Trailblazer

Wieland Meyer wanted to be a medical doctor but, in East Germany under the eyes of the Stasi, freedom of choice was not an option. Discrimination didn’t stop him forging an internationally renowned career in medicine, however

As a young man growing up in East Germany, Wieland Meyer had aspirations to become a medical doctor, a plan thwarted by an act of discrimination. Ironically, this started him on a career trajectory that has had a profound influence on human health.

Meyer, now Professor of Medicine at the University of Sydney and Chief Scientist at the Molecular Mycology Research Laboratory at the Westmead Millennium Institute, has established an internationally recognised research team that has significantly advanced our understanding of fungal disease.

Over one billion people and countless animals are affected by fungal disease worldwide, yet fungal infections have been relatively neglected as a topic for research.

As any mycologist will tell you, the death toll from serious mycoses is similar to that of tuberculosis and malaria. Mycoses can affect all body systems, and are particularly problematic to treat in patients with HIV/AIDS, cancer or bone marrow and solid organ transplants.

Professor David Denning, professor of Infectious Diseases in Global Health at the University of Manchester in the United Kingdom, says “these diseases are poorly represented by most global health organisations and national public health bodies”.

Professor Tania Sorrell AM, director of Sydney’s Marie Bashir Institute for Infectious Diseases and Biosecurity, tells the MJA that “even though the global antifungal pharmaceutical market is about $8 billion and growing at 2%–3% each year, the range of available antifungal drugs is limited and many of these have problems with efficacy and toxicity”.

In hindsight, working in the field of mycology offers an opportunity to advance the health of humans and animals. Yet a young Wieland Meyer had no intention of working with fungi.

“I wanted to study medicine”, he tells the MJA. “I was rejected because in East Germany they wanted to suppress you.”

Professor Meyer was told that there were already “too many Christian doctors”.

Such discrimination was unconstitutional, so he complained to the government. That wasn’t well received and he came to the attention of the Stasi, the East German secret police. He was assigned to study biology — even though there were far more biology students than medical students.

“They wanted to make a point. I knew plenty of people who were rejected from biology, many more than were rejected from medicine. They wanted to give me something I didn’t want to do.”

Nonetheless, Professor Meyer did it, completing a BSc majoring in plant physiology. He encountered an enthusiastic genetics lecturer and switched to genetics, graduating with a Diploma in Genetics — the equivalent of a Master of Science — in 1986. He then took a job at a brewery studying the genetic characteristics of yeasts.

“They wanted to patent their brewery yeast strains so they asked me to type the strains so that no one could steal their yeast stock.”

At this time, Alec Jeffreys had developed genetic fingerprinting and DNA profiling for which he is widely credited with revolutionising criminal investigation.

That was when Professor Meyer developed an interest in DNA and polymerase chain reaction “fingerprinting” of fungi, a skill which would prove crucial in subsequent investigations of infectious disease outbreaks.

Professor Meyer was the first scientist in the world to type fungi using this technique. He completed a PhD in genetics at the Humboldt University of Berlin, Germany, under Professor Thomas Börner. He subsequently took up a postdoctoral position at Duke University, North Carolina, United States, from 1992–1995 with Professor Thomas Mitchell. The focus was on the phylogeny of Candida and the molecular epidemiology of Cryptococcus.

Duke University operated a large, world-renowned tertiary referral hospital. At the time, a large caseload of patients with AIDS was treated at the facility. A number of patients had infections with Cryptococcus neoformans.

Professor Sorrell visited because she had an interest in invasive mycoses and had become particularly interested in cryptococcosis in light of the work by David Ellis on eucalyptus trees as an environmental niche for C. gattii. She started to work with Professor Meyer on molecular typing of Cryptococcus to determine how strains were related.

It was the beginning of a lengthy and ongoing collaboration.

Professor Sorrell invited Professor Meyer to Australia to build a mycology reference laboratory, and the Molecular Mycology Research Laboratory (www.mycology.org) at Westmead Hospital was born.

“We wanted to build a reference laboratory that would aid in diagnosis and studying epidemiology of mycoses, and develop diagnostics that could be used in a clinical setting”, Professor Meyer says.

He subsequently established the Australian National Molecular Medical Mycology Reference Laboratory in 1995. This basic science laboratory is working closely with clinician scientists in the various teaching hospitals around Australia, especially in Sydney where close colleagues such as Sharon Chen, Debbie Marriott and Tom Gottlieb greatly assisted in case recruitment for clinical studies, while Richard Malik and Mark Krockenberger were very helpful on the veterinary side.

Underlying all of Professor Meyer’s work is a desire to develop rapid, simple, reliable molecular identification techniques for human and animal fungal pathogens, and to understand the determinants of fungal virulence.

Research scientist as detective

Understanding the epidemiology of mycoses is critical for early detection and prevention. This is where the research scientist really becomes a detective.

Molecular typing has played a critical role in this process. In 2006, there was an outbreak of systemic Aspergillus cases in transplant patients at a new intensive care unit at a major university hospital in Melbourne.

Professor Meyer and his colleagues were asked to assist with molecular typing of the agent. Initially it was believed that Aspergillus species isolated from the new ceiling were to blame.

However, the Aspergillus species isolated from the ceiling were different to those isolated from patients. The building was fully sealed, yet the Aspergillus strains isolated from patients were identical to strains located in the park outside.

Eventually, it was determined that the building, composed of a metal frame, expanded and contracted every time a helicopter landed on the helipad — actively pumping outside air into the building. It was then sealed in.

The intensive care unit was subsequently closed down and rebuilt.

Another case Professor Meyer’s team helped investigate was a spike in cases of Pneumocystis jirovecii in renal transplant units across Australia. The big question was whether infections were nosocomial.

Professor Meyer’s lab had developed a typing scheme for P. jirovecii. There were clusters of strains, but transplant units across the entire Eastern seaboard of Australia were affected by the same clones.

Within clusters, it was easy enough to explain that contacts could occur in hospital waiting rooms, but how was it that patients in Sydney and Brisbane had the same clones?

Finally, it was established that contacts were occurring during the Transplant Games, where transplant patients competed against one another.

Mycoses are not reportable, but since then there has been concerted effort by the Australian and New Zealand Mycology Special Interest Group to follow up case clusters of fungal disease.

Challenge of identification

Diagnosing mycoses and proving relationships between fungal strains is challenging.

“The majority of medically important fungi grow very slowly, and when you first isolate them they have few morphological characteristics that can be used for identification”, Professor Meyer says.

“A patient can in some cases die before the diagnosis arrives.”

There can be a 3–4-week time lag between isolation of a fungus and sporulation, the taxonomic tool of the classical mycologist.

“To enable an informed choice for proper antifungal treatment a precise identification at the specific level is needed”, he says. “But your ability to identify a given pathogen is only as good as your reference database.”

Classic fungal identification is time consuming and not always accurate. DNA sequencing is an alternative, using the Internal Transcriber Spacer (ITS) regions of the fungal genome.

Professor Meyer and colleagues from around the world created an international database of clinically important fungal pathogens. The current database (http://its.mycologylab.org) contains over 3200 sequences from 524 species affecting humans and animals.

Professor Meyer has also been the driving force behind the development of an international multilocus sequence typing (MLST) database for fungi. MLST employs partial sequence analysis of 7–10 housekeeping genes. MLST is used for epidemiological investigations, to determine whether isolates are clonal or have undergone recombination. Like ITS sequencing, MLST analysis is only as good as the choice of genes or loci selected in each study.

The purpose of the database (http://mlst.mycologylab.org) is to make the MLST schemes publicly available for important human and animal pathogenic fungal species, including the C. neoformans/C. gattii species complex, Scedosporium aurantiacum, S. apiospermum, Pseudallescheria boydii and P. jirovecii.

Basis of virulence

Not every strain of each fungal taxon causes the same kind of disease. Some are more virulent than others. Why is it the case, for example, that in the Pacific Northwest of the US and Vancouver in Canada, Cryptococcus typically causes lung infections and not meningitis?

Epidemiological studies suggested that virulence of fungi is genotype-specific.

Professor Meyer and colleagues, both within Australia and overseas, are actively seeking areas of the fungal genome which code for different virulence features. They have already completed whole-genome sequence analysis of 200 Cryptococcus strains.

“We can compare separate strains and we have found clusters of strains which are much more virulent than others”, he says.

For example, “there are regions of the genome of isolates present only in patients with lung disease that are not present in other strains”.

Medicine and mycology

Looking back on his career, Professor Meyer acknowledges that his current work “probably fulfils me more than being a medical doctor would have”, although being a biologist in the medical field isn’t always easy.

“If you have studied as a doctor you are treated differently than a biologist”, he says.

But Professor Meyer is a trailblazer.

While there is no question that mycology remains undervalued — funding is low while the fungal disease burden is high — Professor Meyer has moved from molecular mycology as a means of industry protection to saving lives (and health care resources) through early intervention.

He is not one to keep knowledge to himself. He has assembled a laboratory comprising scientists from all corners of the globe, and has academic affiliations with universities in Australia, South-East Asia, Europe and South America. He has supervised over 20 PhD students who now work internationally.

Professor Richard Malik, a veterinary specialist who has collaborated with him, says that Professor Meyer has “the best links internationally in his domain”.

“He loves the field, he does a lot to promote mycology as a discipline and he really cares about Australia punching above its weight in mycology”, Professor Malik tells the MJA.

“He is there for his students, he likes and respects vets and doctors and is probably the most collaborative scientist I know.

“He reads widely, goes to the cinema and has a balanced life”, Professor Malik says. “He’s very passionate and doesn’t mind having an argument with other international mycology heavyweights. For him, it’s all about the science, which is all about the truth.”

Professor Meyer’s aim is to ensure that molecular data for identification and typing of pathogenic fungi of humans and animals are globally accessible by linking individual quality controlled databases and establishing international data networks.

This will enable more rapid identification and a more effective, efficient public health response to emerging, highly infectious fungal pathogens.

Being Chair of the 19th Congress of the International Society for Human and Animal Mycology (ISHAM) to be held in Melbourne early next month is important to Meyer.

“It’s a chance to showcase what medical mycology does for the world and how important it is.”

The 19th Annual ISHAM Congress will be held in Melbourne from 4–8 May. For more information and registration visit http://www.isham2015.com.au.

Anne Fawcett BA (Hons) BScVet (Hons) BVSc(Hons) MVStud GradCertEduc(HigherEd)
Veterinarian, lecturer, journalist and blogger for www.smallanimaltalk.com. Her research and teaching interests include the interaction of humans and animals in a veterinary clinical context, clinical veterinary practice and veterinary ethics. Anne is the author of numerous academic publications, including peer-reviewed journal articles and book chapters. She is currently co-writing a handbook of veterinary ethics with Dr Siobhan Mullan, to be published by Nottingham University Press.