What do a 15-year-old Milwaukee student bitten by a rabies-infected bat, a 45-year-old Berlin patient with HIV and leukemia, and a 17-year-old with a rare prion disease have in common?
They took big risks with experimental treatments and won big benefits – while others suffering from the same conditions are nearly universally less fortunate.
In this piece, I present three remarkable stories of people who in recent years survived illnesses previously thought incurable, through risky experimental intervention. Predictably, these stories generated a lot of hype in their immediate aftermath. Follow-ups, however, attract less media attention. What came of these leads? What has been done since?
In the world of medical discovery, an anomaly can be a double-edged sword: promising in marking an intervention that might prove superior to what is already used, but also dubious in its narrow scope of success. What broader insights can the rarity generate about medicine – and what are the limitations of those insights?
Case 1: Playing hide and seek with rabies
What normally happens:
Beware of the bites of infected animals: rabies is a deadly virus transmitted by saliva through breaks in skin. If caught immediately after the bite, rabies can be warded off if the patient receives post-exposure prophylaxis, consisting of the human rabies immunoglobulin (an antibody to start fighting the virus immediately) and several doses of vaccine (to stimulate the person’s immune system to make more protective antibodies over time). However, without post-exposure prophylaxis, the virus will make its way along the patient’s nerves toward the brain. The trip typically takes about three to seven weeks from the day of the bite, after which the frightening and irreversible chain of symptoms begins: anxiety, confusion, fever, muscle spasms, personality changes, hallucinations, feelings of terror, partial paralysis, drooling, difficulty swallowing, and finally, about a week later, death – usually caused by paralysis of the muscles needed to breathe. Before 2004, rabies was thought to have a fatality rate of 100 percent once symptoms began.
The story: In September 2004, fifteen-year-old animal lover Jeanna Giese tried to gently remove a bat that had been flying inside her church. The price of her good deed was the bat’s fang in her finger. As she recounts on her personal website, Jeanna noticed symptoms a month later, starting with fatigue and double vision and quickly progressing to loss of balance, involuntary jerking, memory loss, and inability to stand or swallow. When rabies was confirmed in the Children’s Hospital of Wisconsin in Milwaukee, Jeanna’s parents were told their only child had a mere four hours to live. But Dr. Rodney Willoughby, an infectious disease specialist, offered an experimental treatment – though never been tried before, there was a tiny chance it could save Jeanna. There was also a chance it could leave her permanently brain-dead.
Jeanna’s parents decided to go forward with the intervention, and they watched their daughter get put into a seven day long drug-induced coma and infused with antiviral medication. Miraculously, she came out of it, and spent the next eleven weeks in the hospital undergoing rehab to regain her ability to stand, walk, speak, eat, and perform other daily activities of living. Now a college graduate, Jeanna is one of six people ever known to have survived rabies once symptoms started, without post-exposure prophylaxis. Each survivor underwent similar coma-induced therapy, known as the Milwaukee protocol after the city in which it was first tried.
How it worked: Jeanna’s radical treatment was based off two critical pieces of knowledge on rabies infection. First, most rabies deaths are caused by temporary and reversible brain dysfunction, rather than permanent damage to brain and nerve tissue themselves. Second, those who survived by receiving post-exposure vaccination showed an immune response strong enough to clear the virus after a period of about a week. The logic of putting Jeanna into a coma for that amount of time was to temporarily isolate her brain, affording her body the necessary additional days to develop an immune response.
What’s next? The Milwaukee protocol is nevertheless not a foolproof method, as the six survival cases were among approximately 35 patients in total it was attempted upon. Why the other 29 patients died, no one knows. Some question whether it was the protocol at all that did the trick in the survivors. Perhaps Jeanna and other survivors were infected with particularly weak strains of the virus. Or, perhaps they were endowed with especially robust immune systems. Another point to note is that rabies infection and subsequent Milwaukee protocol can come with side effects; Jeanna, for example, still has problems with balance and coordination.
Thus, while the protocol has promise, those in the field say that the best way to fight rabies remains preventing infection in the first place. In the United States, widespread vaccination programs of domestic dogs have essentially eliminated the animal as a rabies reservoir. Thanks to these efforts and the effectiveness of the post-exposure antibody and vaccine, only about two to three rabies deaths are seen in the United States each year. Still, prevention lags worldwide, especially in developing countries, with the disease killing over 55,000 people annually.
Case 2: How a bone marrow transplant led to the first HIV cure
What normally happens: HIV is a virus that stays with you – for life. It infects CD4+ T cells, a helper component of the immune system, resulting in a gradual decline in cell numbers and corresponding weakened immune protection. If the CD4+ count falls below 200, a person has full-blown AIDS, making a person susceptible to life-threatening infections a healthy immune system would have no difficulty fighting off. To prevent this, HIV patients typically commit to a lifetime of antiretroviral therapy, which slows the replication of the virus and helps maintain the CD4+ count. However, this medication is costly, has side effects, and has to be taken on a daily basis for life.
The story: In 2007, Timothy Ray Brown, also known as the Berlin patient to celebrate the place he received his innovative treatment, became the first person ever to be “cured” of HIV – meaning virus in his blood reached and remained at undetectable levels, without the use of antiretroviral therapy. Mr. Brown was a unique case in that he suffered from two severe illnesses: HIV and leukemia. To treat the latter, he needed a bone marrow transplant. His doctors in Berlin thought about treating his HIV, too, when considering a donor. By genetic luck, about one percent of people are long-term nonprogressors, or “elite controllers” of HIV infection, able to keep the virus at bay with low viral loads, normal CD4+ counts, and very good prognoses. Mr. Brown’s donor was one of these people. After the transplant, Mr. Brown stopped taking his antiretroviral medications, and twenty months later had no detectable virus in his blood, bone marrow, or rectal mucosa. Now, five years later, he still shows no signs of HIV infection.***
*** 6/14/12 update: But just recently, the plot thickened. At the International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies, held in Spain from June 5 to 8, researchers reported that tiny bits of HIV DNA were detected in Mr. Brown’s blood and intestinal cells. However, even if confirmed to be accurate, there is no evidence that the virus is replicating – meaning small pieces might be lying around, but still not causing disease. As coverage by NPR put it, this would mean Mr. Brown may be “functionally cured,” even if he did not achieve a complete elimination of virus, or “sterilizing cure.”
How it worked: One genetic aberration that results in elite controller status is mutations in both copies of a gene called CCR5, which normally encodes for a T cell receptor that HIV latches onto to enter
cells. Defectives copies of the gene knock out CCR5 receptor protein production – and with nothing to grab onto, HIV is thwarted from entering CD4+ cells. Mr. Brown’s donor had these mutations. By bone marrow replacement of Mr. Brown’s CD4+ cells with ones resistant to HIV entry, the virus was no longer able to infect its target cells and cause disease.
What’s next? Why not give all HIV patients a CCR5-negative bone marrow transplant? First, bone marrow transplants are costly and dangerous. Before receiving immune cells from another, a patient has to have his own immune stock destroyed with toxic chemotherapy, making him susceptible to life-threatening infections. Risk of death is over 10 percent – not one many would be willing to take, thanks to the safety and effectiveness of antiretroviral regimens that leads to an average lifespan of 69 years. Another challenge is that one would need to find a donor who both is matched immunologically and has mutations in both copies of the CCR5 gene – quite the difficult find. The experimental treatment also comes with complications: Mr. Brown experienced neurological and intestinal side effects severe enough that at one point he was put into a drug-induced coma so that doctors could effectively manage his symptoms. To this day, he undergoes therapy to restore his balance and speaking.
But there could be a way around the risky transplant, using the same logic. What about inducing the life-saving mutations into a patient’s own CCR5 genes? The gene therapy approach is what was tried in a 50-year-old patient in Trenton in 2011. The patient, who prefers to remain anonymous, had his T cells removed, exposed to a protein that disrupts the CCR5 gene, and then re-infused into his body. A month later, he stopped taking antiretrovirals. While not cured, he was able to control the virus without drugs, and his CD4+ count increased to normal levels. However, the same procedure failed to achieve similar results in five other patients. Some attribute the discrepancy to the fact that the Trenton patient already had one defective copy of the CCR5 gene, meaning the additional help of gene therapy led to greater numbers of resistant cells.
Case 3: Beating back prions in the longest known survivor of Creutzfeldt-Jakob disease
What normally happens: Creutrzfeldt-Jakob disease, sometimes known as the human variant of Mad Cow Disease, is a degenerative brain disease that is universally fatal. Disease is caused by prions, infectious particles of protein that build up in nerve cells in the brain, inducing normal proteins to misfold and form amyloids that puncture and destroy nerve tissue. Patients first experience confusion and dementia, followed by memory loss, hallucinations, personality changes, speech impairment, motor impairment, and seizures. Death occurs within a few days to a few years of the first symptoms, with most patients dead within eight months. The rare disease, which can either be inherited or acquired from the environment, infects about one out of every one million people.
The story: A 2007 paper in the Journal of Neurology, Neurosurgery, and Psychiatry recounts the case of Northern Irish teenager Jonathan Simms, whose symptoms of CJD began in September 2001, caused by eating infected beef. Jonathan’s devastated father Don refused to accept the abysmal prognosis, instead quitting and job and taking to Internet research to save his son from what doctors said would not likely give him more than a year of additional life. One finding Don Simms came across was the work of Dr. Stephen Dealler on pentosan polysulphate (PPS), an experimental chemical shown to be effective in protecting exposed animals from a similar prion disease, scrapie. In January 2003, many court battles later, the family won permission for Jonathan to be treated with the experimental drug that had never before been tried in humans. For months, PPS was infused into Jonathan’s body daily through a pump into his abdomen leading up to his brain. While Jonathan never returned to the person he was before illness struck, he did regain his ability to swallow and ceased making uncontrollable jerking movements.
What is different and tragic about this case, however, was that while the intervention slowed the progression of the illness, it was not actually a cure. In 2011, a decade after contracting the disease, Mr. Simms died at the age of 27. He is the world’s longest known survivor of Creutrzfeldt-Jakob disease.
How it worked: Prion proteins exist in at least two forms: PrPC (PrP = prion, C = cellular), a harmless form, and PrPSC (PrP = prion, SC = scrapie), which causes disease. The experimental drug PPS disrupts the conversion of PrPC to PrPSC, reducing disease-causing prion formation. In vivo experiments in animals show that PPS lengthens the incubation period of the disease (time from exposure to symptoms) and sometimes affords full protection.
What’s next? There are a few reasons to question the generalizability of Jonathan’s treatment. That he was treated nineteen months after the onset of symptoms – when most patients do not make it more than eight months – indicates that Jonathan may have been naturally predisposed to manage infection, meaning his continued survival may have been only partially due to the treatment. Still, other patients treated with PPS showed outcomes mirroring what was seen with Jonathan: while the treatment did not save the patients, it did prolong expected survival. A comprehensive neurological review by Dr. Ian Bone reported that while PPS correlates with extended survival, there remains insufficient evidence to prove efficacy. Dr. Bone stated, “We cannot conclude with certainty that the treatment has a beneficial effect, because it was impossible to make direct comparison with similar but untreated patients. Moreover, with such small numbers the results might be a matter of chance. The report recommends specific laboratory experiments to address the uncertainties."
What do these stories have in common? Medically, they showcase the promise of our own immune systems in fighting off deadly infection. But there is, and ought to be, reluctance in promoting an anomaly as a possible holy grail. What these stories also demonstrate is that despite a universal underlying structure of the human form, our bodies have subtle differences in composition that can give rise to major differences in recovery; and what works for one person does not necessarily work for another. That fact can be the source of both frustration and excitement in medicine.
In science progress, big ideas are not enough. Clever theory must be backed by tangible sources of support. Why are eight to ten billion dollars spent on AIDS research each year, while less than 100-fold that figure is spent on clean water initiatives? One commonly cited measure is the “burden of disease,” but that is not the whole story. The reality is that research dollars go to causes people care about. Media hype, patient activism, and fear are all factors that might contribute to one illness making it to the research spotlight over another.
When prognosis is grim, everyone hopes (s)he will be the exception to the rule. From a patient-doctor perspective, this leads to a meticulous balancing act. How to respond when a patient asks about a media article singing the praises of an experimental new treatment? Doctors must walk an incredibly fine line between offering hope and grounding their recommendations in realism.
Will history books of the future contain rabies, HIV, and Creutrzfeldt-Jakob disease “cures,” based on today’s leads? Or will they go the way of most medical discoveries: important, but only pertaining to a small subset of infected individuals, or to limited circumstances? We cannot predict what the future will hold. But I for one take pride in the research community’s ingenuity thus far. Though we should tread cautiously in not overstating what is known, we should, too, be prudent in not demeaning the remarkable accomplishments of today.