are more and more organisms that may be playing aplaying a role in this.

And I think as Gary mentioned before, to our patients Lyme Disease
is their disease.

It's what makes them sick.

They're not interested as to whether it's a Borrelia burgdorferi
infection or whether it's, you know,one type of genotype of Borrelia or another genotype of Borrelia.

They're concerned with their illness.

And I think that that's really a very important concept.

I think a lot of the issues in regard to its multi system nature was really well covered in the previous talk.

But I also think it's important to understand that this is a
multi-dimensional disease.

I mean,this is something that I picked up on over the last six years as to what does that mean, multi-dimensionality.

One of my credentials was for 12 years I served as the chairman of the department of medicine and I was very loyal to the department of medicine and thought of everything in this way.

When I began working outside the department I began thinking of more of a patient centered manner and I think you have to think of patients their diseases to understand the multi-dimensionality.

And so you have to understand the various biological, neurological, psychological,economical and other aspects that affect the systems.

Systems don't occur out of that context.

And it also affects responses to therapy and the chronicity of disease and the overall disability that patients may have with Lyme Disease or with any other disease.

So I think that's really an important concept.

Furthermore I think we have to -- you know, I'm giving the end of my talk in the beginning, I think a wise thing to do, we to develop the (indiscernible) and we have to develop a universally accepted phenotype of the disease.

I think as Gary just said everyone has a different idea but, you know, that really doesn't cut it with our patients that 26 years off the onset of our illness that we all have a different idea.

You go to the infectious disease doctor he said one with they be thing, you go to the psychiatrist, he says another thing, you go to the neurologist he saiding on hits thing be you go to your friend
and he or she says another thing.

That doesn't cut it.

We have to know what we're talking about.

We have to define the phenotype.

This is really very important for anyone who wants to
do studies with this disease.

We don't have a universal understanding of what the disease is.

Furthermore, no specialty has developed the conceptual or therapeutic model of dealing with this complex disorder or other infectious or post infectious disorders.

I think it's important for this committee, I'm not going to go into it, to look at what has'd happened in the metherlands with the outbreak of Q fever and there they now have a Q fatigue syndromes.

This happened as a result of an environmental contamination with
Q fever and subsequent developed into acute Q fever and then ubsequently chronic Q fever and the manifestations.

It really mimics Lyme Disease very well.

Few medical centers or any centers of excellence are equipped to deal with the full compendium of medical, psychological and social implications.

The ramifications of this is third party parries are not responsive of needs of this population and there are few practitioners who have been specifically trained to deal with this disease.

There's no expertise out this there.

So there are people who go out there with cam passion but not
very much training and try to deal with this disease and they try to
learn as they goa along sometimes well and sometimes quite frankly not very well and I think that that's a real problem and I think it's a problem with the academy.

It's a problem as to why these types of citieses are so often dismissed and not really dealt with in the manner they should.

So we look at Lyme Disease.

It's kind of looking at the old adage of the blind man with the elephant.

This is from another talk, as you can surmise, but it's like every specialty and every group all have a different idea and they're each describing that entity differently so we're not really talking to one another and there really is no common description.

So we've taken quite honestly over the last 20 some odd years besides doing good amounts of clinical trials and things of that sort for Lyme Disease we've taken a biological approach to try to understand the disease, can he saw the ospb and developed a vaccine
that is now in trial in neuron.

We've been involved in looking at the 36, the multiple pathogens with sticks, the various genotypes, we've been involved in genomic sequencing.

I'm very happy to report that we've recently published together with
(indiscernible) the first ever a series of papers in which we are
releasing the data on three genomes of Borrelia that have been fully
sequenced and this I think will really push the field forward.

And it would be good to have that type of information available to the committee in its full form because it's a very important way, important milestone.

We've been involved with Brett I can't Proteomic and I'll show you some data from that with Dick Smith, north well's national laboratory and we've been involved with a protein arry study.

So this is an early study we did not as early as Dr. Osfeld but what we did originally is we kind of -- I was first, you know, a young person and I liked the idea of going out in the field and we went out and flagged for ticks and we wanted to look at what the OspC variation was within this population and we did a slot blot
which I think is familiar to many of the scientists buff the concept is that as you see more and more dots in the slot blot in each one of those rows, the vertical rows, that indicates the vair Borrelia burgdorferi that were in there, the OSPC we were able to identify.

So can you see in different ticks there were as many as one variant to as many as nine variants of Borrelia burgdorferi found in the ticks.

That was an early study we did and it was inspeak are trying to us that perhaps these ticks are much more -- this infection is a lot more complicated than just Borrelia burgdorferi being all put into one pot and we did a subsequent study which was published in infection and immunity where we were able to identify the various tick ice lats that I just showed you previously and were able to categorize them into different OspC types and those were listed on the top part of the graph, the first horizontal row were the tick
isolates indicating each of them indicating a different -- shown to be a different genotype.

But what we saw was when we looked at patients and their skin isolats, there was a much smaller population that were found in the skin that was causing human disease.

And then the last group, the four isolats that we saw at the bot.

Were the invasive isolats, the ones that were found in the blood of net patients.

So what we were able to show was there raise relatively low
population of Borrelia burgdorferi that was actually causing invasive disease.

So when you look at the complexity of what Dr. Osfeld shows, you know, officers Borrelia burgdorferi being in ticks then you now have to kind of be able to expand that out to looking at 20 different genotypes that might be there and how those might separate
from mouse to chipmunk to squirrel to whatever, you know, whether there's any particular appropriatism.

And I think that's an important area.

Subsequently others have done this.

There was a beautiful study by Wormser and Swartz that really was put out almost con comedantly with this and really showed a very similar finding perhaps using different markers but it just shows the complexity of the problem and that one Borrelia is not like another Borrelia.

When we looked at the invasive strains which is, what we wanted to look as were specifically the OspC types that were associated because that was the marker we were looking at and the OspC
is the major protein of Borrelia burgdorferi at least which is enters the skin.

And so we solved the structure of the OspC pro seen and what we were able to show was the ones that were inhave asive, that they
were -- their structure was identical to the noninvasive strains except at the very head of the structure where the elect static force was different.

It had very high positive level of electro positivity at the head of it and that was something that we hypothesized at the time may be an important indicator for invasiveness.

I recently went to a meeting and was able to show that the CMP protein found in Borrelia hermsa has the exact same characteristic had when it goes to the meninges so perhaps our original finding deserves further study.

But as I said before, Borrelia burgdorferi is an expanding and
diverging process.

There are many species that are now being identified.

At one county saw there were as many as 37 different species throughout the world of Borrelia of which 12 ever believed to cause Lyme Disease one way or the other, some of them cultivated, some of them not cultivated, some of them only by CPR evidence but they're
just there to give a feel for how problem that we deal with it.

But in general Borrelia burgdorferi, as I said, sensu stricto is the
species that causes the strain in the United States of afzelii and garinii in Eurasia as well asberg dory.

Different Borrelia have different capacity to cause human disease.

Not all Borrelia are the same.

And I think that this has important implications for this committee as you decide how the research should go further.

It has implications in terms of thinking about the size of studies,
about the geographic distribution of studies, what is the appropriate power, how appropriate size should be powered.

I think all of these things are very important.

And so here is some data that from some collaboration that did I as well as others with mark issue who is now at Abbott, previously as Ibyss and this was funded originally by Darba.

And what we did is they have developed a system for being able for identify where pathogens or a multiple array of pathogens using a combination of broad range PCR and mass Beck.

I won't go into much detail about that.

But what I wanted to do in this slide was for you to look at the pattern of Borrelia genotype distribution in four different parts of country.

New York, Connecticut, Indiana and California.

And what you see is that there's a good amount of difference in the
proportionality of different genotypes.

And if you take what I said before, that different genotypes have different potential to cause disease, you can see that a variation
or an -- on balancing of different genotypes in one part of the country might give you another disease versus another.

There may be antibiotic responsiveness in one region versus another, depending on what the intrinsic resistance of those
organisms are within those particular areas.

This is just thrown out there.

Do I have a lot of data to say that resistance is different from strain to strain and things of that sort?

No,that hasn't been done yet.

But I do think that this is something that needs to be considered when you're developing appropriate trials.

Here's the genotype did Itressty between regions.

This is New York and Connecticut.

You can see that there are 15 genotypes that are very common
and this is mark Essu's system.

There was where they had 42 different genotypes using the IBA system.

In New York there were 16 distinct ones and in Connecticut there were four distinct ones.

Certainly there's overlap but you can see there are differences.

You can see I'm pushing for the multi centered approach to understanding this disease, okay.

And the other thing that you have to realize is that within a tick, how many different genotypes occur.

I showed you our initial, you know, down and dirty slot block but here's a much more elegant study that was done by Mark using very contemporary techniques.

You can see that there are in 34% of the ticks there are at
least two different genotypes.
And in 5% there were greater than three.

So clearly in about 40% of ticks, they are able to spread the disease,they're infected with multiple genotypes.

Which genotype is causing the disease.

How do they impact one another.

So potentially the immune system is fighting two different infections con comedantly.

What is the impact of that.

Is there synergy, sin tagunism, we really don't know.

And again I think this was mentioned briefly by Gary, the complexity of other microbes.

This is not a simple complexity.

You now have multiple genotypes within that tick and at the same time, look of the tremendous variety of other pathogens that are
there as well.

Pathogens that we know are extremely potent immuno modulators.

Pathogens that can cause a significant amount of disease.

What is the impact of babesiosis?

I can tell you that I study toxoplasma in years and I know the impact of toxoplasma and it's activity in certain circumstances and it's tremendous amount of disthe inflammatory affect is dramatic.

How does that impact the way the disease manifests itself.

How does it impact when you begin trials to try to understand disease how it is when someone is infected with just one Borrelia or three Borrelia or nine Borrelia and babesiosis or a porus
environment or Anaplasma, et cetera, et cetera.

What I'm trying to say is that it's extremely complex.

So the Borrelia burgdorferi sensu stricto has been shown to have
pneumonia are you genotypes present in the areas where it's found.

Some genotypes have been shown to persist longer in mice and affect disease severity in humans.

Mixtures of the genotypes may challenge thein immune system in unknown ways.

What are the implications of this for the development of various types of trials?

Well, I know we're not supposed to talk about they are pew ticks but I'll talk about it a little bit in that I think that multi centered therapeutic trials will be required to assess the efficacy over a broad array of patients exposed to various genotypes and vapor variants swells other pathogens. Some will need to be
placebo controlled and powered.

Underpowered studies which purport to demonstrate unfortunately efficacy need to be viewed with circumspection.

That's very important.

When these patients are coming in to >> Captioner: , they're the rare birds.

Most patients with Lyme Disease I'm able to take care of.

As I try to teach my physicians, 90 to 95% of the patients can be seen by nurse practitioners.

They're only coming to see you for the 5% of patients that are not able to be taken care of that are posing diagnostic did I leam.

Diagnostic tests will need to be consider genotypic various.
Epidemiologic studies need to be appropriately powered and extend over a geographic region as possible to understand the variations of this disease which is caused by a complex infection and I respect fluidize agree that anyone that says 200 patients an
appropriately powered study for this complex disease I think they're wrong.

Not that I'm a statistician but I bet you I can find one to agree with me.

Until appropriately powered studied are performed, smaller studies and observations which show treatment breakthrough and failures should be fullically appreciated.

We did all of these strains and we did a lot of sequencing and we came up with our map, our family free of Borrelia and I'll go over this very quickly.

I'm not going to go over our -- an analysis of our genomic studies.

Some of them haven't been published yet so it wouldn't be fair to the others.

But as you can see, this was the complexity.

And what we did was we again to identify in a very rational way the various strains of Borrelia, and you can see which ones they are,
that we wish to sequence the etire genome.

And we did that with Claire phasier at the -- well, she was at the
venture institute at the time but she's now at the University of Care land. (Indiscernible)

What I wanted to talk to you a little bit about is the whole idea of where we are with that because I think it's an extraordinarily powerful tool what we now have available and that is that
we've been able to have the pangeno.

So what our concept was look, there's the whole confusion.

This is the day of technology.

There shouldn't be any question as to what we did.

Let's do it all.

So what we did was we began to sequence the genomes and we wanted
to know how many scream owns did we need to sequence and to get a complete picture of every gene within the Borrelia family tree.

The reason why we wanted to do that was went wanted to know whether Borrelia was more of a closed genome.

It was an open genome it meant there was a lot of genetic data that it could continually battle and we would never know the complete
Borrelia burgdorferi because we would be getting more information from other strains.

If it was a closed genome and relatively tight we would be able
to do that and we would be much closesser to an answer in terms of
diagnosis and treatment.

And so here I just wanted to give you the data since I think that's
important and I think it's exciting.

So we looked at Borrelia burgdorferi,the sensu stricto, that species.

What we were able to show was that as we were going out to about 14 genomes, that the number of new genes that we were identifying was relatively small.

Every time we sequenced a genome there would be another four genes that we began to identify.

It became a point of diminishing returns and that's why we actually stopped at 17.

We got a good idea of the core genome, the part of the Borrelia that was found in all strains of Borrelia burgdorferi.

We know what is essential to that organism now and we have a pretty good idea of what the pan genome is.

The things that we really don't know -- how many minutes?

My time is up already.

All right.

I'm going to be really quick but -- I'm sorry.

And here basically, basically the take home measures when you use the Borrelia species, what happens is that you have it's morbidity open genome type of problem.

But the real question is how the information is going from beg I can't afzelioo andberg do if I.

If it is fluid, with all of these Borrelia that are out there, it may cause that we may have problems toward the future.

I wanted to just mention one last thing about how we took this
information in regard to the genomic or sequencing and how the practical approach to it.

So as soon as we began to see the data on these 17 different strains we began to look for positively selected genes.

And what I mean by positively selected genes are those genes that
are under a certain amount of immune (President Obama??) and therefore their heterogenius from strain to vein and the reason why they're heterogeneous is because they're continually pushed to be positively selected.

We took those genes and we took the genes that were also, that we could preticket were on the surface of the proteins and we made a protein array.

And the Roe 13 array now is well over 500 different proteins, recomedant proseason that we have each cloned and expressed and put on a chip and we began testing Sierra.

And I just wanted to give you some data on 15 Sierra that we received from the CDC.

These are very well characterized Sierra.

All of them were from patients who had initial arrhythomyagrams.

They were by op acid and cultured so we 93 the genotype.


So they represent a broad away of Borrelia.

And what we were able to show was that when you looked at the western load and ELISA, only 54% of them were Sierra positive.

It was nine out of 15.

However, using the protein nitro array we were able to identify all of them as have been ant body to Borrelia.

I think the important part to this, and this is really just at day zero, at initial time point.

But the important point that I'm trying to make is that when you have the knowledge and when you have the information, you're able to -- the level of Sierra negativity, even in the patient we saw that was 60% negative at the time they are seen, they are antibody.

You have to know where to look.

That will only come to us by doing good science and being receptive to it.

So what -- I'm going to finish this up because they are just my

What is needed to solve the chronic Lyme Disease?

Well,we need a standard operating procedure.

We have to define the patient with Lyme Disease and gather
information on the patient'snist a uniform way.

We have to collect the biological samples in a relislable and
useful way.

We have to reproduce them in a reliable manner and this has to
be done across all centers.

We have to reproduce and validate our results.

And we should utilize -- we are very lucky that we do have a very good animal model.

I think we'll here about it with the talk by Steve

I think it's extremely important and I urge the panel to take
note of that because there are very few animal models out there for
persistent infections.

This is really the opportunity to be able to study this in a way that doesn't require having large numbers of patients.

And I think that this is something you should just take note of.

I canis important to develop a chronic lyme bio bank.

A lyme bio is there to thereside the opportunity to (indiscernible) it's a cost effective resource thorough sides high quality clinical information and biological samples to the research community but
all of this is dependent on developing an accurate methodology for phenotype identification and this has to be done in a very careful manner.

And I just wanted to end with this quote.

"Science is not belief but the will to find out."

And I really want to -- I have been very privileged to work with a very imminent group of scientists throughout my career especially in regard to Lyme Disease.

We went out and recruited a group of people who had really very little idea of knowledge of Lyme Disease and its controversies and I think that they've done an extraordinary job.

Actually I just wish each other every one of them could be here to talk about the work that they did.

Thank you very much.


Later in discussing reinfection and relapsing illness Ben Lufts response was - here 100.30 mins in

>> I want to clarify one point. I think that Peter and Gary were
correct, that you can become reinfected with Lyme disease, after
being -- after having air themea myograms.

But the nature of Lyme disease is it's a relapsing disease.

That's the very nature of you getting infected, very erythema myograms, having dissemination, separated by time, the disease comes back and it can give you cardiac abnormalities or abnormalities in your joint, that's a relapse.

That's a relapsing process.

The period of time is well-being with disease relapses, and that can occur in a cyclical manner.

You can have multiple episodes of relapse, and this can go on for years

That's the natural history of the disease.

The natural history of disease ez is it's a relapsing disease.

It's also very interesting that even though you may have this disease, you can be reinfected with another -- with Lyme disease again, even though you've been previously infected.

I just wanted to clarify that.

Link to earlier post on research on Whole Genome Sequences of 13 isolates of Borellia Burgdorferi here

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