interviewFRONTLINE presents Organ Farm

walid heneine, phd

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Heneine is the Chief of the Molecular Epidemiology and Zoonoses Section, HIV and Retrovirology Branch of the National Center for Infectious Disease of the Centers for Disease Control. His primary research involves the monitoring of risks posed by exposure to animal retroviruses. In this interview he discusses the PERV virus threat, but argues that limited human clinical trials should proceed, albeit with caution and stringent monitoring. (Interviewed Spring-Winter 2000.)

Is crossing the species barrier a significant event, in terms of medical science?

I think it is, and the use of tissues in animals from different species could help us find treatments for many human diseases. The transplant surgeons and communities would attest to that, and that's why there has been a lot of work in this area.

What are the public health implications of xenotransplant?

Now we're talking beyond the benefit of the patient. We're talking about whether using these cells or tissues or organs from animals will bring about or introduce infectious agents, viruses that would cause disease in humans and would spread and therefore would have public health implications. . . .

At the moment, with the current state of scientific knowledge, can xenotransplant be made risk-free in public health terms?

As it stands today, I think it is very unlikely that it is going to be risk-free, since we already know that there are several viral agents that already exist in some of these animal organs that we are using in clinical trials. And we know that we cannot eliminate certain viruses from them. Therefore, we will be facing the possibility of evaluating what risks are entailed with exposure to such viruses. . . .

In your view, what is the worst-case scenario that could happen with the spread of virus through xenotransplant?

The worst-case scenario that was on many people's minds, especially the virologists, is that a virus would cross from the animal tissues or organs. It would be able to infect the patient, cause disease, and then from the patient, infect his contacts, family members, and health care providers. It could then secondarily spread into the community and then the population and cause an epidemic. The example that we are aware of is HIV-1. . . .

You can't go forward without taking some risks.  But you can minimize that risk by trying your best to leap in the right direction as cautiously as possible. Do you in the CDC and the legislators and the regulators feel an extra responsibility of care in this scenario because we are, in a sense, creating this opportunity, creating this risk?

The CDC would like to study anything that would affect public health and investigate that in a scientific way, and to provide information and data. Obviously, then the decisions will be taken based on these data and information. So I think the book is still open on how much risk exposure to some of these viruses would result in or what it would mean. That's what we have been involved with: trying to define the amount of risk involved in these exposures.

Can discussion about xenotransplant just take place between scientists and clinicians and research scientists? Or does it have to be a public debate?

It has to involve the public, because eventually some of these consequences of some of these procedures would affect the public as well, if some outbreaks of infections occur in a community. And so definitely the public has to have a say in this, and has to be involved in the discussion. . . .

Is it currently possible to have a pig cell transplant and not be exposed to PERV, the pig endogenous retrovirus?

At present, it is not possible. As far as we know, these viruses are integrated into the DNA of each pig cell from each strain that has been looked at. And there is some information that says that these viruses are even in the animals in the same family of pigs, indicating that they have been there since the pig species evolved. So it's not possible to eliminate PERV from pigs today.

Will any future whole organ trials involving pig organs expose people to that virus?

We already know that these viruses are expressed in different cell types and organs. In the test tube, at least, we can detect these viruses coming out from these cells, so it is very likely that exposure to PERV would be inevitable.

We've already arrived at that scenario, in a sense, because there are people who have had cellular transplants of pig cells. They've been exposed, haven't they?

Yes. Yes, they have. And in some patients, there is some evidence that those pig cells have persisted for a significant period of time, ranging from days to months, in certain cases. . . .

Does the CDC think that maybe we started down that road rather too quickly, before there was enough knowledge of PERV and its risks?

From a PERV and virologic point of view, I think we did not know a lot about these viruses when clinical trials started. So there was a lack of information about the characteristics of these viruses, or availability of diagnostic assays able to monitor patients for infection with these viruses. So clearly, we started with very little information. And there was a lot of pressure on our lab and other labs as well, to provide rapidly important information about what these viruses mean: how do they behave; how they infect the human cells or not; how to develop appropriate and adequate assays to allow monitoring of patients who have been exposed to pig tissues. And while all this was happening there were some clinical trials occurring at the same time. So, in a way, yes, there has been some work with a little bit racing with time, trying to find some information about what these viruses mean in terms of cross-species infections and so forth.

The clinical trials were stopped, weren't they? There was a moratorium. What was the thinking behind that?

When some of these data came out of different labs, saying that these viruses are capable, for example, of infecting certain human cells in vitro, that implied the possibility that patients could get infected when exposed. Then there was some thinking on whether we need to stop and see where we are, to develop assays and appropriate courses so that we can do better surveillance, better patient monitoring. We could be more prepared in case something of that sort happened. That was the reasoning behind putting certain clinical trials on hold -- so that we can be better prepared to address these questions and issues.

Was the CDC at the heart of calling for that hold-up?

It was involved as part of a group of public health agencies. The FDA, the CDC and the NIH were all involved in these decisions.

What is a retrovirus?

A retrovirus is one family of viruses that includes a large number of different types that have been found in different animal species, humans and otherwise. They were called retroviruses because they use a unique way of replication. They have an RNA genome. To replicate, they move from RNA into DNA and then back into RNA. That's the opposite way to what usually happens in a cell, where you move from DNA into RNA then to protein. So they are called "retro" because of that mechanism that they use for replication.

Some of the famous retroviruses are HIV-1 and HIV-2, which cause AIDS in humans. There are two other human retroviruses . . . HTLV-1 and HTLV-2. HTLV-1 causes leukemia and some neurologic diseases in humans. HTLV-2, so far, is not associated with any disease. So retroviruses can cause disease; some don't. Some cause disease in a small proportion of the infected population, and some cause disease in almost every infected person.

Are human beings are exposed to them all the time?

I think we are exposed to different animal viruses, including animal retroviruses. And there is some recent evidence from our lab, for example, that people that are working with monkeys are at an increased risk of getting infected with some of these monkey retroviruses.

In a transplant situation, is it possible that a pig retrovirus could be activated or amplified in its effect by the mere act of transplanting it from the pig to the human host?

We understand very little about what would increase or decrease the expression of these retroviruses in a transplant, especially in the context with a human recipient. So it's very hard to speculate. You can say it's possible or you can say it's not possible. But I really don't know whether the expression of these viruses will increase or decrease.

Transplantation has been known to increase the effect of viruses like CMV, hasn't it?

Yes. The clearance of the expressed virus maybe is a different question, whether in an immunosuppressed host, whether you have stable expression of these viruses. However, they are not cleared or eliminated by the immune system of the host because of the immunosuppression that these patients are receiving to accept the graft. That could be a problem, and that's been known to exist in other viral infections in transplant recipients.

And in the transplant situation, all the recipients, by the very nature of the transplant, would be immunosuppressed, wouldn't they?

Yes, definitely, and maybe more for a transplant of distant origin.

They are very likely to immunosuppressed for life, aren't they?

Very likely.

Viruses, ordinary or retroviruses, can lay dormant for years or decades, can't they? As a layman, one knows that they change, and they can mutate. Does that worry you in relation to xenotransplant?

It is known that retroviruses are able to mutate and change over time. They are able to recombine with each other as a mechanism of change and diversity. So it is a source of concern whether these events can also happen within a transplant situation, and what would be the result of that. It's very unpredictable to know whether these events will happen, and whether they will have some clinical consequences or infection consequences.

To put it crudely, aren't we offering some of these retroviruses a new opportunity to grow when we take an infected pig organ and transplant it into a human?

In a way, yes, and in a way, no. It depends what the end result would be. Yes, it's always possible that . . . you are now introducing these agents into the human body. But it is possible that these viruses are capable of causing an infection that would be very benign. And we still don't know much whether those viruses will be able to take hold and cause an infection that has consequences of disease, and spread.

But we must be offering them a new environment of opportunity that they may never have seen before?

You could argue that, previously, man has lived with pigs in close proximity for ages, and there has been exposure, undoubtedly, to these viruses. . . .

But living with a pig is not the same as living with a pig organ inside you.

True. True. True, and this may have additional risks.

The normal barriers of the skin, the stomach, and the lungs are removed, aren't they?

True. True. A lot of defenses that normally would protect you against infection or against these exposures now are not there when you introduce these tissues with these viruses inside the body. And that's why there are the concerns about transmitting these infections more readily than in any occupational exposure.

That pig organ will be inside someone shedding pig cells, and living still as a pig organ. But it doesn't become human, does it?

It will be a pig organ doing its function, and that happens to help the patient.

And it will be there for their lifetime?

If the transplant works, that's the idea; that's the hope.

Does giving the pig organ human genes increase the risk of pig viruses evolving to infect us?

It's an open question. No one really knows whether these viruses would, for example, resist the defense mechanisms more that we have for porcine viruses that do not have these human antigens, so could escape some of our defense mechanisms.

As you may know, we have antibodies and we have our specific defenses that now we know can protect us against some of these porcine retroviruses. If, for example, you start manipulating the pigs and introducing some of these human antigens on them, it's an open question whether you would compromise those natural defenses that you have for intact porcine viruses. And, of course if you further humanize the porcine tissue or organ, then you would allow it to persist longer in the patient. That would give it more time for a possible infection and so forth to take hold.

If a pig retrovirus was budding off from a human cell, it would take with it some of the membrane of that cell as it shed itself and went off into the bloodstream. And that membrane around it would be partly human, wouldn't it?

That's right.

It would be cloaked in something that was humanly protective, even though it was a pig virus?

That's right. It is known now that our antibodies and our defense system can work and can kill intact porcine viruses budding out from porcine cells, because they happen to have some of these porcine molecules that our antibodies recognize and kill. If this porcine retrovirus infects a human cell and buds off and carries an envelope with it that is of a human origin, from a human cell, then those antibodies will not be able to recognize that porcine molecule on the envelope, and will not be able to kill this virus. So in this way, these viruses would be harder to eliminate through that mechanism.

We are seeking to fool the body's immune system with a transgenic pig organ. The body's immune system is also our main line of defense against animal retroviruses and ordinary viruses. Are we wise to tamper with the very barrier that our body uses to distinguish us, the humans, from them, the animals?

I think you need to keep that balance. You want the transplant to persist and survive and function so that it can help the patient. But at the same time, you don't want to suppress too much the immune system so that it won't be able to protect you from infectious agents. It's a delicate balance that needs to be there, so that both the transplant and the patient will do fine.

Are you aware, as some people have said to us, that this is a real Pandora's Box?

It's very hard to tell today from the data available whether this is the case or not. I think we have to wait for more information to come out as all these studies are being done.

Does it add to your concerns that, if this treatment succeeds, that it not be a treatment aimed at the very few with a very specialized rare disease, if it goes to the big time?

Yes, the idea is to provide treatments for all the patients who need it, and they are numerous around the world. And I think part of the success of the treatment would have to involve the infectious risks that those treatments will be associated with. So a successful treatment would not only work as a good transplant, but would also not be associated with the transmission of any animal infectious agents. That's the ideal situation; that's what everybody is hoping that we will have.

How long do you have to wait, assuming that you have a patient who has had an organ transplant, to know that this is safe, that they will not contract an animal infection?

You can be positive about those viruses we know of, those that we can test for and screen for. We can reliably determine or not transmission has occurred. We will be less positive with those agents that we don't know of, that we can't test for.

What do you mean by that?

I refer to unknown agents that may have been in the pigs and that we would not have previously identified, so obviously you cannot test for these. We have tests available for those that we know of. We can look for them and see whether or not they are being transmitted by these exposures. The concern is for those that we don't know of and that we cannot test for.

How long should the monitoring of xenotransplant patients be carried out for?

Well, it depends. There are no rules here that can say for how long. We do not have the type of information that would allow us to say that within one year or six months or so, that that's enough. All we can do is actually use all the tests available to us, the ones that we know work with different infections and apply them here; see what information these tests are giving us; look at the persistence of the virus in these patients over time; and see whether or not there is any evidence of infection taking place. So it is pretty difficult right now, with very little information available, to determine how long we need to keep monitoring.

I'm interested that you don't say they need to be monitored for life.

Well, to say "for life". . . If, for example, you have an exposure to a porcine xenograft like in a liver perfusion, and then you have monitor for transmission of these porcine retroviruses for a year after that, is that optimal? If everything is negative, would we stop there? Some people say yes, this is enough. If anything would have happened, we should have seen it one year after. So therefore, in this scenario, lifetime monitoring may not be the adequate answer.

In a different scenario, if we get to a point where we have pig kidneys that are working or pig livers that are placed in patients and are working and maintained for long periods of time, then the issue of long-term monitoring would be adequate. So it really depends on what type of exposure you are talking about.

Do you think the first patients for a whole organ transplant would have to be monitored for life?

Again, it's just speculation. People would think as long as it is there, then you need to monitor. Once it's not there, after it's been removed, then you have to question how long you want to monitor after that.

Some of the patients we've spoken to live under some restrictive conditions. For example, why do they have to keep a record of all their sexual partners?

Because of the possibilities that these viruses can transmit sexually. And you would like to be able to go and trace back those infections and be able to counsel people; be able to derive some information that would help everybody that would be exposed to these viruses.

Why would you test the blood of close relatives and family members?

There's an issue of the possibility of transmission to close contacts. You want to be able also to address that question and provide that type of information in case those infections take place. You would like to know how these viruses are transmitted: sexually, by close contact blood-to-blood exposure, and so forth.

One of the patients that we have spoken to in a stroke trial has been advised strongly not to have children at the moment. Why?

I am not aware of this particular case. Again, we know that other viruses like HIV-1 are transmitted from mother to child, for example. So we have many instances where many different viruses can be transmitted perinatally -- from mother to child -- so the question here is still open. . . .

Why are all of them under the restriction not to donate blood?

All the different retroviruses that we know of are transmitted by blood, such as HIV-1, HIV-2 and the other HTLVs. Donating blood would probably present risks to the blood recipient, so therefore it's a sensible precaution.

If there were an outbreak of a "hot virus," what would you do?

Well, we can do follow-up -- try to see first whether there is any clinical consequence. You may get infected, but there may not be any disease. This is still a big possibility. So we would like to see whether there is disease, and be able to see what the risks of transmission are from the infected person to their contacts. We want to investigate all these.

So when you say people could become infected, do you mean that the virus could replicate in someone's body and actually produce no symptoms?

Yes, and we have many instances of these types of infections occurring all the time, with many different viruses, including some retroviruses. You could be infected for life but have no symptoms or no disease.

Could that change, if, at some stage in your life, your immune system became further compromised or exhausted?

Possibly yes, and possibly no, too. We have examples of either scenario.

Do you think that the only way to resolve a lot of these questions is actually to go to some kind of limited human trial?

I think so, and this is what is happening: very cautious progress, and limited trials, with very good monitoring. That's what is now being done.

At some stage, though, those cautious human trials are going to have to involve a whole organ, aren't they?

I think whether that is a sensible thing to do has to be determined based on the information from the research. But I think the way it stands right now, a very close element of monitoring will always be occurring in these trials. And again, as more and more data accumulates, you will be able to modify how much monitoring and all these important questions.

There's an issue of free will versus monitoring, isn't there? Some people may not be willing to live under these restrictions. In that case, could you do anything about it?

It's a delicate situation, because you are dealing with free will and personal freedom. But at the same time, you have the public health consequences, so it is very delicate. And one has to balance both the risks to the public health but also the free will and freedom of the patient and the physician-patient relationship. So it is a complicated situation.

What's your assessment of the quality of work? How much confidence does that give you to maybe move forward on this at some stage?

I think the progress that has been made in the past two or three years has been substantial and impressive. It's gone from knowing very little about these viruses, from only knowing that they exist, to knowing a lot about them -- their characteristics, their DNA sequences, development of assays to detect them and monitor patients. I think the progress has been substantial. The data that has come out from looking at patients that have been exposed has all indicated an absence of infection or transmission.

The numbers are not in the thousands -- they're in the hundreds. But they are telling us something. They're telling us that these particular porcine retroviruses are not easily transmitted. And so you could look at this in a positive way, that this is a step forward to keep things going on. However, you should also keep in mind not to generalize this information to any type of xenograft procedure -- that those negative data can apply to these types of exposures, for example, to pig liver perfusions or spleen perfusions, but cannot be generalized to, say, porcine liver transplants. We have to evaluate those risks by type of transplant, by characteristics of the transplant surgery and so forth. But so far it has been positive, and the progress has been impressive.

All the safety studies can only be is a snapshot of yesterday, can't they? We evolve, things change, things move. How do you feel about that?

There are two ways you can look at this question. You can look back at people that have been exposed and study them. Or there's the other way, which is looking in real time at people in clinical trials, and then see whether or not they are getting infected. Both types of studies are being done, and this is where we say close follow-up and monitoring. You cannot be always there and see whether things change and whether one particular type of exposure would lead to infection more readily than another type. . . .

It's not possible, is it, to go forward on this without risk?

You can't go forward without taking some risks. But you can minimize that risk by trying your best to leap in the right direction as cautiously as possible.

Are scientists out there ready to expect the unexpected, in terms of xeno and its virological implications?

I think we like to think that we are open to study or investigate different consequences. But no one can predict what the result would be.

You can't know the unknown.

You can't know the unknown. And it can be very benign and very boring, or it can be not benign and more risky, or virulent.

The xeno proponents say that this whole thing is, of course, for the benefit of the patients. But are there other things that are driving this process forward? Are there commercial pressures that push xeno? How do you feel about those?

I am less involved in this aspect of the research. I think, like in any industry, there are commercial aspects and there are also non- commercial aspects. We investigate important public health questions, and that's what we are paid to do by the American people.

Are you actually collecting a database of blood samples and biopsies worldwide that may be useful in the future, if things go awry?

There are plans to do that. Right now, all clinical trials are asked to archive samples from these patients for testing in the future should anything arise or should any new viruses identify and so forth. Yes, there are plans to do that.

Are there practical steps that are agreed upon and that will be taken if a virus did produce itself and become seriously infectious?

There are steps to continually follow up those infected persons and try to figure out whether the consequences are benign; whether there is any disease that would be caused by these infections; whether there would be any evidence of transmission of these viruses to contacts and so forth. So there are those plans, too, for the long-term follow-up of these infected individuals.

In the event of an outbreak of an infection, would that involve quarantining the patients who had been involved in the trial, in order to protect the public?

That has been discussed, too. And depending on the way these viruses would possibly transmit, those procedures would have to be implemented. And these have been used before in situations where public health was endangered from transmission of certain infectious agents. I think they are being discussed in case that situation occurs.

Basically, they would involve a quarantine situation until you could study what was actually going on?

Those details have not been worked out.

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