PROF BARRY MARSHALL

Interview with Professor Barry Marshall

Interview

Zoe Wood

Professor Barry Marshall is an Australian Nobel Prize Laureate in the field of gastroenterology and microbiology. Early in his career, Professor Marshall went into internal medicine with a gastrointestinal emphasis, working with Dr J. Robin Warren to demonstrate that Helicobacter pylori is the cause of most peptic ulcers. In this conversation, Professor Marshall describes drinking a dose of the bacteria himself in order to prove causation amongst risk taking in medicine as well as future directions in his field.

I’d like to talk about the very famous story of how you drank a Petri dish containing cultured Helicobacter pylori to make the causal connection of the bacteria with peptic ulcers. Considering the resistance your findings faced by the medical and scientific community, what do you think the reasons were that people were unwilling to consider the connection? For example, do you think there was an economic motive?

What triggered me to do that experiment was a grand round that I did at Fremantle hospital, when I was a medical registrar there. I was in the senior registrar job in internal medicine, so I did a grand round about this bacterium. It became evident that normal non-specialists were just so entrenched with this stress idea – the brain/gut axis. I don’t believe in any of that. They were so entrenched; it was exactly like a religion at that point. You couldn’t move stuff that people knew. Even if you had facts, they just didn’t feel it was right. So the fallback position for everybody was ‘there’s only one person, there must be something he’s doing wrong, otherwise how come it’s not been discovered before?’. So there was that attitude, then the pathologist got up and said ‘well these changes in gastritis are extremely subtle, how can you really measure them objectively? Obviously people with ulcers have got a hole in their stomach and other bacteria can come and live in the ulcer, it’s probably just commensals, you’ve got a long way to go, where’s your animal model?’

At that point, I had been trying to infect rats and mice, guinea pigs and piglets for about six months and getting nowhere. It was kind of frustrating – I had no answer for that. I could not really do the next step. However, I did submit an MD thesis proposal and in that I said that if the animal work fails, then we would try to get a human volunteer experiment. So I had decided that I needed to go to that step. Looking back on it, it was riskier than I originally thought it was because I was pretty certain that I could eradicate it with antibiotics, but the ones I chose in fact probably wouldn’t have worked. I had an endoscopy to make sure I didn’t already have H. pylori. So I drank the bug thinking that I would just be asymptomatic. Most people I knew with H. pylori were infected blood donors. I found 40% of blood donors at Fremantle were infected and didn’t even know they had it. So obviously, it wasn’t killing them and no one could remember where they caught it from. There was no history involved with the infection so it was a bit of a puzzle.

Even Dr. Warren and a couple of other people thought it might have been sexually transmitted, close contact with somebody, because ladies who attended the STD clinic were more likely to be infected than everybody else. There were a whole slough of crazy little pilot studies trying to sort the epidemiology out, it was very confusing. However, I drank the bug and I did become unwell with a vomiting illness and there was no acid in the vomit. That triggered something that I had read in an old medical textbook, The Principles and Practices of Medicine by Sir William Osler in 1910. They described exactly the acute illness that I had. I suddenly realized that these old descriptions of vomiting without any acid in the vomit were probably H. pylori and it became less common and people forgot about it.

Putting it all together at that point, the endoscopy showed a very heavy infection with H. pylori, so it was lucky that I had chosen that strain because I could have chosen one that didn’t infect very well. However, I didn’t get an ulcer and the illness got better after two weeks – it was all over. Discussing it with a few colleagues enabled me to do this hypothesis article for the Medical Journal of Australia. I believe it is either the second or third most cited article in MJA with thousands of citations.

What changes occurred in your life after receiving the Nobel Prize?

I believe Nobel laureates develop a bit of an inferiority complex and maybe some paranoia. One of the things is that I’m always talking about things I know, I’m the font of knowledge for Helicobacter and I keep up in that field, but there are so many other topics that I don’t keep up with. If I pick up the Medical Journal of Australia, I’ll look at the headlines and think that I don’t have time to read certain articles. Similarly, I’m not going to have time to be able to read the journals that I used to read, so I get a bit paranoid about not keeping up.

The other thing is that you’re worried that you don’t have peer review as a Nobel laureate. If you say something, someone is happy to print it or put it up on the web. If I twitter about something and say “this is a load of rubbish” about the microbiome of the stomach, nobody else is saying that. So I think, am I nuts? I’m just looking for a little niche where I can fight the consensus. Anybody who says something is a consensus, I am immediately totally suspicious of it.

Moving on to some of your current research, increasing antibiotic resistance accounts for 15% of patients who are not cured of their H. pylori infections. When these patients are referred to you, you isolate their strain, they receive a ‘tailor-made’ combination of antibiotics. I was hoping you could discuss how much of a threat you believe antibiotic resistance is with respect to H. pylori?

It’s a moderate threat, once you know how to get around it. You learn these principles of microbial therapy in medical school and it’s not going to change. Always, if you find the resistance pattern of the organism, you navigate around it with your antibiotics. The tricky part is that many of the antibiotics I like to use are active in the stomach and are often old. The best example is tetracycline. Everyone says “don’t use that, it’s not very well absorbed, it stays there in the lumen of the gut, it passes out in the stool.” Hang on a minute – that’s great for H. pylori.

There is need for further studies to work out the pharmacology of antibiotics in the gastric mucosa because when amoxicillin fails, we have no idea why it fails. All Helicobacter are always sensitive to amoxicillin. So you should be able to just give people amoxicillin and a PPI (proton pump inhibitor), and expect a cure. We’re not seeing that. So you have to add the third drug, there are different ones.

So I’m not too worried about it with Helicobacter, it’s a bit like a Streptococcus. It’s got a limited repertoire. However, it mutates extremely fast. It’s almost like a virus. According to a paper we did, its right on the top of the list for mutation. The reason is because it doesn’t have to protect its genome. There’s nothing else floating around much except other Helicobacters. So they’re all moving genes around, sucking them in and out as they divide. It doesn’t check the accuracy of its copying. So it’s continuously disabling its ribosomes or changing its ribosomes, so it very easily becomes resistant to macrolides or metronidazole. So it becomes interesting; there’s so many Helicobacter in your stomach – 1010 organisms. So for the stomach, it doesn’t matter that its doing bad copies of itself because it will just continue to have an evolution in the gastric mucosa. That’s why it becomes resistant to these things that require some interaction between an antibiotic and a functional protein, because they disable the protein in some way and then it’s resistant. So I think in the future, we need to do more studies on the pharmacology of the gastric mucosa and immunology. I’m optimistic that we’ll figure it out eventually. But, at the moment we haven’t made much progress in the last 10 years. That said, we still kill 99% of H. pylori that is referred to us.

The Marshall Centre for Infectious Diseases Research and Training has a principle goal in facilitating the development of new vaccines for H. pylori. Given that the bacterium is part of the normal flora as you mentioned before, for approximately 50% of people, do you believe that non-pathogenic H. pylori should be eradicated?

This is the question that I had trouble with. So, statistically it is normal because half the people in the world have it, so they’re not at the two standard deviations from the mean to have H. pylori. However, it is a pathogen even in the normal flora. It’s been normal in stone age Man, ever since humans left Africa 70,000 years ago they’ve been carrying H. pylori – maybe even hundreds of thousands of years before that. So in that respect, you could say it is normal flora and it may have had a beneficial effect. The ones that get the press are due to the fact that it downregulates the immune system a little. The beauty of this might be that if you had H. pylori you were less allergic and everybody’s a little bit allergic so that’s okay. But there are these kids that are outliers in their allergy response who are way up high in their responsiveness. They’re the ones that get anaphylaxis. So maybe if you had H. pylori, you would be less likely to be up in that group, you’d be more down in the middle of the range. As humans migrated out of Africa and visited all these other continents, with different plants and animals, it’s possible that having H. pylori was a bit beneficial. You’re hiding in the bushes from a lion, all of a sudden you start sneezing, that would not be good. Being less allergic might have helped human migrations.

Nowadays, Helicobacter has been disappearing by about 50% every generation in the last 50 years. So since about 1960, in Western countries it’s just been declining. It’s not antibiotics. It’s better hygiene, smaller families and it’s not terribly infectious. If you have both parents infected, each child has about a 50% chance of picking it up from an Australian parent. It’s in the next generation, but not a lot. So you can’t blame me if Helicobacter disappears. I’m killing it, I’m doing my best, but in fact 90% of the work is just done by modern living in 21st century life.

Are there any other medical issues that you would like to see gaining the same attention as the microbiome?

I think the immune system of the gut is important. We can put things into the stomach and into the colon, but the small intestine we can’t really investigate. As far as I’m concerned, there’s only two causes of anything: genetic and environmental, in particular all the viruses that you catch in the first few years of life. I think we’ve got a long way to go but we are on the threshold of cheap sequencing. So what we’re going to see is a lot of cheap sequencing during the lifetimes of lots of people. Then maybe 10 years from now, we will have computers big enough to figure out what it all means. We will probably be able to see that a lot of it is viral triggers – who knows.

 

 

 

Acknowledgements

None

Photo credits

Image 1: SHKP and CUHK Present Distinguished Lecture by Nobel Laureate in Physiology or Medicine [Barry Marshall]. Communications and Public Relations Office. 2013 [cited 30 May 2018]. Available from: https://www.cpr.cuhk.edu.hk/en/press_detail.php?id=1649

Image 2: public domain, accessed from https://pixabay.com/en/bacteria-black-health-microbiology-359956/

Conflicts of interest

None declared

Correspondence

zoe.c.wood@gmail.com

Low-wage migrant workers in Singapore

Six weeks at HealthServe

Elective Report

Sarah Tan Yingli & Kai Yuan Tey

 

B was leaving Singapore that weekend, heading home to Bangladesh. His workplace injury compensation case had finally been resolved. We asked if he was excited for the reunion with his family after so many years abroad, and the subdued acceptance in his sad smile—“[I’m a] little bit happy”—was striking. B had fallen from scaffolding and severely injured his back, leaving him unfit for further work. Under the orders of his employer he spent months bouncing between various hospitals and clinics, looking for the “cheapest rates”. His eventual injury compensation fell far short ofhis entitlement. Ongoing disputes with his employer about his injury compensation culminated with a heated argument during which B was struck in the face. His search for help had brought him to HealthServe, and it was there he was generous enough to share his story.

It is a story that would resonate with the experiences of many low-wage migrant workers in Singapore. A review conducted by the Ministry of Manpower (MOM) in June 2017 found migrant workers account for a 37.9% of the Singaporean labour force.[1] More than half are employed as low-wage labour or in service industries.[1] Despite serving as the cornerstone for Singapore’s booming economic and architectural development, B and his fellow low-wage migrant workers constitute an especially vulnerable population,[2,3] subject to exploitation and often left shouldering significant burdens of illness and injury.

HealthServe is a not-for-profit, non-government organisation that reaches out to a community whom its small staff and indispensable volunteers pointedly refer to as their “migrant brothers and sisters”. Dr Goh Wei-Leong founded HealthServe in 2006, offering migrant workers medical care, social assistance, casework, personal development classes, and a hub for communal recreation. The 2017 Singaporean of the Year title awarded to Dr Goh (and the HealthServe organisation as a whole) has fuelled the long waiting list of medical students keen to assist with its operations.[4] We were fortunate to complete our 6-week internship at HealthServe over the recent summer university vacation.

Working at the clinic

HealthServe began as a clinic in Singapore’s Geylang district providing general practice (GP) and dental services two evenings a week and Saturday afternoons. It has since expanded to include regular specialist dermatology and orthopaedic consulting and two additional worker-dormitory-based clinics offering similar healthcare services.

As interns, clinic days meant arriving 3 hours ahead of advertised opening times to prepare for the imminent rush. Migrant brothers and sisters would come in throngs—busy days, with more than 50 patients waiting before even the first had been seen, necessitated the emotionally draining process of turning some away. HealthServe saw patients from a range of occupational backgrounds. Although most of the patients were men, staff also assisted the occasional female domestic worker referred from the Humanitarian Organisation for Migration Economics (HOME).

The clinics themselves were unlike anything we had experienced. Every role relied on volunteers, from doctors to receptionists. The clinic manager helped interns fill staffing gaps as needed, becoming temporary dental assistants, receptionists, triage ‘nurses’ and medication packers. We soon learnt that even the seemingly menial jobs played pivotal roles in the clinic’s operations, underlining the importance of an effective multidisciplinary team in delivering quality patient care.

Resources were scarce. It was eye-opening to witness how the clinic’s financial dependence on grants and donations impacted healthcare. Proton pump inhibitors were often replaced with H2 antagonists. Measuring tapes substituted for height charts. ECG machines left over from the 1990s tested our abilities to adapt and make do. We embraced the challenge.

We were soon eagerly conversing with the migrant brothers as we triaged the waiting patients, finding joy in the supposedly mundane vitals measurements. They had many stories to tell—of Bangladesh’s six seasons in a year, of the food back home in China, or of their dreams and aspirations. Triaging was an opportunity to exercise our clinical judgment supported by the safety net of the clinical manager’s review. The conversations that unfolded while doing so were potent reminders of the individuals behind the pathological processes it was so easy to become absorbed in. As Sir William Osler once said, “The good physician treats the disease; the great physician treats the patient who has the disease.”[5]

Chronic conditions like diabetes and hypertension were rife, exacerbated by poor diets and a reluctance to seek medical attention understandable when a standard consultation could cost the equivalent of 3 days’ wages. A large proportion of our patients presented suffering from muscle strains, ligament sprains, back and soft-tissue injuries, and chronic pain—the inevitable results of gruelling 12-hour shifts 6 or 7 days a week. Patients with injuries severe enough to stop them working were stuck in a jobless and incomeless limbo between the termination of their work permits and the payment of their workplace injury compensation.[6] Our hearts went out to those who described their predicament—the perpetual uncertainty of the process, the months or even years waiting for resolution, the scheming employers intent on cutting costs, and the meagre compensation eventually received.

Beyond the clinic

The inherent precarity of migrant worker life discourages outspoken resistance against exploitation for fear of pay cuts and retrenchments. Movement restrictions, squalid housing conditions, and passport confiscations are alarmingly common practices.[7,8] In 2014, one manager was jailed after pleading guilty to breaching employment regulations and underpaying wages.[9] But the enforcement of accountability is rare. Many workers arrive already in debt from the 6000 to 15,000 Singaporean dollar employment agency fees paid to secure positions before departing their home countries, leaving some convinced “it’s better to be underpaid than not paid at all.”[10]

Dr Goh, a strong proponent of learning through immersion, would encourage interns to explore migrant worker haunts, travel to dormitories, and encounter the plight of the migrant workers firsthand. We visited some of HealthServe’s dormitory-based clinics and were taken aback. The fencing erected following the 2013 ‘Little India’ riot was reminiscent of a penal institution. A dormitory floor housed 20 rooms, each shared by 8 to 10 migrant brothers. Washing machines and refrigerators were bought by the workers themselves and every floor contained one communal bathroom. The migrant brothers’ days were strictly regimented— waking up at 5:00 AM, taking the shuttle bus to work, and then returning to the dormitories to cook, bathe and sleep.

Referrals

On days when the clinic did not open, our intern responsibilities included everything from sorting medications and autoclaving dental instruments to organising the specialist referrals some migrant brother patients required. These pro bono specialist consultations relied on the goodwill and altruism of Dr Goh’s friends and colleagues who share his outlook on migrant worker health. We would accompany the migrant brothers during these appointments to alleviate their anxiety and offer emotional support. Cases we witnessed ranged from foreign body removal to the diagnosis of kidney stones secondary to horseshoe kidneys (ren arcuatus or renal fusion). Diagnostic reasoning and management plans were tailored to a population so different from the Australian and primarily Caucasian patients we had dealt with in medical school. The social determinants of a patient’s health were a factor in every decision about appropriate treatment options. No matter the outcome, the migrant workers showed gratitude towards their treating doctors and were generous in expressing appreciation towards us for accompanying them to the clinics.

Behind closed doors

Every Thursday afternoon, the staff gather for a lunch meeting at the heart of Little India. As food and laughter are shared, ideas on improving the services supporting the low-wage migrant worker community are exchanged with equal passion. The English lessons and computer classes now run by HealthServe volunteers are just two of the fruits of these weekly meetings. Dr Goh was always open to informal meetings with staff and interns to reflect and recalibrate.

Our experience at HealthServe was enriching to say the least. While there is much more to be done to help the migrant brothers and sisters driving Singapore’s economic progress, it is heart-warming to witness the ever-increasing awareness and support for migrant worker advocacy. Organisations such as Transient Workers Count Too (TWC2) and Migrant Workers’ Centre (MWC) are contributing to one day achieving what Dr Goh sees as his advocacy’s ultimate aim: “Our job in HealthServe is to make sure that we are out of job.”

We appreciate the time taken to read this article. Var Lock Tergo (“God bless” in Bengali).

Acknowledgements

The authors would like to thank HealthServe for providing the consent for writing this report on their experiences. The authors would also like to express their gratitude to HealthServe for the opportunities and experiences provided, and extend the same to everyone they met during their internship who together made the experience so enriching.

Photo credits

Images 1–4: With permission from Xi Zhe Sim, fellow HealthServe intern.

Conflicts of interest

None declared

Correspondence

syt@utas.edu.au

References

1. Summary Table: Labour Force [Internet]. Singapore (SG): Ministry of Manpower; 2018 Jan 26 [cited 2018 Mar 25]. Available from: http://stats.mom.gov.sg/Pages/Labour-Force-Summary-Table.aspx

2. Harrigan NM, Koh CY. Vital Yet Vulnerable [Internet]. Singapore (SG): Singapore Management University; 2015 Nov 4 [cited 2018 May 22]. Available from: https://www.smu.edu.sg/sites/default/files/smu/news_room/Research%20Report_Vital%20Yet%20Vulnerable%20%28FINAL%29.pdf

3. Lyon E. Wage challenges faced by migrant workers in Singapore [Internet]. Singapore (SG): CSR Asia; 2017 Mar 29 [cited 2018 May 22]. Available from: http://www.csr-asia.com/newsletter-wage-challenges-faced-by-migrant-workers-in-singapore

4. Toh WL. GP Goh Wei Leong and healthcare charity he co-founded named The Straits Times Singaporean of the Year 2017 [Internet]. Singapore (SG): The Straits Times; 2018 Feb 6 [cited 2018 Mar 30]. Available from: http://www.straitstimes.com/singapore/gp-and-healthcare-charity-he-co-founded-named-the-straits-times-singaporean-of-the-year

5. Centor RM. To be a great physician, you must understand the whole story [Internet]. Medscape General Medicine Vol. 9 Issue. 1; 2007 Mar 26 [cited 2018 Mar 30]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1924990/

6. WICA versus common law [Internet]. Singapore (SG): Ministry of Manpower; 2017 Jun 28 [cited 2018 Mar 26]. Available from: http://www.mom.gov.sg/workplace-safety-and-health/work-injury-compensation/wica-versus-common-law

7. Singapore: Events of 2016 [Internet]. New York (US): Human Rights Watch; 2017 [cited 2018 Mar 26]. Available from: https://www.hrw.org/world-report/2017/country-chapters/singapore#f176e9

8. Rajah M. What plagues the migrant worker? [Internet]. Singapore (SG): Transient Workers Count Too (TWC2); 2014 Nov [cited 2018 May 22]. Available from: http://twc2.org.sg/wp-content/uploads/2014/11/what_plagues_migrant_worker.pdf

9. Chelvan, VP. Manager jailed 34 weeks for exploiting more than 100 foreign workers. Channel News Asia (International Ed.). 2017 Feb 24 [cited 2018 Mar 26]. Available from: https://www.channelnewsasia.com/news/singapore/manager-jailed-34-weeks-for-exploiting-more-than-100-foreign-wor-7602678#main

10. Han, K. Singapore’s migrant workers struggle to get paid. CNN (International Ed.). 2018 Feb 25 [Cited 2018 Mar 26]. Available from: https://edition.cnn.com/2018/02/24/asia/singapore-migrant-workers-intl/index.html