Predicting unexpected consequences of proposed funding policy changes

The Sydney Morning Herald reported that the government is going to change the basis for funding university research.  With the aim of increasing collaborations between the universities and industry, the suggestion, based on questions at a public forum apparently, is that the government may remove publications in books, journals and conference papers as a criterion for a significant amount of the funding received by the universities.  A formal statement on the matter is expected early in December following a review of the government on its innovation program.

Although this relates to the mechanisms for university funding and hence does not have a direct impact on medical research institutes like QIMR Berghofer, there are some messages that underpin the opinions that are of great significance.  For many years I have been committed to the concept that excellent research should have consequences beyond publications.  The statistics in this respect in Australia are dire and need to be changed.  However the old adage of ‘Too far East is West’ may apply and there is a great possibility of unintended consequences if the more extreme view of ignoring publications prevails in decision making processes.

Research of relevance to industry and with the potential to generate economic and health benefits has its roots deep in research which may not, at the time of their initiation, pass the criterion on being relevant to society.  However without developing a profound understanding of an experimental system, there will be nothing of value that will come. Trying to take a shortcut directly to applications is similar to skipping the training part and expecting to win a marathon race.  As in all domains there is a difference in the quality of research which is generated in laboratories.  Only excellent research will provide insights, to the prepared minds, of useful and potentially useful outcomes.  It is dangerous therefore to totally ignore publications or their quality in defining where funds should go.

Having analysed the operations at this Institute, I categorised the research which is ongoing here (Gannon F, The steps from translatable to translational research, EMBO Reports 2014, Vol 15, 1107-1108). There are steps from discovery through to translation into health or commercialisation and it is important that the right mix is available in an institute or in a country such that a healthy pipeline is generated.  By defining the steps as basic research (D1), disease oriented research (D2), target identification (D3) and target modification (D4) prior to translation to procedures that can be tested in clinical trials, I established that 50 per cent  of our research was disease oriented and 47 per cent covered the steps that screen out discoveries and enrich to the point such that they can be applied.  The new funding proposals that are under discussion should take this pattern into consideration.  If the outcome is that all discovery projects are excluded then there is no doubt that the pipeline will dry up very quickly.  Already the NHMRC, that funds most Australian medical research, appears to look for impacts on health directly from the research that it supports and hence discovery research is harder to pursue.  The ARC funding provides an alternative that may cover some of those areas closer to basic research but unfortunately researchers from the medical research institutes are, bizarrely, excluded from applying for such funds.

The overall message from the government is totally in line with the needs of the country and the demand for change such that there is better return for investment in research is timely.  However it is important to avoid an excessive swing towards to practical outcomes or there will be outcomes that I see as predictable but will be classified as unexpected consequences.

The Walk, The Ride

Recently, I participated in the Weekend to Ends Women’s Cancers to benefit the QIMR Berghofer Medical Research Institute.  This was the third and final two-day 60 kilometre walk event.  I have participated in all three of them, but my feet and legs could only manage to do day one on each occasion.  Still, 30 kilometres is a good ramble.  The best part of the event is the opportunity to talk to people (mostly women) about women’s cancers, their motivation for engaging in the walk and sharing with them the research progress at QIMR Berghofer and elsewhere, that speaks to the continuing need for better prevention, detection and treatment of these cancers.

In August we had the fifth and final Rio Tinto Ride to Conquer Cancer.  This was an equally challenging event—riding 200 kilometres in two days.  I participated in this for the first three years, and again my lack of training or skill meant that I completed only day one of the event riding more than 100 kilometres. Again it was a big demand to go all day up and down hill. In the second year, the wind was in the wrong direction and we had to pedal downhill. I have previously blogged about that event and lessons learned. I have recognised that those participating were doing so for love of somebody close to them, to have a cathartic release of anger against cancer and to obtain hope from the research we would perform using their dollars.

But of course, cancer has not been cured (the implicit message of the Rio Tinto Ride to Conquer Cancer), nor have women’s cancers ended (the implicit message of The Weekend to End Women’s Cancers). This being said, we have seen some great advances, for example: it used to be that 80 per cent of women diagnosed with breast cancer did not survive five years—now 80 per cent do.  But there remains much more to be done. We at QIMR Berghofer and other researchers have to continue in our quest to move towards achieving these goals.  The funding that came to QIMR Berghofer has made an enormous difference.  Some of this is in the form of providing the best infrastructure and equipment that can be available that helps all researchers.  It also has allowed us to initiate programs to attract PhD students to the Institute, thereby looking towards the future.  It has helped us to recruit and retain crucial researchers that are part of our very strong team in the area of cancer in particular.  But most visibly it has allowed research projects to commence that would have otherwise not been possible.  It’s also allowed us to leverage funding from external agencies. Over the years, more than 30 such projects have been initiated.

One conundrum with working in Australia is that unless you have preliminary data you cannot get funding, and of course you need to have funding to get preliminary data.  The Ride and the Walk provided this, and so much more.

Although these high visibility events have come to an end, our need for funding, especially for those stimulatory projects, remains.  It is hoped the community we have bonded with over the years through their participation and support of the Ride and the Walk will stay with us and become regular donors. And you can do so also! Those who are participating in other community events can do so and raise money for QIMR Berghofer at the same time through Team Eureka.  Finally we will be communicating a series of specific projects in need of funding and sharing them with the community that we have grown close to.  Hopefully you/they will identify in this menu of opportunities, topics that they will particularly like to support.  Information on this will be provided very soon.  In the meantime, it is very appropriate to say a major thank you to all of those who directly or indirectly were engaged in the Ride and the Walk.  It is strange that the end of the challenge of participating in these events brings more sadness at the fact that they will not continue than relief at the fact that the pain will not have to be incurred every year.

Bench to Biotech to Bedside with Big Pharma

As a medical research Institute, QIMR Berghofer works hard to ensure that the insights gained from research get translated into the community or the clinic. Sometimes this is a long and slow haul, but when we make progress in transferring mature work from the laboratory, there is a great sense of satisfaction. Treatments to address diseases in patients have to be made robust and their safety tested by thorough evaluation in clinical trials. That is why we talk at QIMR Berghofer of our new paradigm of Bench to Biotech to Bedside (B2B2B). This is in contrast to Bench to Bedside or the other more classical B2B2B which is business to business to business. There is an essential step where industry nous and finances are essential and that is found in Biotech companies and Big Pharma – but B2B2B is easier to promote than variations that would include all industries.

In the recent past we have had two major developments that attest to the quality and relevance of our work. In August 2015 we announced that Bristol-Myers Squibb (BMS) a world leading pharmaceutical giant had selected us for a very significant research partnering agreement. This is in the area of Immuno-Oncology (IO) which is one of the most promising sources of potential new treatments for cancer. There are treatments that are based on an understanding of the interplay between the tumour cells and the immune system. A small but growing number of them have moved into clinical use. Clinically significant improvements in survival for melanoma patients have been recorded and the data are consolidating to a major boost for those with this difficult cancer. Our insights will add to the products that are being brought forward and hopefully will help to extend the range of cancers that can be targeted successfully.

Then last week we announced another agreement – this time with Atara Biotherapeutics, a biopharmaceutical company with a focus on developing meaningful therapies for patients with unmet medical needs in diseases that have seen limited therapeutic innovation. This company have identified opportunities to treat some cancers and autoimmune diseases by targeting viruses that are associated with them and by training the immune system to attack the associated tumour or affected cells. We have a leading track record in these approaches having completed clinical trials where we targeted Epstein Barr Virus (EBV) that drives Naso-Pharyngeal cancers and Cytomegalovirus (CMV) that accompanies brain tumours (Glioblastomas). Because of that, Atara have chosen us to partner with them in developing new and improved means of delivering these and other therapies.  Again this is the first part of B2B2B. We look forward completing the pathway in the next years.

So it is a time to recognise, again, that quality research carried out with an eye on the endpoint of translation can and does characterise QIMR Berghofer. Two significant agreements that arrive at almost the same time is unusual. In each case we hope that the patients will be the beneficiaries of success. Inspiration comes to all at the Institute when projects that had benefitted from years of work end up as part of a pipeline to the clinic. Now we have to re-focus on other research developments that we hope will add to these successes in due course.

We are delivering – Snap shot one

There is always a balance to be reached between boasting about achievements and hiding a candle under a bushel.  QIMR Berghofer Medical Research Institute tries to get its messages out through the media.  There are frequent press releases and some of these get amplified.  However I don’t think we have really managed to do ourselves justice in showing just how great this Institute is.

So to step out of character 🙂 I thought I should launch a new occasional message from the Institute which I am calling We are delivering.  The first of these which highlights aspects of our work is below. It covers some aspects that were highlighted last month.  When you read it you will see that QIMR Berghofer really is a world-leading Institute, fulfilling many of the diverse tasks that you would expect when all those that are in the Institute are committed to having an impact on society through the research which we perform.  This is what we are doing:

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WE ARE DELIVERING—Quality research

  • We published 506 peer reviewed  papers last year. That corresponds to two per working day. This is more than the papers published by any other well-known Medical Research Institute in Australia
  • Our papers are important for researchers world-wide. They were cited
    36 000 times in the last five years. This is more than the citations of  publications by any other Medical  Research  Institute in Australia.

WE ARE DELIVERING—Relevant research

  • A recent report from the Times Higher Education shows that we are ranked 7th in the world for citations used  in patent disclosures. No other Australian university or institute made this list of the 15 top providers of information that led to the patent.

WE ARE DELIVERING—Competitive research

  • We were awarded three of the nine EU-Australia research grants, and are the only Queensland institute to be successful
  • In a national  peer reviewed competition, we were  one of five recipients of a special grant ($6.4 million) to extend our work on dementia. There were no other successful Queensland applicants.

WE ARE DELIVERING—Translated research

  • We announced a very major collaboration agreement with Bristol-Myers Squibb (BMS) a world leader in Immuno-oncology. Immunotherapy is the fastest growing and most promising new approach to cancer treatment and we are recognised as world leaders
  • Research from our laboratories forms the basis for 27 clinical trials that are currently ongoing and we are participating in 23 other external trials
  • We announced, in collaboration with the University of Hong Kong, the start of a phase II clinical trial for the treatment of a specific head and neck  cancer that is prevalent in South East Asia. This is fully funded by donations from Hong Kong.

Thanks to support from our donors and Queensland Health. As you can see,
WE ARE DELIVERING.

A view on the future of biological therapeutics

Today was very much an Indian day.  It started with a breakfast meeting with the Australia India Business Council, followed by a meeting with the High Commissioner to India, and will end with discussions with the Senior Vice President for Research and Development of Biocon India.

Dr Narendra Chirmule has recently joined Biocon after many years in the United States and brought to the breakfast discussions interesting insights on the future of the biological industries.  He pointed to  the differences between biologics and small molecules that have been the traditional therapeutic drugs from the pharmaceutical industry.  The biologicals are more complex to manufacture and to maintain their  consistent composition and therefore need to have a different thought process for acceptance in the clinic.  Specifically he suggested that increasingly the clinical trials that are involved for Biologics will have to adapt to the ongoing outcome of the trial rather than have fixed endpoints.  In this way the information that is obtained in a Phase I trial can be used to modulate the endpoint which would be most beneficial for the treatment of patients.  The manufacturing processes for biologics also are complex and therefore there will have to be greater flexibility in manufacturing than had traditionally been the case for small molecules.

The technical details behind this are still being worked out but it is not a simple matter to scale a process and have a similar outcome at the end.  The side effects of biologics are generally less dramatic than those of small molecules but they are still responsible for about one third of the compounds that fail on their way to the clinic.  Having greater knowledge and being able to predict these perhaps even on an individual basis will be important.  This will give rise to much more involvement of companion diagnostics such that the products are targeted to the right individuals. The growth in this area seems to me to be inevitable and the manner in which it happens, either within the Biologicals producing companies or in parallel with it will be interesting to watch.  Finally because of the manufacturing complexities and the more delicate nature of biologics they will have to have a number of smaller manufacturing units worldwide and hence a global structuring of this industry in the future.

The stress by Biocon on affordable medicines was another aspect that is instructive and the future of Biosimilars will be fascinating to watch particularly in light of the complexities of maintaining a defined product in this particular area.

The visits by our Indian colleagues are another reminder of the great potential that is India and elsewhere in South East Asia and that are of direct relevance to research and industry prospects in Australia.  It also pointed to opportunities arising from the recent trade agreements. As Australia has very efficient regulatory processes and very high quality standards it could benefit by becoming a new manufacturing location for biologicals. The overview from Biocon also reminded me of the various steps that have been taken to date; Small chemical molecules have been the start of the pharma industry. Next were some biologicals that corrected deficiencies in patients (insulin or growth hormone for example) that grew from biotech companies initially. The current growth area is in molecules (biologicals) that can indirectly influence disease outcome by modulating or stimulating the immune response and in parallel with these there are a number of examples where cell therapy is being used either by modifying cells or by stimulating them before injection to the patient.

QIMR Berghofer is very active in delivering understanding, clinical trials and solutions to these later developments. Exciting times are ahead!

Being 70

No it’s not about me although, I can see that on the horizon.  The three scores and ten in this case refers to the QIMR Berghofer Medical Research Institute in Brisbane.  We are celebrating our 70th birthday (anniversary) this year and a special event will be a Gala Dinner Saturday 31 October.  You are all invited!  (The cost is $225 per person).  70 is a significant time period for the existence of a research institute.  We are not the oldest in world, nor Australia, but we are up there as a very long-standing research location. So we should have a Gala to celebrate.

We have come a long way since 1945. The start of QIMR Berghofer came from a realisation that there were infectious diseases in Northern Australia (i.e. Queensland) that were not getting research attention from the rest of the researchers in the country.  Malaria, for instance, was present in Queensland in the 1940’s and was eventually eliminated in 1981.  At the start, the Institute was an external part of the Department of Health in Queensland.  This connection remains strong with the Director, Deputy Director and the Council being appointed by the Minister for Health acting in conjunction with the The Governor of Queensland in Council and the Executive Council in Queensland. Serious official engagement is assured in that way and then authority to act is delegated to the Council and through it to the Director and others in the Institute.

The first home of the Institute was in a prefabricated ex-army hut close to the Royal Brisbane Hospital.

old building

I have worked in prefabricated huts earlier in my career in Galway and their practical use is continued much longer than their natural lifespan.  But this is where QIMR Berghofer started with a great emphasis on infectious diseases and an early interest in Epstein-Barr Virus and Ross River Virus.  It is interesting that the Epstein-Barr Virus work is still carried through very actively at the Institute and is the basis of some of the most recent immunotherapy clinical trials that we are engaged in.

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The Institute eventually found a permanent home on the land of the Royal Brisbane and Women’s Hospital and the first building (Bancroft building) soon became full.  By then the leadership of the Institute had expanded the range of activities such that the new possibilities to study and work towards treatments of cancer were added to the Institute.  It also had great strengths in epidemiology and genetics.

Inevitably growth occurred in all of these burgeoning areas as did the reputation of the Institute.  This resulted in a second 12 story block (Clive Berghofer Cancer Research Centre) being built with the significant support from Chuck Feeney and Atlantic Philanthropies and also Clive Berghofer, a very generous developer from nearby Toowoomba.  Again within  10 years the now two buildings were very full and the State and Federal funds together with another major contribution from Chuck Feeney resulted in the building of the Central block which joined the pre-existing parts of QIMR Berghofer.

At the same time the Institute added mental health as an area of importance and continued to remain true to its mission of working to address health problems in Queensland and of course mental health has joined cancer as being a very major problem worldwide.  Now we have three buildings but a single Institute.

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Buildings are important, but it is what goes on inside that is most significant. And every week the 700 workers here add to our contribution to science and to its translation.

So on Saturday 31 October we will celebrate all of these achievements, and the researchers and employees that have allowed them to happen.  70 is a noble age when maturity and wisdom are well established.  Our task is to point the way forward to the next decades and in doing so we hope that many, like you will join as supporters along the way. I hope to see you the Gala Dinner.

Tribulations and a Trial

In 2002 Rajiv Khanna, at the QIMR Berghofer Medical Research Institute, started work on the potential of a relatively common virus, Cytomegalovirus (CMV), as a target that could stimulate the immune system to attack cancers.  That was a long sentence but each part of it carries with it a subtext of discovery, clarification, testing, trialling, generating materials, getting funds, applying for grants, publishing papers until eventually it came to the stage where Rajiv was aware that he had established how to use the CMV to trick the immune system to tackle some cancers.  That also is a long sentence but unfortunately some cancers are a very short sentence with a very high probability of death soon after detection.  Glioblastoma, the most common brain cancer, is one such example.

This was one of the targets of Rajiv’s work and he carried out his research with a very strong connection to a clinician, neurosurgeon Professor David Walker, at Newro Foundation and Wesley-St Andrew’s Research Institute.  The long wait to do some initial tests had a preliminary end four years ago.  Then, patients who were at the most advanced form of secondary recurrence of glioblastoma were tested with the CMV driven therapy.  The effects were positive in some patients and too late in others but in all cases there were no side effects.  In other words the treatment was safe.  Again saying something is safe is a short sentence but it is built upon layers and layers of hard work.  The process involves taking white blood cells from the patient and growing them in a laboratory under very specialised and very sterile conditions in the presence of the CMV trigger before they are reinjected into the patient.  QIMR Berghofer has extensive certified cellular therapy laboratories of a quality that is rarely found elsewhere world-wide where this work can be performed.

New hope for Michael
New hope for Michael

Having carried the initial safety tests on extreme cases of glioblastoma, today was the start of a much more relevant trial.  The first patient in the trial, Michael O, had been diagnosed with glioblastoma recently.  He had the standard treatments of surgery, radiotherapy and chemotherapy.  In parallel with that, white blood cells from a blood sample were being challenged by Rajiv’s treatment at QIMR Berghofer and grown to a stage where they could be reinjected into him.  The first treatment with this new combination of therapies started today. It was a moving moment with his mother and wife present. A simple injection by Professor David Walker that carried 37 million activated white blood cells into a path through his body to seek and hopefully destroy the tumour cells that escaped chemo and radiation treatment.

Rajiv and some of his team attended this culmination of years of work. The Queensland Minister for Health  Cameron Dick and the media also came to see this significant milestone, but it was not a “circus” event. Too much is at stake for Michael. Fingers are crossed in the hope that this will in fact be a significant change to the outcome in GBM.  The clinician, David Walker at the Wesley Hospital, is very aware of the need for these treatments and has been a great partner in the process but the development of this new treatment also would not have been possible without significant contributions from the public and support from Queensland Health.

So here we have a great combination, a dedicated researcher (Rajiv Khanna), a successful applicant for research funding from the NHMRC and other sources, an aware clinician, David Walker, funding from the community and the State culminating in a new treatment and new hope for a patient.  This is translational research in action and typifies the work that is ongoing at the QIMR Berghofer Medical Research Institute.