From H. pylori to Spanish colonialism: the scales of cancer.

IMO2014Yesterday was the first day of the 4th Integrated Mathematical Oncology Workshop here at Moffitt. This year, it is run jointly with the Center for Infection Research in Cancer and is thus focused on the interaction of infection disease and cancer. This is a topic that I have not focused much attention on — except for the post on canine transmissible venereal tumor and passing mentions of Human papillomavirus (HPV) — so I am excited for the opportunity to learn. The workshop opened with a half-day focused on getting to know the external visitors, Alexander Anderson’s introduction, and our team assignments. I will be teammates with Heiko Enderling, Domenico Coppola, Jose M. Pimiento, and others. We will be looking at Helicobacter pylori. Go team blue! If you are curious, the more popularly known HPV went to David Basanta’s team, it will be great to compete against my team leader from last year. As you can expect, the friendly trash talking and subtle intimidation has already begun.

To be frank, before yesterday, I’ve only ever heard of H. pylori once and knew nothing of its links to stomach cancer. The story I heard was associated with Barry J. Marshall and J. Robin Warren’s award of the 2005 Nobel Prize in Physiology and Medicine “for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease”. In 1984, Marshall was confident in the connection between H. pylori, inflammation, and ulcers, but the common knowledge of the day was that ulcers were caused by things like stress and smoking, not bacteria. The drug companies even happened to have an expensive drug that could manage the associated stomach inflammation, and given the money it was bringing in, nobody was concerned with finding some bacterium that could be cured with cheap antibiotics. Having difficulty convincing his colleagues (apart from Warren), Marshall decided to drink a Petri dish of cultured H. pylori, and within a few days grew sick, developing severe inflammation of the stomach before finally (two weeks after the ingestion) going on antibiotics and curing himself. This dramatic display was sufficient to push for bigger studies that eventually lead to the Nobel prize; I recommend listening to Warren’s podcast with Nobel Prize Talks or his acceptance speech for the whole story.

This is a fascinating tale, but from the modeling perspective, the real excitement of H. pylori and its role in stomach cancer is the multitude of scales that are central to the development of disease. We see important players from the scale of molecules involved in changing stomach acidity, to the single-cell scale of the bacteria and stomach lining, to the changes across the stomach as a whole organ, and the role of the individual patient’s life style and nutrition. These are the usual scales we see when modeling cancer, and dovetail nicely with Anderson’s opening remarks on the centrality of mathematics in helping us bridge the gaps. However, in the case of H. pylori, the scales go beyond the single individual at which Anderson stops and extend to the level of populations of humans in the co-evolution of host and pathogen, and even populations of groups of humans in a speculative connection to a topic familiar to TheEGG readers — the evolution of ethnocentrism. In preparation for the second half of the second day and the intense task of finding a specific question for team blue to focus on, I wanted to give a quick overview of these scales.

From cell to organ

Helicobacter pylori is — as its name might suggest — a helix-shaped bacterium that is about 3 micrometers long and 0.5 micrometers wide that grows in the mucus layer of the stomach; for comparison, the goblet cells that line the stomach and excrete the mucus are ~50 micrometers long and 5-10 micrometers wide. About half of the world’s population is infected with H. pylori — with a higher prevalence in the developing than the developed world — and although all infected individuals develop some inflammation of the stomach, less than 1% get stomach cancer (Peek & Blaser, 2002). However, this still accounts for around 10% of worldwide cancer mortality — or approximately 738,000 deaths in 2008 — making it the second leading cause of cancer-related death (Ferlay et al., 2010). Although H. pylori does trigger an immune response, the immune system is not effective at dealing with it because the bacteria interferes with the local response and the immune cells cannot reach the stomach lining in which the bacteria is often lodged (Kusters, et al., 2006). Thus, at the level of single cells, we already have interesting dynamics.

At the level of the whole stomach, and even more interesting observation is associated with H. pylori — it increases the risk for some cancer while decreasing the risk for others. Stomach cancer is classified into two types: cardia gastric cancer is in the top inch where the stomach meets the esophagus, and non-cardia gastric cancer is in the rest of the stomach. It is well established that the bacteria greatly increase the risk for the more common non-cardia gastric cancer — the risk is nearly six times higher for people infected with H. pylori than the uninfected (Webb, 2001). This makes H. pylori the only bacterium recognized by the World Health Organization as a Grade 1 carcinogen. The mechanism for this carcinogenesis is unknown, but researchers suspect it might be due to to long-term inflammation causing faster cell turnover and thus an increased risk of cancer in the stomach lining — this hypothesis has some support in mouse models (Tu et al., 2008). For cardia gastric cancer, however, the bacteria is associated with lower levels of cancer (Kamangar, et al., 2006; although for some conflicting evidence, see Kamagar, et al., 2007). Further up the food-track, in the esophagus, Islami & Kamagar’s (2008) meta-analysis showed a 45% decrease in esophageal cancer associated with H. pylori infection. Here the leading hypothesis is that the decrease in acidity of the stomach due to colonization by the bacteria causes a reduction in acid reflux — a known risk for cancer of the upper stomach and esophagus. Thus, on the scale of the whole organ, we see a heterogeneous effect due to the bacteria.

From patient to society

It should come as no surprise that at the level of the individual patient, nutrition plays an important factor in the risks and progression of H. pylori infection and stomach cancer (Buiatti, et al., 1989; Toyonaga et al., 2009). What might be more surprising is the role of genetics at the population level. A particular interesting case of this, is what has been come to known as the African enigma (Holcombe, 1992; Campbell, et al., 2001) — African populations have very high occurrences of H. pylori and associated inflammation, but low occurrences of stomach cancer. A proposed explanation for this is host-pathogen co-evolution; for a general overview of the co-evolution of pathogens and their hosts, see Woolhouse et al. (2002). Due to its early acquisition in childhood, and the primarily fecal-oral or oral-oral methods of transmission, H. pylori has been mostly assumed to be vertically or familially — to include transmission between siblings, not just mother and child – transmitted (Ng et al., 2001; Ferlay et al., 2005). Recent studies (Schwarz et al., 2008) based on genetic sequencing support this traditional wisdom in the case of sanitary urban environments, but also stress the importance of horizontal transmission — especially in less sanitary and rural environments. With primarily vertical transmission, host-pathogen co-evolution would predict a specialization of the pathogen and a reduction in virulence (Bull et al., 1991). This is in agreement with the covariance of H. pyloria with geographically distinct human sub-populations (Moodley et al., 2012), and the tolerance of the infection without severe side-effects in most people. This correspondence between certain groups of people and strains of H. pyloria, and the possibility of horizontal transmission can create non-trivial ecological and evolutionary dynamics at the scale of human populations.

Recently, Kodaman, Pazos, et al. (2014) provided strong evidence for the co-evolution of humans and H. pyloria, and the dangers of horizontal transmission. In particular, they considered two nearby Colombian villages that have virtually identical prevelance of H. pylori infection — around 90% — but drastically different rates of stomach cancer — 150 versus 6 per 100,000 individuals. The two villages differ in the genetic admixture of both their human and H. pyloria population. The low cancer village, has a much higher proportion of African ancestry in both the human population and the bacteria — the host and pathogen are co-adapted. The high cancer village, however, has a mismatch with high levels of Amerindian ancestry in the human population, and high levels of European ancestry in the bacteria — according to the authors statistical analysis, this mismatch is the primary cause for the discrepancy in cancer rates. Further, the bacterial admixture of the high cancer village is consistent with the mixtures observed by Falush et al. (2003) in Spanish strains of H. pylori. This suggests that the deadly mismatch of pathogen and host is a consequence of recent horizontal transfer from Spanish colonialists.

No discussion of colonialism is complete — especially not on TheEGG — without mention of ethnocentrism. This brings me to the final, and most speculative, scale of effects for cancer. Our usual context for looking at the evolution of ethnocentrism is as a mechanism for maintaining cooperation in the Prisoner’s dilemma (Kaznatcheev & Shultz, 2011) or a source of irrational out-group hostility in games like Harmony (Kaznatcheev, 2010). A leading alternative hypothesis is that ethnocentrism and xenophobia are adaptations to avoiding transmittable diseases (Faulkner et al., 2004; Navarrete & Fessler, 2006). The in-group mildness and out-group severity of the co-evolved strains of H. pylori‘s effects on cancer — if it generalizes to other human-bacterial admixture mismatches — would be an ideal candidate for a specific mechanism to drive the evolution of ethnocentrism by pathogen-host interaction. Of course, I don’t mean to suggest that H. pylori would be a driving force in the evolution of ethnocentrism, but this speculative connection allows us to potentially couple cancer to the higher level dynamics of populations of human groups. This gives us a truly huge range of length and time scales on which to look at H. pylori and stomach cancer, and in within a few hours team blue will have to narrow down our focus to a specific question within this magnitude.

References

Buiatti, E., Palli, D., Decarli, A., Amadori, D., Avellini, C., Bianchi, S., … & Blot, W. (1989). A case‐control study of gastric cancer and diet in Italy. International Journal of Cancer, 44(4): 611-616.

Bull, J. J., Molineux, I. J., & Rice, W. R. (1991). Selection of benevolence in a host-parasite system. Evolution, 875-882.

Campbell, D. I., Warren, B. F., Thomas, J. E., Figura, N., Telford, J. L., & Sullivan, P. B. (2001). The African enigma: low prevalence of gastric atrophy, high prevalence of chronic inflammation in West African adults and children. Helicobacter, 6(4): 263-267.

Falush, D., Wirth, T., Linz, B., Pritchard, J. K., Stephens, M., Kidd, M., … & Suerbaum, S. (2003). Traces of human migrations in Helicobacter pylori populations. Science, 299(5612): 1582-1585.

Farrell, S., Doherty, G. M., Milliken, I., Shield, M. D., & McCallion, W. A. (2005). Risk factors for Helicobacter pylori infection in children: an examination of the role played by intrafamilial bed sharing. The Pediatric Infectious Disease Journal, 24(2): 149-152.

Faulkner, J., Schaller, M., Park, J. H., & Duncan, L. A. (2004). Evolved disease-avoidance mechanisms and contemporary xenophobic attitudes. Group Processes & Intergroup Relations, 7(4): 333-353.

Ferlay, J., Shin, H. R., Bray, F., Forman, D., Mathers, C., & Parkin, D. M. (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International Journal of Cancer, 127(12): 2893-2917.

Holcombe, C. (1992). Helicobacter pylori: the African enigma. Gut, 33(4): 429-431.

Islami, F., & Kamangar, F. (2008). Helicobacter pylori and esophageal cancer risk: a meta-analysis. Cancer Prevention Research, 1(5): 329-338.

Kamangar, F., Dawsey, S. M., Blaser, M. J., Perez-Perez, G. I., Pietinen, P., Newschaffer, C. J., … & Taylor, P. R. (2006). Opposing risks of gastric cardia and noncardia gastric adenocarcinomas associated with Helicobacter pylori seropositivity. Journal of the National Cancer Institute, 98(20): 1445-1452.

Kamangar, F., Qiao, Y. L., Blaser, M. J., Sun, X. D., Katki, H., Fan, J. H., … & Dawsey, S. M. (2006). Helicobacter pylori and oesophageal and gastric cancers in a prospective study in China. British Journal of Cancer, 96(1): 172-176.

Kaznatcheev, A. (2010) Robustness of ethnocentrism to changes in inter-personal interactions. Complex Adaptive Systems – AAAI Fall Symposium.

Kaznatcheev, A., & Shultz, T.R. (2011). Ethnocentrism Maintains Cooperation, but Keeping One’s Children Close Fuels It. In L. Carlson, C, Hoelscher, & T.F. Shipley (Eds), Proceedings of the 33rd Annual Conference of the Cognitive Science Society.

Kodaman, N., Pazos, A., Schneider, B.G., Piazuelo, M.B., Mera, R., Sobota, R.S., Sicinschi, L.A., Shaffer, C.L., Romero-Gallo, J., de Sablet, T., Harder, R.H., Bravo, L.E., Peek, R.M. Jr, Wilson, K.T., Cover, T.L., Williams, S.M., & Correa, P. (2014). Human and Helicobacter pylori coevolution shapes the risk of gastric disease. Proceedings of the National Academy of Sciences of the United States of America, 111 (4), 1455-60 PMID: 24474772

Kusters, J. G., van Vliet, A. H., & Kuipers, E. J. (2006). Pathogenesis of Helicobacter pylori infection. Clinical Microbiology Reviews, 19(3): 449-490.

Moodley, Y., Linz, B., Bond, R. P., Nieuwoudt, M., Soodyall, H., Schlebusch, C. M., … & Achtman, M. (2012). Age of the association between Helicobacter pylori and man. PLoS Pathogens, 8(5): e1002693.

Navarrete, C. D., & Fessler, D. M. (2006). Disease avoidance and ethnocentrism: The effects of disease vulnerability and disgust sensitivity on intergroup attitudes. Evolution and Human Behavior, 27(4): 270-282.

Ng, B. L., Ng, H. C., Goh, K. T., & Ho, B. (2001). Helicobacter pylori in familial clusters based on antibody profile. FEMS Immunology & Medical Microbiology, 30(2): 139-142.

Peek, R. M., & Blaser, M. J. (2002). Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nature Reviews Cancer, 2(1): 28-37.

Schwarz, S., Morelli, G., Kusecek, B., Manica, A., Balloux, F., Owen, R. J., … & Suerbaum, S. (2008). Horizontal versus familial transmission of Helicobacter pylori. PLoS Pathogens, 4(10): e1000180.

Toyonaga, A., Okamatsu, H., Sasaki, K., Kimura, H., Saito, T., Shimizu, S., Fukuizumi, K., Tsuruta, O., Tanikawa, K., & Sata, M. (1999). Epidemiological study on food intake and Helicobacter pylori infection. The Kurume Medical Journal, 47(1): 25-30.

Tu, S., Bhagat, G., Cui, G., Takaishi, S., Kurt-Jones, E. A., Rickman, B., … & Wang, T. C. (2008). Overexpression of interleukin-1β induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell, 14(5): 408-419.

Webb, P. M., Law, M., Varghese, C., Forman, D., Yuan, J. M., Yu, M., … & Stemmermann, G. N. (2001). Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut, 49(3): 347-353.

Woolhouse, M. E., Webster, J. P., Domingo, E., Charlesworth, B., & Levin, B. R. (2002). Biological and biomedical implications of the co-evolution of pathogens and their hosts. Nature Genetics, 32(4): 569-577.

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About Artem Kaznatcheev
From the Department of Computer Science at Oxford University and Department of Translational Hematology & Oncology Research at Cleveland Clinic, I marvel at the world through algorithmic lenses. My mind is drawn to evolutionary dynamics, theoretical computer science, mathematical oncology, computational learning theory, and philosophy of science. Previously I was at the Department of Integrated Mathematical Oncology at Moffitt Cancer Center, and the School of Computer Science and Department of Psychology at McGill University. In a past life, I worried about quantum queries at the Institute for Quantum Computing and Department of Combinatorics & Optimization at University of Waterloo and as a visitor to the Centre for Quantum Technologies at National University of Singapore. Meander with me on Google+ and Twitter.

3 Responses to From H. pylori to Spanish colonialism: the scales of cancer.

  1. Pingback: Helicobacter pylori and stem cells in the gastric crypt | Theory, Evolution, and Games Group

  2. Pingback: Cataloging a year of blogging: cancer and biology | Theory, Evolution, and Games Group

  3. Pingback: Hackathons and a brief history of mathematical oncology | Theory, Evolution, and Games Group

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