A 5,300 Year Old Stomach Ache

In 1991, one of the best preserved mummies was found frozen in the Ötztal Alps, a mountain range near the border of Austria and Italy. This 5,300 year old man was named Ötzi and has been fascinating nosey scientists ever since. So far, scientists have learned about Neolithic fashions and dietary habits, and even identified his cause of death...solving one of the oldest “cold cases” in CSI history. (For the curious, poor Ötzi appears to have been attacked. He took a blow to the head and an arrow to his shoulder).


The well-preserved remains of the “iceman” named Ötzi.

Remarkably, genetic studies of folks living in Austria today reveal that Ötzi has some living relatives. Researchers found that at least 19 people may share a common ancestor with Ötzi, but the odds of one being a direct descendent of Ötzi himself are very remote. Some of these living relatives can be seen in a series of commercials for the auto insurance company Geico:

 

Ötzi provides a window into our past - a glimpse of what life might have been like 5,300 years ago. It turns out that Ötzi suffered from many of the same problems that we still have to contend with today. His body shows signs of heart disease, tooth decay, and joint pain, possibly caused by Borrelia borgdorferi, the bacteria that causes Lyme disease. The latest secret that scientists Frank Maixner and Albert Zink have coaxed out of Ötzi is that he was infected with another bacterial species that still causes grief in millions of people here and now:  Helicobacter pylori.

This is an artist’s rendition of Ötzi. But scientists didn’t just find a 5,300 year old human ancestor that day. They also found 5,300 year old bacteria.

Thanks to a landmark study in the 1980s, we now know that Helicobacter pylori is a causative agent of gastritis or stomach ulcers. Previously, doctors believed that stomach ulcers were simply caused by environmental factors - too much stress, spicy food, or smoking. But Drs. Barry Marshall and Robin Warren had a “gut feeling” that this model was wrong after they repeatedly found bacteria in the peptic ulcer biopsies from patients.

For decades, doctors believed that gastric ulcers were caused by stress. The idea that they were caused by a bacterial infection was a profound discovery and revolutionized treatment of this common ailment.

A lot of medical professionals had a hard time swallowing the idea that gastric ulcers were really an infection. Marshall and Warren faced great difficulty getting their results published in scientific journals. Many other doctors at the time mentioned how controlling the acid in the stomach usually helped patients feel better, and they balked at the idea that bacteria could survive in the acidic milieu of the stomach. Today, we now know that some bacteria can thrive in even the most inhospitable of places, including areas of high acidity. Helicobacter pylori is one such “acidophile” – it grows best under acidic conditions. This also explains why some ulcer patients recover after taking medication that reduces stomach acid; acid reducers cause a gastric climate change that is less favorable to the growth of Helicobacter pylori.

On June 12, 1984, Barry Marshall drank a culture of live Helicobacter pylori. He developed an ulcer, which he successfully treated with antibiotics. A tabloid newspaper first covered “the guinea-pig doctor” story, alongside stories of alien abductions and celebrity gossip. Ultimately, the stunt finally convinced the skeptics and won Marshall and Warren the Nobel Prize in Physiology or Medicine for 2005.

How do we get infected with Helicobacter pylori? The bacteria can be contracted through saliva or accidental ingestion of material coming out of the other end of a person. Somewhere along the way, a little poo from an infected person got into your food/water (or on your hands) and found its way into your gut. As gross as that sounds, it must happen a lot because Helicobacter pylori is present in the gut of billions of people. However, it causes ulcers in only 10% of them. 

Scientists don’t currently know why the bacteria attack the stomach lining of some people but not others. But if you are one of those unlucky few, the damage caused by the bacteria allows stomach acid to pass through the protective lining, which can cause bleeding and digestive problems, and obviously a lot of pain and discomfort.

But thanks to the renegade efforts of Barry Marshall, doctors now know how to treat gastric ulcers more effectively with a simple course of antibiotics. It is perhaps no surprise to you now that our old friend Ötzi had Helicobacter pylori in his tummy. The bug is very common and easily contracted, especially in his day when hand sanitizers were not easily accessible. Whether Ötzi’s Helicobacter pylori actually caused a gastric ulcer is hard to say, as his stomach lining was not preserved well enough to draw firm conclusions. One day we may find a specific type of genetic mutation in people prone to stomach ulcers, which would allow us to revisit the question.

If you want to learn more about the cracking of the stomach ulcer mystery, check out the following video.

 

Contributed by:  Bill Sullivan, Ph.D.

Follow Bill on Twitter.


Williams AC, Edwards HG, & Barry BW (1995). The 'Iceman': molecular structure of 5200-year-old skin characterised by Raman spectroscopy and electron microscopy. Biochimica et biophysica acta, 1246 (1), 98-105 PMID: 7811737


Tito RY, Knights D, Metcalf J, Obregon-Tito AJ, Cleeland L, Najar F, Roe B, Reinhard K, Sobolik K, Belknap S, Foster M, Spicer P, Knight R, & Lewis CM Jr (2012). Insights from characterizing extinct human gut microbiomes. PloS one, 7 (12) PMID: 23251439


Maixner, F., Krause-Kyora, B., Turaev, D., Herbig, A., Hoopmann, M., Hallows, J., Kusebauch, U., Vigl, E., Malfertheiner, P., Megraud, F., OSullivan, N., Cipollini, G., Coia, V., Samadelli, M., Engstrand, L., Linz, B., Moritz, R., Grimm, R., Krause, J., Nebel, A., Moodley, Y., Rattei, T., & Zink, A. (2016). The 5300-year-old Helicobacter pylori genome of the Iceman Science, 351 (6269), 162-165 DOI: 10.1126/science.aad2545

Complexities Of Allergic Disease

Last time we discussed the main players involved in the immune response to allergens, in the reaction called Type I hypersensitivity. We know that hay fever and other allergies are a result of atopy, the genetic predisposition to mount excessive IgE-mediated immune responses. Atopy is derived from a Greek word that means unusual or out-of-place. Although the immune overreaction is indeed out of place, the prevalence of allergic disease in society is not. Approximately 25% of the world’s population suffers from allergies, making it one of the most common chronic diseases. Unfortunately, this number is actually increasing, so researchers are trying to understand the factors that contribute to allergic disease.

Advances in genome sequencing and the completion of the Human Genome Project have allowed scientists to use genome-wide association studies (GWAS) in attempts to identify certain disease-causing genes. While many candidate genes have been described for hay fever, each search appears to reveal additional candidates. It has become clear that hay fever is a complex disease, driven by genetics and environmental exposures, both pre- and postnatal. Because of this complexity, atopy does not follow a Mendelian model of inheritance, like eye or hair color.

To perform GWAS, researchers collect blood or tissue samples from individuals with the disease of interest and from symptom-free control subjects. In many allergy studies, the controls are within the same family, which helps tease apart genetic differences that might actually contribute to disease. This is helpful because 300,000 to 1 million changes in the DNA are tested. These changes called single nucleotide polymorphisms (SNPs), a type of mutation that indicates a single change in the DNA base pair. If certain SNPs appear more frequently in the individuals with the disease, they are said to be associated with that disease. Additional DNA sequencing is performed to determine the exact change, and then ideally that SNP is studied in the lab to understand the consequence of the change on cellular function.

Sometimes mutations give super-human agility, strength, or intelligence. Other times they set us up to have wild and potentially unnecessary symptoms like Beast’s blue fur. Or perhaps equally annoying, the itchy watery eyes, nose, and throat from hay fever that come from a super-human response to harmless allergens.

A few notable candidate genes have been identified as associated with hay fever or with higher levels of circulating IgE antibodies, as we learned is a hallmark of atopy. Cytokines are the main signaling molecules that trigger activation of B cells to produce IgE antibodies, and not surprisingly, people with hay fever have mutations in genes that encode for cytokines or regulate their production. Also associated with hay fever are changes that enhance and stabilize the IgE receptor on mast cells and basophils, contributing to more intense symptoms. Genes responsible for airway smooth muscle contractions, contributing to cough and wheeze, are also implicated. SNPs have been identified in the genes encoding chemical mediators that cause ongoing symptoms such as leukotrienes, and in the specialized effector cells involved later in allergic inflammation response, such as eosinophils.

These are just a few examples of genes; dozens of others are being studied to learn exactly how they contribute to hay fever. Furthermore, some genes are only associated with allergies in the context of specific environments, further complicating the identification of true disease-causing genes. One clue that environmental factors influence allergies comes from studies of twins. Twin studies have shown that between monozygotic (identical) twins there is on average a 65% (range, 42-82%) chance that if one twin has allergies, the other will also have them. Between dizygotic (fraternal) twins, there is on average a 33% concordance rate (range 15-52%).

Some differences in twins are obvious, but other differences like allergies require epidemiological studies to tease apart.

The “hygiene hypothesis,” proposed by D. Strachan in 1989, became a popular basis to explore the increased incidence in allergic disease. Strachan observed that increased family size was associated with lower rate of allergies. He proposed that if allergies were prevented by early childhood infections, unhygienic contact with older siblings may protect against hay fever. Immune responses to pathogens like bacteria and viruses use a T-helper 1 (Th1) cell response. We know that Type I hypersensitivity reactions are mediated by Th2 cells’ stimulation of B cells to produce IgE antibodies. So the theory is that early childhood infections bias the immune system towards a Th1 response and suppress Th2 responses.

If Strachan’s hypothesis is correct, the Bates family should be allergen-free.

Strachan performed additional epidemiological studies to investigate the hypothesis that infections and larger family size protect against hay fever. He published a report in 2000 stating that decreases in family size do not appear to explain the increased incidence of allergies. Many additional studies looking into the protective effects of childhood infections have shown inconsistent results; some show a “protective” effect whereas others show either no association or early childhood infections correlated with development of allergies.

The “hygiene hypothesis” developed into a much broader “microflora hypothesis” which proposes that urbanization and a Western lifestyle limits our exposure to bacteria, viruses and parasites in general. Clean water, increased Cesarean sections, reduction in breastfeeding, increased antibiotic and antibacterial use, and reduced exposure to farm animals have limited our exposure to our microbial “old friends”. According to this idea, these “old friends” have evolved with us to the point where we require them for proper immune function.

 

“The Wonder Years” cast knew that we get by with a little help from our friends.

The diversity of our microbiome is decreasing, which may have detrimental effects on general health and the efficiency of our immune system. W. Parker proposed the term “biome depletion” to describe this current phenomenon. A few recommendations can be found here to increase microbial diversity in the gut.

Just like the Biodome, our biomes are not closed systems and can let in and respond to passer-byers, for better or for worse. In the case of Pauly Shore, it’s always for the worse.

If there weren’t already enough factors to consider in development of allergies, let’s peel back another layer. In addition to acquiring genes and microbiota from mothers during birthing and breastfeeding, in utero we are largely influenced by our mother’s environment through epigenetics. We’ve discussed epigenetics previously; briefly, it describes changes in the DNA and DNA-associated structural proteins that act to turn genes on or off. Epigenetic regulation either gives a green light or red light to production of specific gene products, or can act as a volume knob to finally tune gene expression. The process is plastic, allowing our genes to respond to the present environment.

Upon conception, epigenetic reprogramming occurs in the zygote, like a reset button. However, some epigenetic marks remain and are inherited by the offspring. So before and largely during pregnancy, the mother encounters various environments and the body responds using epigenetics to regulate genes at the appropriate time. These changes occur in the embryo or fetus as well, as a way to prime the baby for its eventual environment.

There is evidence that the immune system is under epigenetic regulation. At birth, atopy-prone infants tend to have diminished Th1 cell responses, thought to be influenced by the maternal environment. Additionally, maternal diet, microbial exposure, and smoking can influence epigenetic regulation of key genes involved in immune regulation and allergy development.

While there is no consensus on allergy prevention, there are many options for treatment of allergies, which will be discussed in the final allergy article in this series – coming soon!

Contributed by:  Julia van Rensburg, Ph.D.

Follow Julia on Twitter.

Dávila I, Mullol J, Ferrer M, Bartra J, del Cuvillo A, Montoro J, Jáuregui I, Sastre J, & Valero A (2009). Genetic aspects of allergic rhinitis. Journal of investigational allergology & clinical immunology, 19 Suppl 1, 25-31 PMID: 19476051

Grammatikos AP (2008). The genetic and environmental basis of atopic diseases. Annals of medicine, 40 (7), 482-95 PMID: 18608118

Strachan DP (2000). Family size, infection and atopy: the first decade of the "hygiene hypothesis". Thorax, 55 Suppl 1 PMID: 10943631

Parker W (2014). The "hygiene hypothesis" for allergic disease is a misnomer. BMJ (Clinical research ed.), 348 PMID: 25161287

Martino D, & Prescott S (2011). Epigenetics and prenatal influences on asthma and allergic airways disease. Chest, 139 (3), 640-7 PMID: 21362650

The Friday Five

Highlighting some of the coolest science news we’ve seen lately.

1. Paleo, Atkins, raw, juice...diets, diets, diets! Sort the fact from the fiction with this excellent article, “10 Fad Diets, Debunked”, by Esther Inglis-Arkell.

2. The new film odyssey, Interstellar, blasted into theatres recently. Director Christopher Nolan went to great lengths to try and get the science right in the movie, which included consultation with theoretical physicist Kip Thorne. The video below details how they worked together to imagine a real black hole.

Unfortunately, not all of the science in the movie is accurate. 

3. In this week's episode of “The Big Question”, Craig Benzine explains why your voice gets higher when you inhale helium. Interestingly, it is not the pitch that changes…

4. Here, kitty kitty…what’s the difference between a wildcat and a domesticated one? Nothing – they both hate you. Jokes aside, scientists have recently performed a genetic comparison between the two and found a number of genes that were enriched due to domestication. These genes may explain why your housecat is less shy, tamer, and more responsive to a reward. Interpreted another way, they also explain why we can't really stroll through the woods with tigers.

5. Our ongoing coverage of new species named after celebrities converged with another subject that constantly fascinates us: Ozzy Osbourne. A new species of frog was recently found in Brazil and named Dendropsophus ozzyi. The males have a bat-like mating call, which reminded the researchers of the infamous concert when Ozzy bit the head off a bat during the show.

Scientists named this new species of frog after Ozzy because it makes a bat-like noise, which reminded them of Ozzy's strange stage diet in the 1980s.

Science quote of the week:

"Science fiction has become science fact today - Hollywood is good, but Rosetta is better" –Dr. David Parker, in reference to the first time humans have landed a probe on a comet.

Contributed by:  Bill Sullivan

Follow Bill on Twitter: @wjsullivan

ORRICO, V., PELOSO, P., STURARO, M., SILVA-FILHO, H., NECKEL-OLIVEIRA, S., GORDO, M., FAIVOVICH, J., & HADDAD, C. (2014). A new “Bat-Voiced” species of Dendropsophus Fitzinger, 1843 (Anura, Hylidae) from the Amazon Basin, Brazil Zootaxa, 3881 (4) DOI: 10.11646/zootaxa.3881.4.3

  Montague, M., Li, G., Gandolfi, B., Khan, R., Aken, B., Searle, S., Minx, P., Hillier, L., Koboldt, D., Davis, B., Driscoll, C., Barr, C., Blackistone, K., Quilez, J., Lorente-Galdos, B., Marques-Bonet, T., Alkan, C., Thomas, G., Hahn, M., Menotti-Raymond, M., O'Brien, S., Wilson, R., Lyons, L., Murphy, W., & Warren, W. (2014). Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1410083111