In his critically acclaimed book, Thinking, Fast and Slow, the Nobel laureate Daniel Kahneman lays out his theories about how we analyze and interpret data. Kahneman divides the thought process into two systems.1 System 1, or thinking fast, uses association and metaphor to generate a rapid analysis of the issue at hand. It functions quickly without deliberation, and does not require much oversight. Think autonomic nervous system. In contrast, System 2, responsible for thinking slowly, provides the more thoughtful, careful and reasoned analysis. It is probing and questions our assumptions about issues. System 2 represents the epitome of higher cortical brain function.
In one of Kahneman’s classic experiments assessing how one might enhance the activation of System 2, a group of Harvard undergraduate students were asked to solve a simple puzzle about the likely occupation of a hypothetical graduate student. They were provided with a set of variables including his possible fields of study and a personality sketch. “Half of the students were told to puff out their cheeks during the task, while the others were told to frown. It turns out that frowning generally increases the vigilance of System 2 and reduces both overconfidence and the reliance on intuition.” So, I am asking all readers to frown for the next several minutes as you read about some novel and interesting research findings. Intuitively, these studies may seem far afield from rheumatology. The first concerns the relationship between microbes and their hosts. The second describes the role for Bacille Calmette Guerin (BCG) as a vaccine that could attenuate type I diabetes. The third attempts to explain how an emotional stress such as depression can increase the risk of developing bone metastases in women with breast cancer. To paraphrase the late Steve Jobs, we need to be creative and “think different.”
The Gut of the Matter
This past summer, it would have been very difficult to avoid reading something about how microbial flora impacts our health. The human microbiome, a term coined by the late Joshua Lederberg, MD, consists of all microbes, their genomic material, and the sum total of their interactions within the host, namely each and every one of us. There are 10 times more microbial cells than human cells in the body. In total, the microbiome harbors 3,000 kinds of bacteria with 3 million distinct genes, compared with just 18,000 genes belonging to our own cells. In an excellent review of the topic, published in The Rheumatologist, Jose U. Scher, MD, clinical instructor of medicine, and Steven B. Abramson, MD, professor of medicine, both at the New York University School of Medicine, describe how the gut microbiota should be viewed as an extension of the self.2 As the authors stress, its rich milieu contains far more genetic and antigenic material than the host. They lay out in elegant detail how the microbiome may drive the pathogenesis of rheumatic diseases such as rheumatoid arthritis (RA) and the spondylarthropathies.
This concept of microorganisms influencing health and disease via noninfectious pathways has caught the attention of the lay press. A recent article in The Economist predicted that, “looking at human beings as ecosystems that contain many collaborating and competing species could change the practice of medicine.”3 Writing in The New York Times, the author Moises Velasquez-Manoff takes this view one step further. In an op-ed piece published in August 2012, he argues that immune dysregulation is the root cause of autism and a host of other diseases.4 According to Velasquez-Manoff, “scientists have repeatedly observed that people living in environments that resemble our evolutionary past, full of microbes and parasites, don’t suffer from inflammatory diseases as frequently as we do.”
This is not a new idea; though “the hygiene hypothesis” was coined in 1989 by Professor David Strachan of the University of London as a way of explaining the higher incidence of asthma and allergic diseases in Western countries, the original theory should be credited to the prolific Russian zoologist, Elie Metchnikoff. His early work over a century ago described the process of phagocytosis, for which he was awarded the Nobel Prize in 1908. He also observed and reported on a population of Bulgarians who had an extremely long life expectancy, which he attributed to their high consumption of yogurt. Metchnikoff proposed the need for “good” microbiota to maintain harmony within the host. He practiced what he preached and purportedly drank sour milk every day as a way to increase his fecal lactic acid levels. Talk about being ahead of his time! Recent studies have confirmed that, in fact, elevated fecal concentrations of short-chain fatty acids may help reduce systemic inflammation.
Why We Are Not Gastroenterologists
Despite the growing popularity of fermented foods and probiotics as dietary constituents, treating specific diseases by dietary manipulation has met with little success. To date, efforts to treat rheumatoid arthritis or lupus in this way have failed. Perhaps dietary adjustments are incapable of manipulating the microbiome to the degree required to modulate disease. Here are two novel strategies that have shown efficacy: worms and fecal transplants. Helminths have been shown to diminish immune responsiveness in naturally colonized humans and reduce inflammation in experimental colitis. Crohn’s disease involves overreactive Th1 lymphocyte pathways, and helminths blunt Th1 responses.
In one clinical trial, patients with Crohn’s disease were treated by ingesting the microscopic eggs of the intestinal helminth, Trichuris suis.5 In humans, the eggs live for about two weeks, but during this brief period, they appear to influence the host immune system and prevent it from attacking host tissues. In the study, patients ingested 2,500 live T. suis ova every three weeks for 24 weeks, and about 80% of patients showed a clinical response, with nearly 75% achieving disease remission. There is now commercial support for developing this product as a novel immunomodulating agent. Given the favorable response noted in Crohn’s disease, will the spondylarthropathies be considered the next therapeutic target?
Another treatment that may cause stomachs to churn concerns the use of fecal transplants. For many hospitalized patients, Clostridium difficile infection can be a serious, and even fatal, infection. This bacteria colonizes the human intestinal tract after the normal gut flora have been altered by antibiotic therapy, so one group of investigators devised a novel treatment that avoids the use of additional antibiotics. They developed a protocol whereby they transplant fecal microbiota from healthy donors into the bowels of infected individuals using a colonoscopy procedure. A multicenter study recently confirmed the efficacy of this approach, reporting a cure rate of over 90%, far exceeding the results using standard therapies.6 Reading the authors’ description of their methodology reminds me why I am not a gastroenterologist: “Stool was suspended in non-bacteriostatic saline and mixed by hand or with a blender until the consistency was such that the suspension could be aspirated into 60 cc catheter-tipped syringes and injected via the biopsy channel of a colonoscope. Before aspiration, the fecal suspension was filtered through gauze pads to remove large particulate matter to achieve an appropriate consistency, which approached that of malted milk.” This is information overload! No doubt your System 1 is now fully activated, thinking fast, and commanding you to move on.
The TNF Story—In Reverse
As rheumatologists, we are accustomed to viewing tumor necrosis factor (TNF) as an “evil” cytokine that activates immune cascades, resulting in damaged joint tissue. But TNF has many other functions that are highly beneficial. Its name belies its important role in destroying cancer cells. TNF is responsible for maintaining host immunity to tuberculosis (TB). It has also been observed that, in type I diabetics, TNF destroys T cells that are autoreactive to insulin. Yet, clinical trials using higher doses of TNF therapy have been hampered by the cytokine’s systemic toxicity. One solution would be to find a surrogate that, when administered, would induce TNF production safely. BCG, derived from an avirulent strain of mycobacterium, is known to promote TNF production and has been formulated into a vaccine form (Food and Drug Administration approved) that can be safely administered to humans. BCG therapy has been previously used to treat melanoma and bladder cancer, but its use as a stimulator of the innate immune system in the treatment of autoimmune diseases has been limited to rodent models of diabetes.
A recent proof-of-concept study led by Denise L. Faustman, MD, PhD, associate professor of medicine at Harvard Medical School in Boston, concluded that BCG treatment transiently modified the autoimmunity that underlies type 1 diabetes.7 Patients with longstanding diabetes were vaccinated with BCG and it was observed that the majority of insulin-autoreactive T cells released into the blood following the treatment were dead. Regulatory T cells were induced following vaccination, autoantibody levels declined, and the fasting level of insulin secretion temporarily increased.
This study is intriguing to rheumatologists for a number of reasons. First, it demonstrated the benefit of a vaccination strategy in an established human autoimmune disease. Most often, these trials show efficacy in animal models of human disease but fail when adapted to patients with established disease. Second, the BCG vaccine stimulated the release of an adequate concentration of TNF to generate the desired effect on the innate immune system. In the past, controlling the scope of TNF release using experimental therapies has been very challenging, limiting its use as an experimental therapy. Third, perhaps these results should make us think about what effect, if any, our use of the anti-TNF therapies may have on the course of type I diabetes. Just thinking, slowly.
Can Stress Promote Cancer Metastases?
This is an intriguing question that a group of researchers at Vanderbilt University in Nashville recently attempted to answer. Using a mouse model of breast cancer bone metastasis, they demonstrated that activation of sympathetic nerves, which is typical in chronic stress or depression, promoted the colonization and establishment of metastatic cancer cells within the bone marrow, resulting in an increase in bone osteolytic lesions.8 This effect was mediated via a β-adrenergic receptor–dependent response of the host bone marrow stroma to catecholamines, which are released upon sympathetic activation, and via the promigratory activity of RANKL, a cytokine that is known to promote bone resorption.
Interestingly, blocking sympathetic activation with a β-blocker, or blocking RANKL signaling in cancer cells, inhibited the stimulatory effect of sympathetic activation on bone metastasis in this mouse model. It may come as a bit of a surprise to learn that the sympathetic nervous system (SNS) can play an important role in determining the development of metastases. Since the SNS pathways extend to the bone marrow and the bone cortex, they may provide the mechanistic link between stress and the spread of cancer. A number of preliminary clinical studies have confirmed a potential role for beta blockade as an adjuvant therapy for the prevention of metastases in patients with breast, ovarian, and hepatocellular cancers.9
Seeing Things Differently
We are just beginning to understand some of the ways our bodies work in health and disease. As we attempt to make further progress in unraveling the vexing illnesses that constitute the field of rheumatology, we need to “think slow and think different.” I believe that, as a discipline, we are already thinking this way. This approach has been transformative; after it failed as a treatment for septic shock, who would have predicted that anti-TNF therapy would have such a profound impact on the management of RA? Without this way of thinking, would researchers have discovered that the inflammasome serves as a key activator of inflammation in diseases as diverse as Crohn’s disease and gout? Who would have cared about the citrullination of the amino acid arginine and why this chemical reaction matters in the pathogenesis of RA? (For a more detailed discussion of this topic, please read the “Rheum with a View” article by Richard Panush, MD, in the September 2012 issue of The Rheumatologist, p. 40.)
The future discoveries in medicine will require a combination of hard work, a fair amount of luck, and large doses of critical, creative thinking. As Kahneman observes, we often have a tendency to become overly reliant on our intuition, which leads us to activate System 1 instead of System 2. Think slow, not fast.
The results of the studies described above have broad implications for our community. Can we manipulate the microbiome to our advantage when treating rheumatic diseases? Can we do so without resorting to using a colonoscope or feeding patients worms? Will vaccine therapies for selected autoimmune diseases ever become a reality? Does the cancer metastases model data translate to RA? In some patients, do RANKL and the SNS play similar roles in translating emotional stress into disease flares?
The “sex life of the screw worm” was one of many federally funded studies that was attacked as being frivolous by the late U.S. senator from Wisconsin, William Proxmire. From 1975 to 1988, his Golden Fleece Awards highlighted what he considered to be government waste in support of dubious science. But a $250,000 study of this pest, which is lethal to livestock, has, over time, saved the U.S. cattle industry more than $20 billion. Think grateful, that our tax dollars are being used wisely. And keep thinking different.
Dr. Helfgott is physician editor of The Rheumatologist and associate professor of medicine in the division of rheumatology, immunology, and allergy at Harvard Medical School in Boston.
References
- Kahneman D. Thinking, Fast and Slow. New York, N.Y.: Farrar, Straus & Giroux; 2011.
- Scher JU, Abramson, SB. The microbiome: A voyage to (our inner) Lilliput. The Rheumatologist. 2011;5(11):1, 32-35.
- Me, myself, us. The Economist. August 18, 2012.
- Velasquez-Manoff M. An immune disorder at the root of autism. New York Times. August 26, 2012: SR1.
- Summers RW, Elliott DE, Urban JF Jr, Thompson R, Weinstock JV. Trichuris suis therapy in Crohn’s disease. Gut. 2005;54:87-90.
- Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012;107:1079-1087.
- Faustman DL, Wang L, Okubo Y, et al. Proof-of-concept, randomized, controlled clinical trial of bacillus-calmette-guerin for treatment of long-term type 1 diabetes. PLoS One. 2012;7:e41756.
- Campbell JP, Karolak MR, Ma Y, et al. Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice. PLoS Biol. 2012;10:e1001363.
- Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, et al. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol. 2011;29:2645-2652.
