Dr. Ian Lipkin, 9/18/2012, TWiV

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LIPKIN interview on TWiV, posted 9/18/2012

RACANIELLO:

This Week in Virology, the podcast about viruses--the kind that make you sick.

You're listening to This Week in Virology. This is a special episode recorded on September 5th, 2012. I'm Vincent Racaniello and with me is Professor Ian Lipkin. Thank you for joining me today, Ian.

LIPKIN:

A pleasure.

RACANIELLO:

Today we’re here to talk about a paper that will be published on the 18th of September. And the title of this …The journal is mBIO. The title is “A Multicenter Blinded Analysis Indicates No Association Between Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Either Xenotropic Murine Leukemia Virus-Related Virus or Polytropic Murine Leukemia Virus.” And let me read just the last names because I think everyone should know who’s on this paper. Alter, Mikovits, Switzer, Ruscetti, Lo, Klimas, Komaroff, Montoya, Bateman, Levine, Peterson, Levin, Hanson, Genfi, Bhat, Zheng, Wang, Li, Hung, Lee, Sameroff, Heneine, Coffin, Hornig and Lipkin. It’s not, probably, the biggest authored paper you’ve ever had. Right?

LIPKIN:

It’s close.

RACANIELLO:

It’s close. So this is the culmination of a study you’ve been coordinating for—over a year now. Is that right?

LIPKIN:

It’s two years.

RACANIELLO:

And this began in 2009 with the report that XMRV, a new retrovirus, might be involved with Chronic Fatigue Syndrome. And it’s been quite a ride since then. And there have been a few positive studies but mostly negative ones. So, can you tell us what…why was this study undertaken—that you have coordinated? LIPKIN: There are two issues in pathogen de-discovery.

(Racaniello laughs.)

One, of course, is to persuade the scientific community that you've done everything necessary to address the question, whether or not you've made a substantive link or not. And the other is to do everything that you can for the community that you're trying to serve, which is the patients, the families of those who are afflicted with the disease.

And although many in the community have felt for a long time that this issue was settled, many members of the community have not felt that to be the case. And the people who participated in the study who were critical in generating the data that led to the whole XMRV/polytropic murine leukemia virus link to Chronic Fatigue Syndrome/Myalgic Encephalomyelitis were Harvey Alter, Judy Mikovits, Frank Ruscetti, Shyh-Ching Lo, and of course, the people who worked with them.

Now, although some would say that these individuals retracted their papers, when you talk to them, they did not, in fact, retract those papers. They will tell you that they were pressured by journals to retract, to participate in retraction, so while the journals may have retracted the papers, the authors did not. And until the authors have a chance to go over the original information and the original assays to try to test these with well-characterized samples, and then find the hypotheses wanting, they're not going to be willing to come out in public and say, "You know, we made an error. It was an honest mistake, but we find no evidence for this link between these viruses and this disease."

And this is why, in fact, this study was undertaken. It was undertaken with very strong support, even after some of the negative papers began to appear, from Tony Fauci, Francis Collins, Tom Frieden and Harold Varmus, because they realized it was critical that we address this in a forthright , coherent, comprehensive, indisputable fashion.

So what we set out to do was to identify cases using criteria that were established by the laboratory people as well as the best clinicians in the field. They were collected over a wide geographic area, so that if there were differences in the cause of Chronic Fatigue Syndrome in one part of the United States or another, we would not be confounded by just looking at one area. This is very important. We made certain that the controls we selected were matched well, and we collected the samples that the investigators responsible for the original work wanted us to collect. We coded them. We sent those samples to them. We allowed them to use whatever assays they wanted to use. The only thing we insisted upon was that the criteria for calling a sample positive or negative had to be set up in advance and that once they were established, they would not change. And we then allowed them to proceed .

We found .. you know, they found what they found and once we collected all those data, if there was any sort of discrepancy from one sample to another because they received more than one sample, we tried to reconcile them.

And at the end of the day, what we found, in fact, was that, although the laboratories were able to recognize the positive controls, those were provided to us by John Coffin, there was no association between Chronic Fatigue Syndrome or Myalgic Encephalomyelitis if you prefer, and either of these two viruses.

No one found any sequences by PCR. The serology was a little more tricky because we don’t really have positive controls for it, and the results were somewhat discordant. But, again, there was no association between the presence of antibodies as described by Frank Ruscetti and the status of the case.

So, when all these data were assembled, we met in teleconference and everyone agreed that the hypothesis was…had been tested and found not to hold up; and I will say that, you know, in deep appreciation for the sincerity of all the investigators, everyone held to their word. So they are speaking out and saying, you know, we feel that this study was fairly done. We feel that the hypothesis has been tested, and we find no association between the viruses that we previously reported and this disease.

Now, I have been involved with other sorts of studies where we have tried to look at the role of infections in chronic diseases, ALS and enteroviruses, Borna Disease and Chronic Fatigue Syndrome, a measles virus and MMR in autism and I’d never had an opportunity before to get as many people involved. So that when we’re finished, there’s absolutely no question but that we’ve tested it and found that there’s no link. And I’m hopeful that this is going to settle the issue once and for all.

There has been a side benefit to this whole process, and that is we have established a working group of people who are capable of collecting materials. We’ve been able to store sera and PBMC so that other investigators who want to do either microbiology, or genetics or proteomics will be able to access those samples through the NIH. There will be calls for proposals, and there will actually be funding associated with that.

During the interim, we offered the laboratories and the investigators and the clinical sites who were engaged with this work to put forward proposals to do something with these materials in advance of that RFA, though without any funding. Two of those groups..well, several groups applied. Two of them were selected by the entire team, and they will be receiving plasma samples that they can then study. The primary focus has been on microbiology and genetics, but I’m sure there will be other applications as well.

So, we’ve been able to hold back as much of the sample as possible. So, I know some in the community –the scientific community—feel that this was not money well spent, but the fact is, I think that we have obviated a lot of, you know, missteps that might have followed with clinical trials and such for antiretrovirals. And in addition, we have been able to establish a sample bank that will be helpful for years to come. And we’ve been able to hold, I think, the attention of the community.

RACANIELLO:

So the samples that are going to be available … are the samples collected as part of the study?

LIPKIN:

That’s correct.

RACANIELLO:

So that’s a hundred forty-seven case case patients, a hundred forty-six matched controls… LIPKIN:

That’s correct.

RACANIELLO:

And you have enough material for many years of investigation…is that the numbers? LIPKIN:

Well that depends on how greedy people are, as usual, but there are at least 15 PBMC samples. Now those are difficult to aliquot, so those will go to individual projects. The plasma, however, we can aliquot, and for people who want to do proteomics and microbiology using these plasma samples, we have enough for, probably, fifty laboratories.

RACANIELLO:

So, tell me how these samples were selected. You mentioned that all the investigators were given the opportunity to participate in that. So, did each group have X number of patients for the study…?

LIPKIN:

Yeah. RACANIELLO:

How did that work?

LIPKIN:

So, our initial…so we initially did a power calculation, trying to figure out how many samples we needed, based on the worst and best case scenario from the Mikovits paper and the Lo paper, so we could determine the minimum set. And, based on those calculations, we sought 150 subjects with disease and 150 who were matched controls.

Now, we brought in more than that, obviously, because as we began to examine these people and they met clinical criteria, we collected their blood, we also sent those bloods off before deciding to include them to a clinical laboratory here at Columbia and we used other laboratories as well, commercial laboratories as well, to make sure that they didn’t have hypothyroidism or some sort of cryptic hepatitis or anything that might confound our, you know, the diagnosis…

RACANIELLO:

Right.

LIPKIN:

…of Chronic Fatigue Syndrome. And, so, initially, again, we had six sites across the United States and the notion was that each one was going to get 20 to 25. At the end of the day, some were more successful at recruiting than others were; but, on average, we had somewhere between 20 and 30 patients selected per site and with matched controls.

Now, the laboratories…so the clinicians met, the laboratorians met. Everyone decided, and again agreed on what the criteria would be that would be used , you know, should be. We used the most stringent criteria possible. So, we selected people who met the Canadian criteria, people who they said met the Fukuda criteria. We also decided that we wanted to select people who had a prodome that was consistent with an infectious disease. So, fever, night sweats, lymphadenopathy, swollen lymph nodes, anything suggestive of an infection so we would give the hypothesis the best possible chance of success, which had not been done in the past. So that there would be no way to go back and a priori criticize the study design and say, “You know, if you’d looked at this population, you would have found XMRV.”

RACANIELLO:

Um-hum.

LIPKIN:

Or pMLV. And it’s critical that you do that. If you just go into a freezer and try to pull out cases that have been previously called positive, you can always say, “Well, maybe there was a thaw, maybe the titer dropped. Who knows what could have gone wrong?”

In this instance, everything was pristine, from the selection of the cases, the criteria that were used, the processing of the materials. So the samples were sent to us overnight. We purified PBMC using, you know, standard classical methods. Everything was stored in freezers here so there was no possibility for contamination. And we have had no pMLV or XMRV in our laboratories and all the assembling we do is done in positive pressure conditions so we don’t have to worry about contamination of materials. And, in fact, you know, we didn’t have any evidence of contamination. So, we set it up, again, so people could do what they wanted to do. This means that some labs did things that other people didn’t do. So, the FDA analyzed PBMC as well as plasma, as did, you know, the Mikovits-Ruscetti –Hanson laboratory and the plasma was really only analyzed—analyzed alone—was at the CDC.

Now during the course of this study, you know, lots of things happened that made it very difficult to continue. And I think it was Harold Varmus who said this is worth a paper in itself. Or maybe a movie.

RACANIELLO:

Didn’t you do that already?

(laughter, sounds like both Racaniello and Lipkin)

LIPKIN:

So, as you may recall, Judy Mikovits had difficulties in the WPI…

RACANIELLO:

Um-hum…

LIPKIN:

…the WPI which stands for the Whittemore Peterson Institute. The “P” in “WPI” stands for “Peterson,” who doesn’t talk to the Whittemores any more, so that’s another story in itself.

RACANIELLO:

He’s on this paper, right?

LIPKIN:

Yes, he’s on this paper as well. He was one of the original people who, along with Paul Cheney, describe this group in Incline Village where the syndrome was early to be reported. And then Judy Mikovits wound up afoul of the WPI and she wound up in jail…

RACANIELLO:

Um-hum…

LIPKIN:

…which was quite remarkable because I wound up involved with negotiations trying to broker an agreement between her lawyers and Judy Mikovits and the Whittemores to get her out of jail…

RACANIELLO:

Um-hum…

LIPKIN:

…and essentially what happened was that when it began to look as though the hypothesis was, you know, was unraveling, people began to push, you know, the onus of responsibility onto Mikovits for that work. And, of course, she wanted to have access to her lab notebooks so that she could at least describe what she had done and relate it to the individuals there. She took those lab notebooks, and I had conversations with Harvey Whittemore about whether or not she should have access to her lab notebooks. And I would say, you know, I understand that you want to keep the original lab notebooks, but every scientist is entitled t have copies of his or her records. How else can they talk about what they’ve done, replicate their work, provide detailed protocols and so forth. Well that didn’t rest very well. She was accused of stealing intellectual property. Well, if the hypothesis doesn’t hold up, where is the intellectual property?

So there were all these things that were circling and then we had to find a way for her to be engaged in the study. So Maureen Hanson at Cornell agreed to receive samples processed by Frank Ruscetti . Harold Varmus agreed to allow Frank Ruscetti to participate in the study and to receive samples and characterize them. And at one point, you know, the CDC said “We don’t really have the time and energy to invest in this,” and I appealed to Tom Frieden and I said “We need to close this loop once and for all so that we don’t have another situation with MMR which lingers, you know, for more than a decade. And we still have people who have … who are reluctant to vaccinate their children with MMR, in spite of the fact that, you know, that’s been clearly laid to rest.”

So, everybody got on board, pushed this very strongly, and this was the result.

RACANIELLO:

So Judy was… How did Judy participate in this?

LIPKIN:

So Judy … while Judy was in jail …

RACANIELLO:

Oh…

LIPKIN:

…and after Judy got out of jail, Judy was…she was in contact regularly…

RACANIELLO:

Yes…

LIPKIN:

…regularly with Frank Ruscetti and with Maureen Hanson and was responsible for the study design and for making decisions about how to call a sample positive or negative …

RACANIELLO:

Yes…

LIPKIN:

…and review the data and participate in writing the paper. There was a lot of negotiation in the drafting of this paper, as you might imagine, because, you know, it’s a very…it’s very sensitive…

RACANIELLO:

Sure.

LIPKIN:

But everybody signed off on this. We went through, literally, fifty different iterations of the paper…

RACANIELLO:

Um…

LIPKIN:

And after it was signed off on by all the authors, then it first had to go up the chain at the NIH and the CDC, so that…

RACANIELLO:

Right, right….

LIPKIN:

…so that, you know, they could approve it as well.

RACANIELLO:

Do you still have the original Word document with all the changes embedded in it? That might be a historical …

LIPKIN:

Yeah. The problem is it crashes.

(Racaniello laughs.)

RACANIELLO:

It’s too big…

LIPKIN:

It’s too big for Mac.

RACANIELLO:

So none of the samples you used were samples from any other previous study, is that correct?

LIPKIN:

That’s true. These are all … well, I can’t say any previous study but any previous study in which these people had been engaged.

RACANIELLO:

Okay. And the positive cases, the individuals diagnosed with CFS, were these individuals who had the disease for varying lengths of time—short, medium, long…?

LIPKIN:

Yeah, so you know, in the paper we spent a fair amount of time talking about the nature of the disease. One of the challenges, of course, with a disease like this one, is that because it’s called Chronic Fatigue Syndrome, you can’t get there during the acute period, during the acute ichthus, but the mean age of onset was 35 plus or minus 8.5, so there isn’t anybody here , you know, it’s not like we were able to get people six months after the onset of illness…

RACANIELLO:

Right…right…

LIPKIN:

…which would be the closest you could be and still have a diagnosis of Chronic Fatigue Syndrome. And I don’t really see any way in which such cases are going to be found.

RACANIELLO:

Right.

Now you did…one of the things that was done…that were done…so let me back up a bit. You received blood samples in your lab, is that correct?

LIPKIN:

That’s correct. So, the patients would be seen, bloods would be drawn, they would be sent to us…

RACANIELLO:

They were drawn somewhere else, right?

LIPKIN:

The bloods were all drawn in commercial, you know, in a commercial phlebotomy suite, and they were shipped to us overnight. They were received, which, you know, means we were receiving five days a way…

RACANIELLO:

Um-hum…

LIPKIN:

…because they also have clinic on, on Fridays, and we would then process them, and we would aliquot them, and we would code them with bar codes, and then we would send off a sample of plasma to clinical laboratories to test for things that we wanted to know about, and this hasn’t been done before in the past either, but we looked at, you know, a wide range of parameters that we thought might be important as exclusionary diagnoses, and I’ve mentioned some of these already, like evidence of liver disease…

RACANIELLO:

Right.

LIPKIN:

…and so forth. …

RACANIELLO:

Other viruses…

LIPKIN:

But Table 1 has a whole series of different things that we think are important. And you can look at various exclusionary criteria.

So, once those laboratory values came back, we then decided which of the samples would be taken and would be submitted to the individual labs for testing.

RACANIELLO:

What was the cut-down from the original samples to what was actually tested for viral sequences, the 147, the 146?

LIPKIN:

I don’t remember the total, but that’s how we got down to 147…

RACANIELLO:

All right.

LIPKIN:

146…it’s … it wasn’t as though we drew 200, for example, because a lot of these cases were excluded at an earlier time point because they simply didn’t meet various criteria.

RACANIELLO:

Right, right.

So one of the tests that were…so then you sent these coded samples out to the various and then you said they could do what they wanted with them, assay them…

LIPKIN:

Correct.

RACANIELLO:

Assay them the way they wanted.

LIPKIN:

Correct.

RACANIELLO:

And one of the ways that CDC and FDA was to do PCR on plasma or PBMC?

LIPKIN:

Correct.

RACANIELLO:

So, in some cases this was RT PCR, they would produce…

LIPKIN:

That’s correct.

RACANIELLO:

They would produce RNA for the samples, reverse transcribe…What kind of primers were used for the PCR? Was this agreed upon by everyone or…

LIPKIN:

No, no, that’s a critical point, and I appreciate your bringing that up.

For the purposes of this study design, I really don’t care what primers people use. Because if I ask you, and you have previously reported something as being positive, to use my primers, and you don’t get a finding that correlates with what you’ve previously reported, you’ll simply tell me that this is because I forced you to use my primers. So we wanted to circumvent that criticism, so the one thing we did do is we said to people, “Whatever primers you want to use, whatever reagents you want to use, after the point of collection, obvious—we can’t vary that—that’s entirely up to you. You tell us where you want to purchase these primers and we’ll pay for them.” So we then did, is we actually arranged for various commercial suppliers to provide reagents to people who needed them. But they were the reagents that they designated, and they list them, and you can obviously look up what they’ve used. And these differ from laboratory to laboratory.

Now we did ask that people go back and sequence their products and see what they found but that’s not terribly informative. What’s really critical, obviously, is the end result. And that is to say, can you confirm or refute the finding of the relationship between the virus and the disease. And that’s where, of course, you know, none was found, right.

RACANIELLO:

So the CDC and FDA both did RT PCR with plasma. So that’s looking for virus, correct?

LIPKIN:

That’s correct. They were looking…

RACANIELLO:

RNA sequences…

LIPKIN:

Nobody was doing a viral purification protocol.

RACANIELLO:

Right.

LIPKIN:

So it’s not like they did a nuclease treatment and then extracted…

RACANIELLO:

Uh-huh

LIPKIN:

They were just taking plasma and doing traditional extraction. The FDA wanted to access PBMC. Now, as you may recollect, from the early days of the response of the criticism of the Mikovits paper, what Mikovits-Ruscetti said was that the key was...

RACANIELLO:

…right…

LIPKIN:

That the growth of these cells was then allowed an expression of virus. So we provided the reagents that were required to culture the PBMC so that they could test that hypothesis. That didn’t make any difference. That didn’t. But it could conceivably have done so. But it didn’t.

RACANIELLO:

Right.

LIPKIN:

So those were also negative.

RACANIELLO:

So those were also…That was PCR of cultured PBMC…

LIPKIN:

That is correct.

RACANIELLO:

That is not RT PCR. This is extracting DNA…

LIPKIN:

Yes, but again, the key issue here is the cultures. So…

RACANIELLO:

Yeah.

LIPKIN:

So again, the FDA did not culture their samples, and this is one of the reasons why it took so long to get through this study, is because you have to be able to culture these cells…

RACANIELLO:

Sure.

LIPKIN:

And sometimes, you know, and sometimes Frank Ruscetti found that he wasn’t able to propagate the cells, so we had to send him another aliquot and he had to try again, so that then takes…

RACANIELLO:

Right.

LIPKIN:

…takes several weeks. And then after that was done, the PCR was done, whether it was plasma or PBMC. All the PCR was done for that group in Maureen Hanson’s laboratory up at Cornell.

RACANIELLO:

So they looked for viral RNA or DNA. It would be integrated DNA presumably.

LIPKIN:

Correct.

RACANIELLO:

All negative on the ca… The positive cases, the CFS/ME cases which are 147, none were positive in any case for PCR or RT PCR.

LIPKIN:

Correct.

RACANIELLO:

The same for the controls which was 146, for PCR’s and RT PCR’s, including the cultured PBMC’s. Right? So that CDC, FDA and Mikovits-Ruscetti-and Hanson. So that’s resoundingly negative.

LIPKIN:

So, the only issue is the plasma. Serology.

RACANIELLO:

Right.

LIPKIN:

And there…

RACANIELLO:

What was done there? Tell us how that was done.

LIPKIN:

Well, Ruscetti has a proprietary assay that he uses to test for antibodies which react with cells, and as you see, there was no difference between cases and controls. Controls were 6.2 percent, cases 6.1 percent, and because we don’t have a positive control, I really don’t know what that means.

Now,

RACANIELLO:

Right.

LIPKIN:

Many, many years ago when I was working with…I was asked by CDC to look into the potential role of Borna Virus and Chronic Fatigue Syndrome … this was back in the mid 1990’s to late 1990’s, there was a report that came out of Japan suggesting that Borna Virus was implicated. And 50 percent of cases were reported to have nucleic acids and there was a family found where three-quarters of the people in the family had Borna Virus nucleic acids, and were also antibody positive. So Brian Mahy, who was then Director of DVRDD, who ran afoul, ad you may remember, of this whole issue of whether or not enough money was being invested in this research, asked me to look into this, and I looked into Gulf War Syndrome which was also very topical at the time and I looked at these Chronic Fatigue Syndrome patients, many of them coming out of a clinic that was run in the Karolinska, which at that point was one of the best clinics for CFS in the world. And we found no evidence of Borna Virus nucleic acids. And our ELISA’s were positive but our Western Blots were negative.

And when I tried to report this finding, I wound up going to progressively less impressive journals until I finally wound up with the one in which it was published. And there was a great deal of reluctance to publish the paper because, the saying at that point was, you know, you’re just not good enough at doing this, and this was why it’s all negative.

(Racaniello laughs.)

And it took almost two years to publish that particular paper, which is how I learned the lesson of making certain that people who originally do the report are the ones who are engaged in proving or disproving the concept.

But at that point, the one thing that struck me was that many of these individuals, I think it was close to two-thirds, something like 67 percent, were reactive with Borna Virus proteins in ELISA but negative in Western Blot, but they were also reactive with FLG (?) and Beta galactacytase, and I would love to conclude that they had polyclonal B-cell activation, so at the very end of this paper which appears in the Journal of Neurovirology, I said these patients are clearly sick in some way. They have some kind of immunological activation. I don’t know why, but it is not Borna Virus.

So I am convinced, after working in this field for, you know, for a very long time, that this is a bona fide syndrome. I don’t believe that it necessarily has a single cause. I don’t pretend to have insights into the pathogenesis of CFS, but one of the things that we want the community to take away very clearly is that the people who have engaged in this study and many others around the world are committed to trying to understand why they’re ill. We have reagents , we have resources now that can be applied to this task, and that just because this particular hypothesis hasn’t borne fruit does not mean that there won’t be an answer downstream. And we’re trying, you know, to do that work as rapidly and efficiently and as rigorously as we can.

Now one of the other things that I think is important for your listeners to take away from this particular investigation is that we need to have rules for interpreting data. We need algorithms by which, when people have a tantalizing finding, it can be tested. And, you know, we’ve got Koch’s postulates and people use Koch’s postulates to this day, but they don’t serve us very well in this day when we don’t have an animal model for a disease and we don’t have the ability to grow the organism necessarily, so I have another paper that’s under review right now. It’s not on Chronic Fatigue Syndrome, but it’s specifically about the issues of how you talk about levels of certainty, levels of confidence, in the association between a finding and a consequence. And I hope to be able to talk with you about that at a later time.

RACANIELLO:

What kind of rules are you thinking about?

LIPKIN:

Well, I have three levels.

RACANIELLO:

Um-hum.

LIPKIN:

The lowest level is the phenomenon. You know, you find something in a…but it doesn’t tell you necessarily that there’s any linkage.

RACANIELLO:

Right.

LIPKIN:

And then the next level talks about finding something in association an organ that’s affected.

RACANIELLO:

Um-hum.

LIPKIN:

It looks at clusters of disease where you find something that examines a burden. It talks about biological plausibility based upon analogies to other systems. So, for example, you know, this virus causes cancer in cows. It could equally well cause cancers in humans. You know, papilloma virus, for example.

And the last level, the most compelling level, of course, which I call level 3, is where you either complete Koch’s Postulates or you demonstrate that a very specific drug…

RACANIELLO:

Um-hum

LIPKIN:

Can eliminate disease, or you demonstrate that by vaccination, the incidence of disease drops dramatically.

Of course, Koch’s Postulates is the, you know, is the gold standard, but I don’t think it’s essential.

RACANIELLO:

How…in this case, the XMRV-CFS story, how did we not follow those rules?

LIPKIN:

Well, I think, with the initial publication, we had an association. We had some epidemiological data that suggested there were differences between cases and controls, but that can be….you can be confounded. Let me give you a couple of examples.

There was one particularly poignant one a few years ago where someone thought they had found the cause of a disease. I don’t want to go into more details because I don’t want to embarrass these people. But in essence, it was a respiratory disease. It was a disease of children and unfortunately the samples were collected during an outbreak of respiratory disease…

RACANIELLO:

Um-hum.

LIPKIN:

In a given geographical location and the controls came from a different one and during a different time of the year. And as a result there was this respiratory pathogen that was passing through the population that had nothing to do with the disease in question. So you probably know what I’m talking about.

RACANIELLO:

Um-hum.

LIPKIN:

But that’s why we decided to select all of the cases within a certain time frame so that we could be certain that we weren’t being…you know, just looking at an outbreak that was passing through a community. And in addition, this was the reason we decided to go for geographic diversity as well.

RACANIELLO:

Right.

So, the virus XMRV was originally identified in a screen of prostate tumors, and although your paper has nothing to do with prostate cancer, there are still some individuals who believe that there may be an etiologic role for this or a related virus in that disease. Any thoughts on that?

LIPKIN: Well, you know, I agree. And according to the strategy that I would pursue, in this sort of work, I would suggest, if you really wanted to address it rigorously, though I’m not eager to jump back into the world of XMRV…

(Racanniello laughs.)

And I don’t intend to, I’ve done my…As I explained, I’ve done my bit for NIAID for the year in this respect, I think what would be required would be the people who originally published that work should be sent blinded samples collected from individuals with disease and they should asked to test them and report their findings. But until the original group that makes the report withdraws the finding, based either because they say they made an error that they’re admitting to or they re-test new samples and say “We’ve done the best we can to approach this problem rigorously,” that question is going to be open.

RACANIELLO:

Right.

LIPKIN:

And I think that’s unfortunate and a disservice to patients who are continuing to pursue this hypothesis.

It is imperative that we find ways to rapidly address and reconcile these kinds of findings with, you know, with other data, so that we can move on.

RACANIELLO:

Well, it seems that that requires people to work together and you were sort of a third party in this case, so you were able to get this to work, it’s probably why NIAID came to you in the first place, but when you have people having different findings, it’s hard to get them to talk to each other. So what do you do? You call ‘em up and say…?

LIPKIN:

How do you get to yes?

It’s very difficult. I find that breaking bread with a little bit of alcohol is quite helpful.

RACANIELLO:

Yes. What if you don’t drink?

LIPKIN:

Great. It’s even better.

RACANIELLO:

So you mentioned just a few minutes ago you hope this is your last association with XMRV. Yet, it sounds like you’re interested in CFS/ME. What’s the future…

LIPKIN:

I am. Indeed.

So, what we’re doing is…We have two efforts under way. First, with the Hutchins Family Foundation we have obtained some support to pursue pathogen discovery and biomarker discovery in people with CFS/ME and what we’ve done is go to all of these clinicians and others who have previously found agents using commercial laboratories and have constructed a Mass Tag system which allows us to rapidly look at their leading candidates. And in addition, we are going to be pursuing high-throughput sequencing on the Illumina platform. We’re also doing RNA Seq. We’re looking for RNA markers and we’re looking for LNC RNase and for any other insights we might have that would enable us to understand the pathogenesis of the disease or develop markers that could be used for diagnosing people or making predictions about who is likely to respond. We also have a large proteomics project associated with this. So…and I am, you know, completely unbiased with respect to what we find, so we’re using unbiased high-throughput sequencing proteomics, same sort of thing, so it really is a discovery platform.

RACANIELLO:

What about the microbiome? Could this have some role in the disease?

LIPKIN:

So, the microbiome, unfortunately, in this project, we were not allowed resources to do those kinds of collections, which I think is something that needs to be done.

Under the auspices of the Hutchins Family Foundation, we are, indeed, collecting rectal swabs. So we would still be able to look at those types of materials.

RACANIELLO:

The other issue that…as you know, there are a lot of individuals who have followed this story, many with the disease, many of them accept or will accept the conclusion and hope to move on, but there will be a vocal cadre of them who don’t buy it, and some of them will say, “Well, you haven’t looked in the right place. Why PBMC’s? How do you know that is where the action is?

LIPKIN:

Well, that’s a good point and that’s another reason for doing this study as we did. We gave these investigators an opportunity to specify what samples they wanted. And they wanted PBMC. And they wanted plasma. And they wanted an opportunity to culture the PBMC. So when you start a study like this, you have to have ground rules. The ground rules that I insisted upon are, you know, the criteria for …

RACANIELLO:

Right.

LIPKIN:

Case selection, for sample selection, for sample processing, for analysis, for reporting have to be established in advance. And that’s the only …

RACANIELLO:

Um-hum.

LIPKIN:

…control that I’m applying from the outside. So, you can never exclude the possibility that had we looked someplace else, we would have found something different. But given that the original reports were based upon similar types of samples, similar types of analyses, these individuals felt comfortable with saying, “We believe that this study was fair.” So, we have a press conference, you know, on the 18th, where Harvey Alter, Judy Mikovits, Frank Ruscetti will be present and they will have an opportunity to answer questions from the press, and based on my understanding of what we’ve talked about, there won’t be any surprises. They’re going to say, you know, “We put our full weight of enthusiasm, belief nd confidence in what was done here, and we feel that we were given a fair shake, and that I think it’s time to move on.”

RACANIELLO:

In fact you have…this podcast will be released on the 18th and I have a—this is your press release which shows that what you’re saying is correct. Everyone seems to be agreeing here. And I should read the last …

LIPKIN:

The last quote from Mikovits?

RACANIELLO:

Yes. Do you mind if I read that?

LIPKIN:

Not at all.

RACANIELLO:

It will have been spoken.

“Although the once-promising XMRV and MLV hypothesis …

LIPKIN:

Start higher than that…

RACANIELLO:

You want me to go higher…?

LIPKIN:

“I greatly appreciate the opportunity …”

RACANIELLO:

"I greatly appreciated the opportunity to fully participate in this unprecedented study. Unprecedented because of the level of collaboration, the integrity of the investigators, and the commitment of the NIH to provide its considerable resources to the CFS community for this important study. Although I am disapponted that we found no association of XMRV/pMLV to CFS, the silver lining is that our 2009 Science report resulted in global awareness of this crippling disease and has sparked new interest in CFS research. I am dedicated to continuing to work with leaders in the field of pathogen discovery in the effort to determine the etiologic agent for CFS."

Ah yes, the next quote is yours…

LIPKIN:

Well, that’s okay. The important quote is hers. And I think that takes an enormous amount of courage and class.

RACANIELLO:

It always does to admit you’re wrong. But that’s the key. That’s the key to moving forward. And of course, in your paper, the discussion begins “Our results definitively indicate that there is no relationship between CFS/ME and infection with either XMRV or pMLV. And that is, everyone signed off on that, you say.

LIPKIN:

They’ve all signed off on it. Everyone has read the press release.

RACANIELLO:

I would agree with XMRV for sure, and pMLV as far as you’ve shown here, but maybe somewhere else in the body there’s another virus that is…that is causing this… or some pathogen.

LIPKIN:

Oh…

RACANIELLO:

And I’m pointing that out

LIPKIN:

Oh, I am…I am heavily invested, personally and professionally, in that search. Not personally, but professionally.

RACANIELLO:

Professionally. When you find it, we’ll have you here to talk about it. Anything else you’d like to say before we wrap up?

LIPKIN:

Thank you.

RACANIELLO:

Thank you for coming by. I appreciate it. So the press conference is going to be live streamed, I understand?

LIPKIN:

Indeed.

RACANIELLO:

And we will put a link at virology dot ws and TWiV dot TV so that everyone can find it and listen to it as well on the day of the 18th. Ian Lipkin is a Professor in the Center for Infection and Immunity at the Mailman School of Public Health at Columbia University . Did I get everything right there? LIPKIN:

Perfect.

RACANIELLO:

Thanks for joining me today.

LIPKIN:

Pleasure.

RACANIELLO:

I am Vincent Racaniello and you can find me at Virology dot WS. You’ve been listening to a special episode of This Week in Virology. Thanks for joining us. We’ll be back next week. Another TWiV is viral.

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