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Medical Reporting Spring 2012

It is difficult to pinpoint the source of persisting pain once an injury has healed; thus chronic pain patients are often told the pain “is all in your head.”  But new research led by a team of neuroscientists at McGill University could change what it means to have chronic pain — that it in fact lies in neuronal pathways and is far more complicated than simply being “in your head.”

The research paper, which was published in Molecular Pain, pinpoints a new drug with the acronym “ZIP,” which selectively removes certain pain memories while leaving others intact.  Scientists have known for years that there is a connection between chronic pain and neuronal pathways, but this is the first time a drug can actually erase the pathways to remove pain.

“This is the first time that we can foresee medications that will target an established pain memory trace as a way of reducing pain hypersensitivity,” Dr. Terrence Coderre, a McGill professor of anesthesiology and neuroscience who led the research team, said in an interview with Science Daily.  “We believe it’s an avenue that may offer new hope to those suffering from chronic pain.”


What is chronic pain?

In 2010, the National Institute of Health came up with a blueprint to push forward partnerships between pain scientists and non-pain neuroscientists to examine the transition from acute to chronic neuropathic pain.  “Chronic neuropathic pain conditions are difficult to treat and we currently lack an understanding of the mechanisms underlying the transition to a chronic pain state after acute nerve injury,” the report states.

There are 116 million Americans suffering from chronic pain, compared to the 11.9 million Americans with cancer, according to the Institute of Medicine of the National Academies and the American Cancer Society, respectively.  Worldwide, there are about 1.5 billion people suffering from chronic pain.

“Chronic pain is any pain that lasts for more than 3-6 months and beyond that,” said Dr. Terrence Coderre.  “In a number of injuries, the tissue that’s injured may heal, but the pain will remain.”  The McGill team’s report published in Molecular Pain perhaps defines chronic pain in the most succinct way: “Chronic pain occurs when normally protective acute pain becomes pathologically persistent.”

Whether back pain, arthritis, or phantom limb syndrome — chronic pain is a major health problem in the US.  According to the NIH report, chronic pain has an economic burden of $100 billion per year in medical expenses and lost productivity in workers.  A 2006 survey conducted for the American Pain Foundation, meanwhile, discovered that 51% of respondents felt they had no control over their pain; 77% felt depressed, and 86% said their pain caused an inability to sleep well.

In the past, a number of different approaches have been used to treat chronic pain.  Anti-inflammatory drugs are commonly used to treat pain caused by arthritis, but if used over a long period of time, can cause damage to organs.  The use of opiates to treat pain could eventually lead to abuse and dependence.  But ZIP could remove this memory trace once and for all–given there isn’t any “periphery” pain (like inflammation) continuing, which would in turn create new neuronal pathways.

“We were interested in targeting something other than periphery or opiate systems of the brain,” Dr. Coderre said.  “We wanted to target memory traces.”

But the word “memory” is not to be confused with the traditional sense of cognitive memory — the kind that holds your dreams, thoughts, and images of your past.  There is, so to speak, two different types of memory that will be discussed in this article — the first being memory dealing with chronic, or physical, pain; the second being cognitive memory, which is the conscious memory of an event.  The neurons involved are in different places — for cognitive memory, they lie in the hippocampus, while the pain neurons lie in these pain traces.

“In a pain memory trace, the neurons amplify the signals and get accentuated, causing the pain to last longer,” Dr. Coderre said.  “You develop what’s called pain hypersensitivity.”


ZIP and PKMzeta

If chronic pain has been so difficult to treat, then how exactly does ZIP work?  Dr. Todd Sacktor, Professor of Neurology at SUNY and co-author of the McGill study, has been interested in memory research for nearly 30 years.  He was particularly interested in how long-term memories were stored, and discovered a particular enzyme called PKMzeta 20 years ago.

“Memories are thought to be a strengthening of connections between neurons,” Dr. Sacktor said.  “No one knew what was causing this strengthening in a persistent fashion… In 2006, it became clear that PKMzeta is the main storage mechanism for long-term memory.”

As an enzyme, PKMzeta catalyzes chemical reactions.  What ZIP does is prevent the chemical reaction from occurring, and thus the neuron connections are not strengthened.

“ZIP is a little peptide that fits into the PKMzeta molecule like a key fitting into a lock, but it’s a broken key,” Dr. Sacktor said.  “The way it usually works is that ‘keys’ get locked in PKMzeta, and then the altered key gets spat out and is functionally different, and acts to strengthen the synapse.  But ZIP is a broken key that doesn’t get out, and so the memory collapses.”


Cognitive Memory and “Eternal Sunshine”

When many first hear about a drug erasing memories, they immediately recall the science fiction movie “Eternal Sunshine of the Spotless Mind,” in which the main character undergoes memory removal to forget the painful breakup of a relationship.  This may be possible in the future, if ZIP is targeted at cognitive memory.

“The important thing to note about… ZIP is that it could potentially work in all neurons, including the area of the brain that’s responsible for your cognitive memories,” said Dr. Coderre.  “Therefore, you could potentially affect all your memories.”

It goes back to the little enzyme: all memories — whether you think about them or not — are being maintained by PKMzeta.

Although the McGill team including Drs. Coderre and Sacktor did not concentrate on ZIP’s effect on cognitive memory, there is another branch of research called “reconsolidation blockade” that is investigating this front.  Reconsolidation occurs every time a long-term memory is brought out of storage and “remembered,” changing slightly each time the brain recalls it (in other words, memories aren’t accurate documentations of the past like we may have thought).  The memories are then re-stored in the brain as the slightly altered version.  The goal is to develop an extremely specific version of ZIP, which only becomes active when a certain memory is recalled.

“This might allow a specific, recalled long-term memory to be erased, rather than all long-term memories,” Dr. Sacktor said in a 2009 New York Times interview.  “How this reconsolidation work fits in with PKMzeta is actively being explored.”


Ethical Implications, Future Steps

There is already an ethical debate — a theoretical one — in which people are arguing over the implications of ZIP.  If a highly advanced version of this drug got into the hands of the wrong people (political dictators, for example) could it be used as a form of torture or brainwash (literally)?  Or are these merely the dismissible arguments of conspiracy theorists and science fiction fanatics?  Dr. Sacktor believes that even though it may take 10 years or more before ZIP can be used clinically, human manipulation of memory is eventually bound to happen.

“When it actually happens, people who are scared of it are going to be even more scared of it,” he said.  “People who want it, are going to really want it — it’ll be the same as in vitro fertilization and abortion.  Religion will say it’s the end of the world.”

But perhaps what is most fascinating about this research is that it opens doors into the arena of other memory disorders such as Alzheimer’s.  PKMzeta was discovered to be involved in the web-like clusters found in the brains of Alzheimer’s patients, although research is still in the beginning stages on this front.

“Elucidating the molecular mechanism of long-term memory may one day be key, I hope, to developing treatments of memory disorders,” Dr. Sacktor said in The New York Times interview.  “But don’t forget how long this development from basic science discovery to clinical usefulness takes— decades for even the most important findings, such as germ theory and the structure of DNA.”

Final senior paper for my Advanced Reporting class at NYU, Spring 2012.

A young dark-haired German doctor takes the stand at a Physicians’ Research Network event in New York City as the doctors in the audience applaud him.  He speaks with a thick German accent, pronouncing HIV “HI-wee.”  Although he is an oncologist by profession, Dr. Gero Hütter is known to be the first doctor to have successfully cured a man of HIV.  Dr. Hütter speaks for an hour about the case that was a milestone in medical history — more for its “theoretical” value than for its clinical practicality — and when he makes the statement “cured,” several of the audience members exchange glances and shake their heads in disbelief.

Many doctors have questioned whether Hütter had the right to claim he’d actually cured someone of HIV.  It’s not so much that these doctors and researchers don’t believe what he’s saying, as much as the long-standing taboo in linking the words “HIV” and “cure.”  Yet The New York Times and New York Magazine wrote long features about this particular case, using words like “innovative,” “miracle,” and the phrase “absolutely no trace of the virus.”

But the speaker at the beginning of the event had said, “We will have more of a theoretical conversation going on here tonight.”  It would be a conversation about shifting concepts and attitudes; one that opened up different possibilities to finding a cure.  Now that Dr. Hütter’s case had opened the door, the medical world could begin believing in what was once thought impossible, and directing its energies to practical research for cures.

HAART and why it may not be enough

Thirty years ago, the appearance of an unknown virus devastated the world, stigmatized minority groups, and caused social and cultural upheaval, especially over gay rights and the use of contraception.  Since 1990, the total number of people infected with HIV has risen steadily from 8 million to the current 34 million — 22.9 million of whom live in Sub-Saharan Africa.  Though the numbers continue to rise, modern medicine in the developed world has made enormous progress in treating the infection.

Today, a patient infected with HIV can be expected to live a long and otherwise healthy life if placed on highly active antiretroviral therapy (HAART), usually a “cocktail” of drugs the patient must take for life.  Although the treatment does not completely eliminate infection from the body, it forces viral numbers down to such a low level the virus is virtually harmless.

Dr. Robert Siliciano is a Pharmacology and Molecular Sciences professor at Johns Hopkins University.  His two areas of research focus on testing HAART efficacy and exploring HIV latency — a state in which the HIV virus still exists in memory CD4+ T cells but no longer replicates.  Patients who’ve been on on HAART may not be sick, but still harbor this long-lasting “reservoir” of HIV which creates an elusive barrier to fully eradicating the virus.

Dr. Siliciano’s website states, “The benefits of HAART in reducing morbidity and mortality are clearly documented, but major questions remain about how best to use this therapy and how to make it available to all who need it.”  Because HAART does not completely cure patients, the treatment of HIV infection is a lifelong challenge, complicated by drug resistance and toxicity.

“[HAART] essentially allows infected people to have a normal lifespan particularly if they start treatment early and take the drugs correctly,” Dr. Siliciano said in a phone interview.  “The latest studies are confirming that people who start treatment early have a normal life expectancy, which is a huge change [from 20 years ago]. But everyone will have to be on treatment for life because of this long-lived reservoir of HIV.”

In the early days of HAART, drugs came with many side effects — certain antiretroviral drugs caused nerve damage, others caused metabolic problems, fat redistribution, and even diabetes.  Optimal HAART has very little side effects, but some HIV-infected patients can still develop resistance to treatment.

“Drugs can be a nuisance to take… people lose their pills or forget to take pills,” said Dr. Abigail Zuger, an infectious disease physician practicing in New York City.  “Some people who are vulnerable to diabetes can develop lipodystrophy — they become fat in the stomach, thin in arms and legs.  Short-term effects include upsetting people’s stomachs… Some drugs can lead to anemia, some change the way the kidneys work.”

Although HAART treatment has made extraordinary improvements since it was first developed in 1996, many of the 34 million people infected are not on the ideal HAART treatment.  In resource-limited settings and third-world countries, HAART regimens are antiquated and fairly toxic.

“Efforts to roll out HAART to resource-limited settings have stalled for economic reasons,” said Dr. Siliciano.  “So out of the 34 million people infected, there aren’t too many on optimal HAART — they should be, and would have to be on it for life.  That’s a lot to ask and one reason why we need to think about ways to essentially cure people.”

Another consequence of HAART is the long-term economic burden placed on the healthcare system, something that could be alleviated if a cure is found.

“We’re looking at millions of HIV-infected people and a very large healthcare burden on the world,” Dr. David Margolis, professor of medicine, microbiology, and immunology at University of North Carolina, said in a phone interview.  “If you just look at treatment long term, that’s an incredible economic burden and it will dilute us to fix other economic problems or healthcare needs.”

And while most HIV patients can live healthy and happy lives on HAART, the virus can cause complications that may not occur in a virus-free person.  On top of that, Dr. Margolis said, the negative social “stigma” of having AIDS still lingers.

“Finding a cure is not necessarily driven for the cost reason,” said Dr. Judith Aberg, Director of Infectious Diseases at NYU Langone Medical Center.  “Life still remains shortened depending on a patient’s CD4 count when it started.  There are still morbidities involved… and this is attributed to having a chronic viral infection where there’s more inflammation in our body causing damage – coronary heart disease, more malignancies than in age-matched peers.  So if you can cure, you can actually prevent these other co-morbidities.”


The Berlin Patient: Hype and Theoretical Repercussions

For many years, the idea of a cure seemed impossible.  Dr. Margolis, like most doctors, agreed that “we don’t really need anything better than [HAART],” even while acknowledging why a cure would make sense.

Then a remarkable story broke in 2007 and 2008.  After two separate bone marrow transplants, a man known as the “Berlin Patient” had apparently been cured not only of leukemia, but also of HIV.

The Berlin Patient, 40-year-old Timothy Brown, had been diagnosed with HIV in 1995 and originally expected to live only two years after he found out.  Fortunately, the development of antiretroviral therapy allowed him to continue his normal life, at least until he discovered he had leukemia in 2006.

Brown was treated by Dr. Hütter.  Although he was an oncologist who had no extensive experience in virology, Dr. Hütter was aware of a certain protein called CCR5 that the HIV virus uses as an entry point for immune cells.  1 percent of the Northern European population genetically lack CCR5, thus making them naturally immune to HIV infection.

“The highest frequency of this mutation is in Northern Europe around the Baltic Sea,” Dr. Hütter said during his presentation at the PRN event.  The mutation is absent in Africans, Asians and Indians.

When chemotherapy didn’t work, Dr. Hütter searched for a bone marrow donor who was a match for Brown and also lacked the CCR5 protein.  Out of 232 matches, one was a perfect fit.  After the bone marrow transplant was successful and Brown was taken off HAART, no sign of HIV was detected in his body.  Several years and rounds of testing later, there is still no sign of the virus in any “compartment.”

“As oncologists we say after five years of disease-free, we call people ‘cured’,” Dr. Hütter said during his talk.  “Now it’s been more than five years, so from an oncological point of view [Brown] is cured from leukemia and he’s also probably cured from HIV.”

Dr. Pablo Tebas, director of the adult AIDS Clinical Trials Unit (ACTU) at University of Pennsylvania, backed up Hütter’s statement during his own presentation on gene therapy at the PRN event.  “The definition of a cure is a permanent remission of disease and its consequences in the absence of therapy,” he said.  “By this definition, Brown is cured.”

Bone marrow creates immune cells that HIV targets through a process called hematopoiesis — during which stem cells derived from bone marrow are able to develop into mature immune cells.  But bone marrow transplants are so risky that they kill about a third of patients, and Dr. Hütter believes they are so dangerous that “they can’t be justified ethically” unless a patient is in a desperate situation, like advanced leukemia.

While the story was exciting at the time, and the media portrayed it as a “miracle,” many doctors remained skeptical.  “I think that most people believe this patient was a fluke, a happenstance,” said Dr. Zuger.  “And I don’t think to the best of my knowledge that anybody is taking bone marrow transplantation treatment seriously.  It’s too expensive and much too dangerous — it would be unwieldy to do it on the scale required… It was an interesting scientific happening, but it didn’t change my thinking about the feasibility of finding a cure.”

But the importance of the Berlin Patient lies not in the notion that bone marrow transplants could be the generalized cure.  Rather the case proved, at least theoretically, that HIV/AIDS could be cured.  This, in turn, has stimulated research aimed to eradicate HIV.

“[The Berlin patient case] did push, I think, at least the willingness of patients to take risks and the FDA and investigators to consider riskier procedures,” Dr. Aberg said.

During his presentation, Dr. Hütter showed selected screenshots of the hundreds of e-mails he’d received from HIV-infected patients (their names blocked out), begging him to cure them, too.  One patient wrote, “You are my only hope.”  Hütter received e-mails like this daily, but despite an attempt to find a “Patient #2” to test the same treatment as proof of principle, he has not been able to recreate the case in any other patient.

Bill Bahlman has served over 26 years at the AIDS Clinical Trials Group (ACTG) and agrees that with all the media attention, many HIV-infected patients became excited about the possibility that a bone marrow transplant could work for them, too.  Bahlman stressed that it was important for the HIV/AIDS community to understand that doing bone marrow transplants could not be an actual cure due to the high risk of mortality.  In other words, the Berlin patient’s case was ‘a’ cure — not ‘the’ cure.

“As a story that sparked media interest, it also sparked a lot of research,” Bahlman said.  “[In the past], ‘cure’ was kind of a dirty word – finding one was unbelievable.  Even though the Berlin patient may be considered a fluke, it has prompted new initiative research.”

Dr. Margolis believes that due to frustrations in the past in attempting to find a cure, many skeptics of the Berlin Patient concluded that it’s impossible to eradicate infection.  “That’s not true, we just don’t know how to do it yet,” he said.  “The way the Berlin patient was cured may not give us the idea of how to cure millions people in the world, but it is proof that it can be done.

“When we published the results we were called irresponsible for even bringing up the idea that a cure could be done.  All the progress that’s been in made in the past 2 years is because of the Berlin patient, as people turn resources to this goal of a cure in a rational way.”


Zinc Finger Gene Therapy

Dr. Pablo Teblas identified the two main research initiatives for finding a cure during his presentation at the PRN event.  The first is the full eradication of the virus from the body, either by eliminating the HIV reservoirs or through gene therapy.  The second is a “functional” cure — the ability to maintain or boost the immune system so that it can control HIV replication in the absence of antiretroviral therapy.  A functional cure would most likely be in the form of a vaccine.

Dr. Paula Cannon, a leader in the gene therapy field, was prompted by the Berlin Patient case to use zinc-finger nucleases (ZFNs) — DNA binding and cutting proteins — in human hematopoeitic stem cells (HSC).  This type of gene therapy would target and remove the CCR5 gene in an HIV-infected patient.

“Through zinc-finger nucleases, we’re able to knock out the CCR5 gene at very high levels in hematopoeitic stem cells,” Cannon said in a phone interview.

Dr. Ricky Hsu, an Associate Clinical Professor at the NYU Medical Center, is also conducting research on zinc finger technology with a company called Sangamo BioSciences, Inc.

“Zinc finger technology is so specific that it can go right to the gene that is responsible for the CCR5 receptor that HIV latches onto,” Dr. Hsu said during a phone interview.  The procedure involves clipping out the CCR5 receptor, which creates a resistant T-cell.  Externally, these resistant T-cells are multiplied by the billions in cell culture and then reinfused into the patient.

Clinical trials using this gene therapy technology have already been conducted, and have shown that reinfusing these resistant T-cells to HIV-infected people causes a substantial increase in T-cells in the body.  Secondly, these resistant T-cells were able to survive over a year and a half after a single infusion and also continued to replicate.

“There would still be reservoirs of latent viruses throughout the body, so this technology would allow intermittent T-cell infusions, hypothetically every 2-4 years, so that HIV can be controlled without long-term toxicities,” Dr. Hsu said.  “It itself is not a cure — these infusions would still have to be given continually.”

Dr. Hsu also mentioned the future possibility of modifying stem cells in gene therapy, which would continually make resistant T-cells to replace the non-resistant T-cells.

Along with his zinc finger research, Dr. Hsu is studying the CCR5 gene in people who have a deletion of one of the genes, making them heterozygous and thus likely to progress with HIV more slowly if infected.  The Berlin Patient’s donor had both CCR5 genes deleted — but 10% of Caucasians are heterozygous.

“In prior studies, one patient stopped HAART after he got the infusion of these resistant T-cells and he was absolutely undetectable,” Dr. Hsu said.  “They found this person was heterozygous CCR5.  My other study is looking at people who are heterozygous with this gene, and doing this gene therapy while stopping all HAART treatment.”


Targeting the Latent Reservoir

Researchers headed by Dr. Margolis at University of North Carolina, as well as a group at the NYU Langone Center Division of Infectious Diseases are working on the second branch of cure research — the problem of the latent virus reservoir.  It’s a complicated issue that, once resolved, may completely eradicate the virus and promise a more realistic solution than gene therapy.

For years doctors believed that if these last hidden “latent” cells could be destroyed, then HIV would be cured.  The first problem was finding a way to reactivate the cells to begin producing the virus again; the second was destroying the virus once it was “coaxed” or “prodded” out of latency.  Researchers began testing experimental drugs that could target the latent reservoir and reactivate the cells to begin producing HIV again.

“The idea is that if you can induce [the cells] to start making the virus they harbor, they will either self-destruct or they will be targeted by the immune system,” said Dr. Nathaniel Landau, Professor of Microbiology at the NYU Medical Center.  “It’s still a long shot, because it’s not clear that those cells will self-destruct… Secondly it’s not clear the immune system will be strong enough to get rid of them.  People should not have any false hopes that we’re just about to cure this.”

So the latent reservoir research has two main branches which would theoretically work together to make a cure.  Dr. Margolis is doing Part 1 — the “poking and prodding” of the latent HIV reservoirs, while doctors like Elizabeth Miller and Thomas Norton at the NYU Medical Center are exploring the second half of the equation — looking for ways to stimulate the immune system of HIV patients enough to be able to destroy the HIV virus once it is coaxed out of latency, primarily through the use of HDAC inhibitors.

Dr. Margolis, 52, has been doing research that led up to this point for the past 20 years, and expects to see a cure in his lifetime.  He is motivated and encouraged by several factors, particularly by the fact that a focused, intensive therapy or cure would be less expensive than a lifetime on HAART.

HAART generally costs around $20,000 a year in the developed world.  Along with delivering therapy, patients must pay for medical care — they have to see a doctor, take blood tests, etc.  If most people with HIV infection are in their teens or twenties, they may be living 40-60 years on lifetime HAART.

“It’s hard to imagine what the dollars will be, but it’s easy to imagine that we could come up with focused therapy that’s complicated and somewhat expensive, but overall is less costly than a lifetime of medical care,” Dr. Margolis said.  “So that’s really the reason to eradicate: The lifetime burden of infection.”

Finally, the spread of HIV will not be controlled, nor will the population of HIV-infected people be reduced, unless there is a way of removing people from the infected equation.

“Condoms can prevent, but bad behavior always happens,” Dr. Margolis said.  “The last reason is really the aspirational reason — people with HIV infection all over the world carry the stigma of infection — it’s different from having diabetes, for example.  Maybe you can’t put a price tag on that.  That is why a lot of people who have access to therapy want there to be a cure.”