Tracking the spread of deadly diseases

Dr Kathryn (Kat) Holt, Bio21 Institute, The University of Melbourne

Kathryn-Holt-700x500-2Kat Holt is using genetics, maths and supercomputers to study the whole genome of deadly bacteria and work out how they spread. Studying a typhoid epidemic in Kathmandu, she found that it didn’t spread in the way we thought epidemics did. Her research, published in Nature Genetics, will change how we go about responding to epidemics.

With the support of her L’Oréal For Women in Science Fellowship, Kat will be using the same techniques to understand how antibiotic-resistant bacteria spread in Melbourne hospitals. Are people catching these superbugs in hospital, or are they bringing the bugs into hospital with them? Can we give the intensive care clinicians early warning of a drug-resistant bacteria in their patients?

Kathryn (Kat) has been a pioneer ever since she became the first student at the University of Western Australia to undertake an honours year in the then-fledgling area of bioinformatics.

Kat ventured across the Nullarbor to the other side of Australia—to the Walter and Eliza Hall Institute of Medical Research in Melbourne—where she sought advice from bioinformatics guru Prof Terry Speed. As a result, she ended up as a doctoral student at the world renowned Sanger Institute at the University of Cambridge, one of the homes of the human genome project.

There, she spent the next 4 years learning, developing and using the latest genomics techniques to investigate the evolution and genetic diversity of Salmonella typhi, the bacterium that causes typhoid fever. That meant working with samples from patients in Kathmandu and also Kolkata, Indonesia, the Mekong Delta and Nairobi.

Her work challenged our ideas on how typhoid spreads and led to a paper in Nature Genetics. She found that family members each had different strains of the bacterium. It wasn’t a single new strain spreading between them. So increases in infection were driven mostly by climate, not by outbreaks of a novel genetic strain. “In the wet season, you get flooding, the drinking water becomes contaminated, and you get transmission and a lot of infections. So, in the one season you have infections caused by a whole variety of genetically different typhoid bacteria.”

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It was a discovery that could only come from sequencing the whole genome, “It’s a very recently emerged pathogen, so there’s little genetic variation to track. To get anywhere with it, you have to sequence the whole genome.”

Now, an expert in bacterial genomics, she is back home, still working on infectious diseases. And in Australia, some of the biggest problems of infection lie in hospitals. One of Kat’s major current projects is using genomics to study the origin, evolution and spread of antibiotic resistance in hospitals, particularly the role of Klebsiella, a bacterium that is rapidly becoming a problem worldwide because of its capacity for survival in a broad range of environments and its propensity for picking up novel genes.

Having already started her study of Klebsiella by taking swabs both from patients admitted to hospital free of infection, and from patients who develop an infection while in hospital, she now wants to use those same swabs to broaden the study to other species. “We can leverage what we already have to look at drug-resistant bacteria in general.” And the $25,000 L’Oréal Australia and New Zealand For Women in Science Fellowship she has just been awarded will allow her to do so. It’s one of five significant projects she is starting this year, most of them funded by Australia’s National Health and Medical Research Council.

To pursue this work, in the past few months Kat has established a laboratory and her own research group at the University of Melbourne’s Bio21 Institute. But it’s not a place of sinks, pipettes, fridges and Petri dishes; it’s a group of computer terminals for analysing data. The sort of studies she undertakes are highly computer intensive, and she and her team spend a lot of time using the supercomputers of the Victorian Life Sciences Computation Initiative.

“Genomics allows you to address a whole range of questions using one set of data: whether a bacterium is harmless or dangerous; its evolution; its transmission; what environments it can live in; what drugs are likely to be effective.”

She learned that lesson first hand in May and June 2011. An outbreak of a virulent new strain of the normally harmless gut bacterium Escherichia coli (E. coli) led to widespread panic and the death of more than 50 people in Germany. As the crisis unfolded, the huge Chinese genomics laboratory BGI sequenced the DNA of the bacterial culprit, and posted the data on its website.

When Kat saw what was there, she dropped everything else and began to analyse the data and blog about what she found. “From looking at the sequence, I could see what sort of E. coli it was, and why it was dangerous,” she says. “It was a hybrid of different strains which did not have a typical profile. In particular, it carried a whole new combination of virulence genes I hadn’t seen before.” She could also see how it had evolved as a new strain, and guess at where it came from.

“While it was too far into the outbreak to be of much assistance, it provided a good demonstration of the power of genome sequencing. If the public health authorities had undertaken such sequencing at the beginning, we could have learned a lot more about the bacterium more quickly.”

Kat is the daughter of two biomedical scientists. So she grew up hearing all about science, and carefully avoiding biology at school. When she reached university, Kat wasn’t sure what she wanted to do, so she took on a combined Science/Arts degree majoring in genetics and philosophy. “I continue to use what I learned in philosophy all the time—analytical thinking, writing, the underlying logic of things, how we know things.”

But, like her parents before her, she became hooked by biology in the end. “I just got caught. I found it really interesting. And I could see how biology fitted in with the maths I was doing. Eventually I put the two together.”

It was at the Sanger Institute that the bacterial element of her work emerged. “I went there thinking I was going to do something in human genomics, but what I found really engaging was the work to do with pathogens because of their relevance to global health, particularly to infectious diseases in developing countries,” Kat says. “I found it really inspiring to be doing my PhD in an area where a relatively small amount of effort can lead to big wins.”

Back in Melbourne, she is now responsible for a group of five postgraduate students, two staff and a whole lot of projects. “I now spend a lot of time on administration as well as hands-on research, but I’m starting to build a higher level vision of research.” For instance, she’s now part of a bid to the Australian Research Council for funding to establish a collaborative centre involving “scientists from quite different backgrounds pursuing a common goal. It’s very exciting. But I still really love getting a few hours to sit down and analyse my data, and I’m also very passionate about teaching bioinformatics to students.”

“It’s very empowering to be able to know enough about biology to ask questions, but also to have the analytical skills, in terms of statistics and computing, to be able to analyse data and answer those questions in meaningful ways. The challenge of bioinformatics today is getting people up to scratch in both of those areas, so that they don’t just answer other people’s questions, but can ask and answer their own biological questions.”

Outside the laboratory, Kat and her husband, also a scientist, enjoy travelling together, including field visits and to scientific conferences. Both work and recreation for them are ways of opening their minds to new experiences—pioneering.

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2011 Masters in Epidemiology, The University of Melbourne
2009 PhD (Molecular biology), Wellcome Trust Sanger Institute and The University of Cambridge, UK
2004 Bachelor of Science with Honours (Genetics)/Bachelor of Arts, The University of Western Australia

Career highlights, awards, fellowships, grants

2013-2015 Chief investigator on National Health and Medical Research Council (NHMRC) project grant Identifying key players in the spread of antimicrobial resistance, worth over $785,000
2013-2016 Chief investigator on four other NHMRC research grants, worth over $2.2 million
2013 Invited seminar speaker, Molecular Microbiology Meeting, Sydney
2012-present Research Fellow/NHMRC Early Career Fellow, Bio21 Institute, Dept Biochemistry and Molecular Biology, The University of Melbourne
2012-present Honorary Research Fellow, Telethon Institute for Child Health Research, WA
2012 CASS Foundation Travel Grant to attend Molecular Epidemiology and Evolutionary Genetics of Infectious Diseases conference, US
2012 Visiting Researcher, Pasteur Institute, France, funded by Rod Rickards Fellowship and administered by Australian Academy of Science
2012 Invited conference speaker, UK Society for General Microbiology Conference, Dublin, Ireland
2012 Invited seminar speaker, Giessen University, Germany
2012 Invited conference speaker, session chair and workshop convenor, Australian Society for Microbiology Annual Conference, Brisbane.
2011-2012 Victorian Department of Health Food Safety Evidence for Policy Research Grant, Genetic fingerprinting of Listeria and Salmonella: How Different is Different?
2011 Early Career Researcher Grant, The University of Melbourne
2010 Invited seminar speaker, Pasteur Institute, Paris
2010-2012 Postdoctoral Research Fellow, Department of Microbiology & Immunology, The University of Melbourne
2005-2009 PhD Studentship, Wellcome Trust Sanger Institute, Molecular Pathogenesis, UK
2005 Research Technician, Bioinformatics Division, Walter and Eliza Hall Institute
2004-2005 Graduate Research Assistant, Department of Biochemistry, University of Western Australia
2002-2005 Research Assistant, Telethon Institute for Child Health Research, WA
2002-2003 Contract Programmer, CreativityCorp

Top five publications

Holt KE, Parkhill J, Mazzoni CJ, Roumagnac P, Weill FX, Goodhead I, Rance R, Baker S, Maskell D, Wain J, Dolecek C, Achtman M and Dougan G (2008) High-throughput sequencing provides insights into genome variation and evolution in Salmonella Typhi, Nature Genetics 40(8):987-993. (Impact factor 36, 236 citations)

Holt KE, Baker S, Weill FX, Holmes EC, Kitchen A, Yu J, Sangal V, Brown DJ, Coia JE, Kim DW, Choi SY, Kim SH, da Silveira WD, Pickard DJ, Farrar JJ, Parkhill J, Dougan G and Thomson NR (2012) Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe, Nature Genetics 44(9):1056-1059. (Impact factor 36, 17 citations)

Holt KE, Thomson NR, Wain J, Langridge G, Hasan R, Bhutta ZA, Quail MA, Norbertczak H, Walker D, Simmonds M, White B, Bason N, Mungall K, Dougan G and Parkhill J (2009) Pseudogene accumulation in the evolutionary histories of Salmonella enterica serovars Paratyphi A and Typhi, BMC Genomics 10:36. (Impact factor 4, 53 citations)

Heaton T, Rowe J, Turner S, Aalberse RC, de Klerk N, Suriyaarachchi D, Serralha M, Holt BJ, Hollams E, Yerkovich S, Holt K, Sly PD, Goldblatt J, Le Souef P and Holt PG (2005) An immunoepidemiological approach to asthma: identification of in vitro T-cell response patterns associated with different wheezing phenotypes amongst 11 year olds, Lancet 365(9454):142-149. (Impact factor 34, 220 citations)

Rohde H, Qin J, Cui Y, Li D, Loman NJ, Hentschke M, Chen W, Pu F, Peng Y, Li J, Xi F, Li S, Li Y, Zhang Z, Yang X, Zhao M, Wang P, Guan Y, Cen Z, Zhao X, Christner M, Kobbe R, Loos S, Oh J, Yang L, Danchin A, Gao GF, Song Y, Li Y, Yang H, Wang J, Xu J, Pallen MJ, Wang J, Aepfelbacher M, Yang R, E. coli O104:H4 Genome Analysis Crowd-Sourcing Consortium (Holt KE, Studholme DJ, Feldgarden M, Manrique M) (2011) Open-source genomic analysis of Shiga-toxin-producing E. coli O104:H4, The New England Journal of Medicine 365(8):718-724. (Impact factor 53, 161 citations)

Dr Kathryn Holt (credit: L’Oréal Australia/
Dr Kathryn Holt (credit: L’Oréal Australia/
Dr Kathryn Holt (credit: L’Oréal Australia/
Dr Kathryn Holt (credit: L’Oréal Australia/