When Pfizer research scientist Jim Mobley was asked to switch his research focus from asthma to arthritis, he had no idea he would stumble upon a fascinating concept that may change the way pharmaceutical companies develop drugs. And surprisingly enough, he made this discovery not in the lab but in the library.
By researching current literature, analyzing epidemiology — the study of disease patterns in human populations — and looking at archeological records, he hypothesized a relationship between rheumatoid arthritis and tuberculosis. Central to this idea is the notion that epidemics may play a role in human evolution.
Rheumatoid arthritis is different from osteoarthritis — the most common form that results from the normal wear and tear of the joints. RA is one of the many autoimmune diseases such as lupus, Type 1 diabetes and multiple sclerosis.
“(Autoimmune diseases) are incorrect usages of our immune system,” Mobley said. “Our immune system thinks that it’s fighting something foreign when it’s not.”
In the case of RA, the unwitting casualties are usually the smaller joints, like the fingers and wrists. According to Mobley, 1 to 2 percent of Americans are affected by the disease.
Tuberculosis, on the other hand, is caused by an infection of Mycobacterium tuberculosis. The bacteria enter the lungs, eventually making it very difficult for the victim to breathe. It is possible to carry the bacteria without contracting the disease, though. While very rare in the United States, the disease still kills two million people each year worldwide.
Since Mobley was unfamiliar with RA, he was able to examine the field with a fresh eye. This allowed him to notice unusual trends in the literature other scientists may have overlooked.
“I paid attention to those things that were unique to this disease — that really didn’t make sense to me,” he said.
Two things struck a chord. First, he saw throughout scientific studies that animals injected with one species of bacteria were most likely to contract RA. This species was Mycobacterium tuberculosis.
Second, he found interesting cases involving Enbrel, a drug used to treat RA. Enbrel blocks tumor necrosis factor, a chemical messenger that alerts surrounding cells of infection.
“It tells the surrounding cells that ‘I’ve been infected by something — you’d better pay attention,’ ” Mobley said.
While blocking TNF stops an overactive immune system from attacking itself, it also sometimes caused people who carried the tuberculosis bacteria to contract TB. This may be because TNF is important for TB immunity.
“There had to be, in my mind, some causality to tuberculosis,” Mobley said.
Newton’s apple came in the form of two books, one on tuberculosis and one on rheumatoid arthritis. From one he learned where and when the major TB epidemics had occurred — the most recent one was over two hundred years ago in Europe. From the other he discovered RA was not spread out uniformly across the world population as he had thought — certain countries and populations had higher incidences than others. Mobley had these two books within a few feet of each other, these sources of information on two seemingly unrelated diseases.
And in a moment of serendipity, he saw the connection.
The higher incidences of RA “almost perfectly mirrored” the death rates from TB, Mobley said. A certain Native American population had peak death rates from TB nearly seven times higher than those in England and North America over the last two hundred years. Generations later, this same population had rates of RA nearly seven times higher than the rest of the world. In Africa, where TB had been relatively nonexistent, RA was now also absent.
Because the matching trends were more than 100 years apart, Mobley surmised that the connection had something to do with genetics and natural selection.
Other diseases also possess this relationship with one another. The genetic mutation that causes sickle cell anemia, if only present on one chromosome, affords protection from malaria. Similarly, only one mutation of the gene that causes cystic fibrosis gives protection for cholera-induced diarrhea. Mobley also noted two diseases with a direct relationship — a mutation that provided resistance to the bubonic plague now seems to make those survivors’ descendants HIV-resistant.
The common thread is epidemics. Epidemics can induce genetic change, in essence causing evolution on a small scale. Survivors of epidemics can pass their resistance on to future generations, but those without resistance take their weak genes to the grave. “This is Darwinian selective pressure at its best,” Mobley said.
“Genetic mutations that allowed people to survive tuberculosis epidemics two hundred years ago are combining and coming together in the descendants of those individuals, making their immune systems very much stronger and unfortunately, inducing these autoimmune-type diseases,” he said.
Mobley published his idea in the journal Medical Hypotheses, asking “Is rheumatoid arthritis a consequence of natural selection for enhanced tuberculosis resistance?” Bruce Rothschild, who had been looking at archaeological evidence that fit with Mobley’s hypothesis, contacted Mobley. Rothschild found that prior to 1785 there was no record of RA in Europe — only after the occurrence of TB epidemics. This suggested the epidemics were responsible for the existence of RA.
In addition, 6500-1000 years ago, the only place in the world Rothschild was able to detect RA was in a small Native American population between the Tennessee and Green Rivers. This population showed no evidence of having had tuberculosis.
Because other populations in North America showed evidence of tuberculosis, Mobley thought this Native American population may have been a group of people who had survived a TB epidemic, their resistance then making them susceptible to RA. Rothschild’s findings supported his hypothesis. At the genetic level, Mobley found that genes that were mutated more often in the RA population were mutated less often in the TB population. What was good for RA was bad for TB. “It’s this yin and yang,” Mobley said.
After months of research outside of the laboratory, it was now time to use what he had learned to help him design new drugs. Mobley stresses that this is only a hypothesis, and can not yet be proven.
Normally, a large pharmaceutical company like Pfizer would find new drug targets — any sort of molecule whose action a drug can block to treat a disease — by reading the literature and going to scientific conferences, Mobley said. If a lab reports that a certain chemical may play a part in a specific disease — or interact with a known drug target for that disease — it is added to a list. After a while, of course, the list becomes very long.
“I’m not going to just start on them alphabetically and go down the list,” Mobley said.
Instead, Mobley chose targets that were highly expressed in RA but not in TB. By considering TB, he was able to give higher priority to targets he believed would be more effective, targets which he might otherwise not have looked at immediately. Mobley has narrowed the list down to about a dozen targets, including tumor necrosis factor, the molecule blocked by the current RA drug Enbrel. He has recently proposed one of these targets for the development of a new drug.
Mobley doesn’t believe other pharmaceutical companies are using methods like his, but he thinks they will in the future.
He also thinks the causative effect of tuberculosis-resistance may extend to all autoimmune diseases. Of the variety of mutations that help an individual survive tuberculosis, different combinations may lead to susceptibilities to different diseases. “I think it’s a shuffling of the cards as to which autoimmune disease that you potentially suffer from,” he said.
Mobley’s next project might involve another unlikely connection: patients with schizophrenia don’t get RA.
“But that’s the kind of thing that I like to look for,” Mobley said. “What doesn’t make sense, what doesn’t quite fit.”