Tuberculosis diagnosis in animals and humans | Innovations

Tuberculosis diagnosis in animals and humans

Tuberculosis diagnosis in animals and humans

Updated 21 May 2013, 9:31 AEST

ATSE Clunies Ross awards celebrate innovation in technology

DESLEY BLANCH:  We start with the story of how the diagnosis of tuberculosis was fundamentally changed around the world – thanks to four Australian scientists who were acknowledged this week as heroes in Australian science and technology and presented with prestigious Clunies Ross awards.

TONY RADFORD: And when you come along and have a test and you suddenly say, hang on, three out of four of those results you were calling positive and treating, were wrong. It certainly shakes people up a bit. 

DESLEY BLANCH:  Tony Radford, together with Jim Rothel, Stephen Jones and Paul Wood are the four awardees who invented and commercialised revolutionary technology that is greatly assisting in global TB control in both humans and cattle.  They played a role in successfully eradicating bovine TB in Australia.

In 1985, Dr Paul Wood led that CSIRO team in searching for a rapid--that’s within 24 hours--test for tuberculosis in cattle as TB was a major issue in Australian cattle at the time.

DR PAUL WOOD : Australia was running a national campaign to eradicate tuberculosis and brucellosis from its herds and while it was going pretty well in the south, we still had some real significant problems in the north of Australia with our more remote pastoral areas.

DESLEY BLANCH : Paul’s team included fellow awardees Drs Jim Rothel and Tony Radford and which was formed to develop a revolutionary test to be more accurate than the 100 years’ old skin test which was quite unreliable.

DR PAUL WOOD : The skin test is a test that’s done in the field in cattle. It’s subjective in nature because people have to feel and feel for a lump and decide whether the lump is significant enough. So it’s very subjective. Cattle had to be held for three days and in the remote areas they’re very stressed, so we needed a rapid test, in this case less than 24 hours, we wanted it lab-based, so it was more subjective in its readout.

TONY RADFORD : The problem with the skin test was that it was highly non-specific. It tended to cross-react and cause false-positives in any number of cattle and that was costing a lot in terms of dead cattle and wasted time and so what we needed to develop was something that was a lot more specific and really did identify truly infected animals.

DESLEY BLANCH : Tony Radford came on board the team as a molecular biologist.

TONY RADFORD : I came on to do all the cloning, clone genes, look for proteins, find things that would actually assist in getting a better test and I worked with Paul who was the immunologist who actually did the fundamental work in defining the system that we were going to use.

DR PAUL WOOD : I was very fortunate early on to go to Northern Territory and see the situation where TB was diagnosed in cattle up there. So that helped me focus on some of the parameters we had to work on, so I knew it had to be pretty robust, couldn’t have a lot of manipulation steps in it. So that helped us form the sort of ideas. Because it had to be lab-based we always knew it was going to be with a blood sample taken from the animals and then processed in the lab.

TONY RADFORD : We had to strictly look at the immune reaction that we could find in the animal. It may sound simple, but in fact, we had to come down to finding what’s known as the T-cell reaction, because nothing else was going to be there and then we had to find a way of making that simple and easy and making it fast and that is what we did.

DESLEY BLANCH : A patent was lodged for a simple lab-based method to measure an immune response to TB infection.  The crux of the invention is its reduction of a complex principle to a simple practice – and the critical trial for the new test involved a dairy herd in Victoria thought to contain TB infected animals and included an animal named “Dream Illusion”.

DR PAUL WOOD : We got a call from a veterinarian who said he thought he had an infected herd and when I tested all of the animals, there was only one animal positive. So he rang me, and he said look sorry, there wasn’t much there, and I said, yeah, just one animal, Number 53.

And when I post-mortemed that animal it had TB and because it was a dairy herd, it had a name and the name was “Dream Illusion”.

DESLEY BLANCH : But he used the older former test hadn’t he and he had taken how many days to get a result?  And you had your test result in?

DR PAUL WOOD : Well at that stage, it was still a prototype, but what we were looking for was a 24 hour turnaround, whereas the old test was a three day and as I said, it was a rather subjective test.

DESLEY BLANCH : And he called you all those days later and said I found, sorry only one animal?

DR PAUL WOOD : Yeah, he was apologetic, and for me it was that complete elation you have as a scientist when you realise that what you thought was a good idea is actually a practical solution. So we don’t have too many moments like that and that was one great moment for me.

DESLEY BLANCH : And dear old Dream Illusion became a mascot for the project.

DR PAUL WOOD : Dream Illusion’s tag sat on our fridge in our lab for many, many years.

DESLEY BLANCH : This is when you and your team knew that you’d invented a new diagnostic test for TB as you’ve said, but it would still be another five years before this became a commercial reality and this was when Commonwealth Serum Laboratories, they are a large Australian drug development company, they came on board and how Stephen Jones became involved in the project, to do what?

DR PAUL WOOD : Well, this is where you need a bit of luck in science. So we had a prototype lab-based test but we needed a commercial product and fortunate for us CSL had started a diagnostic program.

 Stephen Jones was recruited into that program and we were able to convince CSL to have a look at this and develop a kit, a commercial kit for bovine TB so that’s work that Stephen did. But, of course, then we had to actually take it out in the field and prove it really works. So over the years, we tested many, many thousands of animals and in the end we tested them all around the world.

DESLEY BLANCH : Well first the TB test was for cattle and other tests followed for what other animals?

DR PAUL WOOD : Well, TB is a problem in many species, so obviously in humans, but in the veterinarian community, TB in cattle is a problem in New Zealand and they had possums as a reservoir; in the UK where they had badgers as a reservoir for TB; in South Africa where they had lions and elephants. So we were able to adapt the same sort of technology and walk across the species, so we developed a primate assay  we developed one for deer and of course eventually one for humans as well.

DESLEY BLANCH : Well, that’s it, that was next. You teamed with Stephen Jones at CSL to adapt the technology into a new test for human TB diagnosis. And while it was exciting technology, in late 2000, CSL withdrew its interest in the field. So this is when Tony Radford re-enters the story, but we’ll talk to him in a moment. But what did you do from then on, for you?

DR PAUL WOOD : We’d proven that the test worked in cattle and CSL approached me one day and said, well, do you think this would work with humans?  And I was able to pull out a whole lot of data that I’d used with a project with the Children’s Hospital to show that it would.

So then they set about a commercial product but CSL’s focus changed to become more of a blood product company, and we risked the loss of this technology overseas and that’s when we got together as a group and said look, let’s do this; and eventually Tony Radford and Jim Rothel were the ones that went ahead with finance--local finance, to create Cellestis and to license the technology from CSL.

TONY RADFORD : I was concerned that the technology could be lost full stop, not just to Australia but to the world and I felt that it was important that we got it out there. And Jim, Paul and I and Stephen all knew a way in which we could improve upon it and make it a really good human diagnostic and we saw a lot of potential in that. So we said, let’s start a company and do it ourselves.

DESLEY BLANCH : So what’s the main advantage of the test you developed called QuantiFERON-TB Gold over the skin test used for decades on humans since the 1890s?

TONY RADFORD : The real advantage in our test is specificity which means in fact, that if you’re a positive in our test you truly are infected. It has a very low rate of false-positive reaction, so that means that 99 per cent of people that are positive truly have infection.

When you compare that to the skin test in a Western society, often the skin test, three and four of people are a positive are in fact not infected at all and they may go on to get treatment that they didn’t need for nine months which is just a complete waste of time, money and effort. It also undermines the efficacy of the programs and costs money and so that’s what we did. We made a specific test and it was fast.

DESLEY BLANCH : Then you had to get it approved. You formed the company, made the test. What year is this?

TONY RADFORD : Ah, we formed the company in 2000 and we got it approved at the very end of 2001 with the FDA.

DESLEY BLANCH : The FDA, that’s the United States Food, Drug Administration. So despite this commercial resistance remained. Nobody was buying it. Why?

TONY RADFORD : Well, not nobody, Desley. (laughs)

DESLEY BLANCH : Some people were buying it, but not enough. You’re the commercial man.

TONY RADFORD : All right. Well, what happened is we improved the test to make the QuantiFERON Gold Test by 2004 it was,  and at that time we had a really specific test and at that time, we had to really convince people to change their minds about what they thought about TB testing. But, of course, they’ve been using the skin test for 100 years and when you come along and have a test and you suddenly say, hang on, three out of four of those results you were calling positive and treating, were wrong. It certainly shakes people up a bit.They are a bit staggered by the fact that they’ve been treating so many people for so long, for so little purpose. So we had to convince them of that, and, of course, we also had to change the practice.

Our test is a laboratory-based test, the skin test is done in the clinic, so it was a change of practice and a change of funding and a change of mindset.

DESLEY BLANCH : Was this among vets, was among regulatory bodies or government bodies, was this were it was - guidelines had to be developed or?

TONY RADFORD : Well, most of my work was done in the human test and that’s where guidelines had to be developed. We had to do lots of clinical research, we had to give the data, convince the people that wrote the guidelines, people around the world from the Japanese Ministry of Health to the United States Centre for Disease Control, everybody that in fact, this was working, that it was giving the right answer and that it was cost-effective.

DESLEY BLANCH : So Tony, you were an inventor, a developer and clinical researcher and you brought a start-up through to a successful international medical production and sales company and delivered a product that changed medical practices and which enhances global tuberculosis control. So why then was the company in 2011 taken over, what was your thinking at that point, because you’ve run a successful company for 12 years?

TONY RADFORD : Twelve years it would have been yes. Well, apart from being all of those things Desley, I’m also a director of the company and as a director my responsibility was to accept a very fair price when it was offered and it was a very fair price offered for the company. 

And it was also to my mind a good company to deal with. I felt the product was going to someone that would expand its sales and they’ve done that. They’ve gone out and taken it to the world. They want to do more in TB and they’ll do more work in TB and expand upon what we have done. So I felt very comfortable with the people we were dealing and withQiagen and what they’ve done subsequently.

DESLEY BLANCH : A Tuberculosis diagnosis in animals and humans is technology that has spanned more than 25 years in the lives of Jim Rothel, Stephen Jones, Paul Wood and Tony Radford.  It all began with the Australian cattle industry.

DR PAUL WOOD : It’s great to look back over 27 years and it started with funding from the cattle industry. The Australian Cattle Industry put the money into CSIRO because they were concerned about finishing off the TB eradication program, so they supported our work and it’s a credit to industries like that that really do put their own money back into research in this country.

DESLEY BLANCH : And what is their advice to the following?

DR PAUL WOOD : I think you want to tackle big issues. You want to look for where are the unmet needs in veterinarian health and in medical health. You want to be a bit brave, don’t get discouraged. It can be a long haul. Because it’s a long haul you’ve got to enjoy it. So you really need to enjoy the process as well as the outcomes and I think science as a career is a fantastic thing and I’d encourage people to get into it.

TONY RADFORD : Well, my advice particularly to people who came down the scientific pathway is that you’ve got to get out and take a risk.  You’ve got to see your opportunity and take it and if you don’t you’ll always be wondering. And what you’ve also got to do is realise that it’s not always about science. It’s often about the personality, it’s often about how you do things, being effective as a scientist is getting something to happen and you don’t always get something to happen by ramming the data down somebody’s throat. Sometimes you have to be subtle, careful and plan it. Try hard and always remember there’s EQ as well as IQ and you’ll get somewhere.

DESLEY BLANCH : So what’s your key to working together so successfully over such a long period of time?

TONY RADFORD : Well, there are two things I often say and one is rather glibly, is trust. Trust is the big thing and we’ve trusted each other implicitly over 25 years and then there’s always been a constant stream of abuse between all of us, so we’ve kept our egos down and no-one’s actually got their head above the parapet.

DESLEY BLANCH : Other winners of the ATSE Clunies Ross Award announced this week are Drs Simon Poole and Steven Frisken who have contributed to the development and commercialism of advanced optical components and subsystems which support the Internet.  Dr Ian Croser was recognised for developing world-leading radar capability to the Australian Defence Force.

Contributors

Paul Wood

Guest

Tony Radford

Guest

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