Science Interviews


Sat, 11th Jun 2011

Ulcer Causing Bacteria - Converting the Enemy

Barry Marshall, QE2 Medical Centre in Perth

Listen Now    Download as mp3 from the show Passengers in a Bacterial Body

Chris -   In 2005, two Australian researchers, Ron Warren and Barry Marshall, won the Nobel Prize for their discovery in the 1980s of the bacterium Helicobacter pylori, which causes ulcers and stomach cancers in some of the people who carry it.  Compared with the past though fewer people today actually carry it, but many of those who do harbour the bug without any apparent harm. This has taken Barry in an entirely new direction since.


Department of Pathology

Fujita Health University School of Medicine

" alt="Helicobacter pylori" />Barry -   If everyone in the world used to have it until the last 100 years, maybe it was doing something useful for humans.  When humans didn’t have much acid secretion, we didn’t have much protein in our diet. In the stone age we probably had malnutrition half the time. Then Helicobacter really couldn’t do much because we didn’t have enough acid to develop ulcers and we didn’t live long enough to get cancer.  So Helicobacter in that situation was almost symbiotic, but what was it there for?  We still don't know.  However, in the 20th century, talking about the clean and hygienic theory of why people get so much asthma, allergies, things like that, we’re all too clean. Maybe the kids should be out in the backyard eating dirty stuff, dirt and what have you.  So Helicobacter, if you have it, puts you more back into the 19th century hygiene mode, and there’s some data that suggests that children with Helicobacter have less chance of having asthma or eczema, around 30% less risk.

Chris -   So you can trade an ulcer for asthma instead.

Barry -   Right, that's correct.  But if we study Helicobacter, maybe we can get the best of both worlds.  You see, maybe we could have a Helicobacter that didn’t actually hurt you, but actually down regulated the immune system or was a useful treatment for something like asthma.  People are starting to get very excited about Helicobacter as possibly a super probiotic and my work is currently on that. Not so much in probiotic, but more like using Helicobacter as a vaccination because if you could use it as a vaccine delivery vehicle – I'm going to explain that in a minute – then you'd have a vaccine the people would drink and buy it in the supermarket. Or it would just be a little capsule that they would get from the pharmacy, and it would not require going to the doctor or prescriptions or your poor little child having all these vaccinations. There's so many vaccinations these days, it’s getting out of hand.

Chris -   So what are you actually trying to do?  You're trying to produce an attenuated form of H. pylori that won’t trigger the ulcerogenic (ulcer provoking) outcome but will nonetheless confer what we think are these positive benefits, this symbiotic benefit, from having an infection with the agent?

Barry -   That's correct.  So, we could see that most of the Helicobacter that cause ulcers have got certain toxins in them.  We can choose one that doesn’t have the toxin, or we can choose strains from people who have had absolutely no symptoms all their life. We have collected these types of strains for example, from elderly people who never had those illnesses but have Helicobacter.  So we’ve got those strains and we can then say, “Okay, well let’s clone in the DNA from the flu virus H1N1.”  So that takes maybe two weeks to do.  Now we’ve got a Helicobacter that doesn’t hurt you, but it’s got flu virus particles sticking out of its surface.  So theoretically, if you now drink that one, your immune system will react against the flu virus and the Helicobacter at the same time and you should be vaccinated against the flu. That would be great because if you had a new flu pandemic you could have 200 million doses of this type of product in 8 weeks. You wouldn’t have to have a massive warehouse with 100 million pounds worth of vaccine which is going to go out of date in 12 months and you’d have to throw it away.  You would just have your little ampule of your vaccine strain, ready for emergencies, and you could easily scale it up.  You just then borrow one of the fermenters at the Guinness factory and you'll have a million cans of it in a week or so.  So, I'm pretty sure that that is where vaccination is going to go.  You're tricking the immune system into doing something it does naturally, but do it without actually having to have an injection or the flu virus itself.Hypodermic needle

Chris -   So you'd foresee a big library of H. pylori which will present various microbial epitopes (antigens) which would then stimulate an immune response, all be it in the context of an H. pylori infection. You could keep on superdosing people with different strains, with these different antigens in them, to fulfil their normal requirements of a vaccination repertoire that we’d give to kids.

Barry -   So we’d have a Helicobacter which doesn’t make you sick and it only lasts for a few weeks or a month, or so.  So, this type of illness you can imagine is a bit like having dandruff in your stomach.  That's the level of irritation you get, but it’s enough to actually stimulate the immune system.  The other thing about Helicobacter is that you can put potentially four or five different things on it.  You see, you can put the flu virus on the flagella, you could put rubella on the inside, and you could put whooping cough (Pertussis) on the back of it.  There are a lot of different places where we can construct the proper antigen and give it to somebody.  So, we’re gearing up now for clinical trials.  We are kind of getting back into humans.  So, if you see somebody outside my hospital throwing up, they might not actually be a patient.  They might be somebody in one of my research studies because we are currently dosing people with these Helicobacters, trying to find the right one which is going to be harmless, but could potentially vaccinate you.

Chris -   Barry Marshall, speaking with me at the (QE2) Medical Centre in Perth in Western Australia.


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Interesting idea.

I'm not sure I like the idea of using live bacteria as vectors to deliver viral antigens. 

H Pylori is a very difficult to treat infection, and can have very debilitating, if not lethal consequences. 

Bacteria not only can mutate through replication errors, but they can both pick up environmental genes, as well as sharing genes via plasmids, and thus they can change.

Sometime, someone will make a mistake, and will inadvertently release the next epidemic.

I was thinking about the use of less harmful natural "flora" as a delivery vehicle such as Bacteroides or Lactobacillus, but that would likely mean a higher likelihood that the therapeutic bacteria would escape into the wild.

Perhaps giving an oral dose of staph epidermis, or some other bacteria that doesn't colonize the gut at all, but again one should choose a bacteria vector that would be unlikely to escape into the wild.  Perhaps choose something that colonizes some animals but not humans, but also that humans are frequently exposed to so that they would likely carry a resistance.

In fact, that may be a problem with H Pylori.  The minority of the population would carry a resistance to the bacteria prior to exposure, so those with having prior exposure might have little reaction, and those with prior exposure might have worse reactions, if not risking long-term colonization. 

No matter what, I would encourage designing the bacteria with extreme susceptibility to at least 2 or 3 independent medications.  Perhaps even a custom medication bomb that would be specific to these designer bacteria.  And, it would have to be redundant due to the bacteria's propensity to develop drug resistance. CliffordK, Wed, 15th Jun 2011

Did you listen to what Barry said though? He's identifying avirulent, transient-carriage strains that don't persist, so they wouldn't need treating anyway. chris, Wed, 15th Jun 2011

I read the interview.

And, in most cases it may be self-limiting.  But, is that true in all cases?

People who have never had prior exposure to H Pylori, and thus have no prior anti-H Pylori antibodies
People who receive the vaccine on a regular basis, every year
People who are colonized with H Pylori, and are unable to mount an adequate immune response against it.
People with AIDS, or Transplants, or other imuno-deficiencies

"Live" vaccines such as OPV are given to children despite a low incidence of vaccine associated illness.  For a long time, vaccine associated polio was limited in the USA by giving children a couple of doses of IPV followed by a single dose of OPV.  However, the use of live OPV has now been discontinued in both the USA and UK.

OPV is still used in countries that have difficulties giving children multiple doses of IPV.

H Pylori, for the most part is non-lethal, but it has been associated with severe GI problems. 

What happens if the attenuated version is cultured with the wild version (I.E. a carrier person receives the vaccine)?

I certainly support the idea of scientific progress, but I get concerned with the idea of doing wide distribution of live designer pathogens, especially when we have methods to deliver an equally effective vaccine without live bugs.  What we need is a better method to take them from development to distribution, as well as perhaps better storage methods.  Can we make a long-term vaccine storage facility in Antarctica? CliffordK, Thu, 16th Jun 2011

Hi Clifford

Regarding polio, the reason that the live (OPV) has been phased out in polio-eliminated countries like the UK and the US is because the live form is infectious (by definition) and leaves the body (via faeces), re-seeding the environment with polio. And because the virus occasionally reverts to type (reverses the disabling mutations that attenuate the vaccine) this poses a difficulty with eradication, because it sustains the presence of wild-type polio in the environment.

Therefore, as we move towards eradication, authorities are switching towards (dead) IPV to prevent this occurrence, except in risk countries where it is prudent to remain with live vaccine for various reasons.

As far as the H. pylori story goes, you ask what happens if a modified H. pylori mixes with a virulent type, there are various ways to disable the bug or to prevent a risky recombination from happening to reduce the danger. However, the research is at any early stage with the first steps being to identify these avirulent strains.

You raise very good points though.

Chris chris, Sun, 19th Jun 2011

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