Phenotyping human diseases in mice: an interview with Professor Carola Vinuesa

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Prof. Carola Vinuesa THOUGHT LEADERS SERIES...insight from the world’s leading experts

Please can you give a brief introduction to phenotyping human diseases in mice?

One of the main obstacles to finding effective therapies for human diseases has been our limited understanding of disease pathogenesis: we lack detailed knowledge of the cellular and molecular mechanisms that lead to the development of disease.

In the last few years, sequencing the entire human genome has become available and affordable, which means we can now identify every genetic variant in an individual that is predicted to be damaging.

This information coupled with cutting edge genomic editing technologies such as CRISPR/Cas9 for the first time allow us to generate mice that harbour the precise genetic changes predicted to cause a disease in an individual or groups of patients.

By analysing the appearance and behaviour of proteins and cells (i.e. “phenotyping”) in these mice we can finally start connecting particular genetic variations to disease.

This understanding of disease pathways allows clinicians and scientists to develop targeted therapies that are likely to be more effective than current treatments, particularly in the case of autoimmune diseases.

Why is the mouse such a good model for understanding human disease?

The mouse is a good model for understanding human disease because first and foremost, mice share over 95% similarity with our genome, and mice and humans have highly conserved systems and pathways.

For example, the mouse immune system utilises a remarkably similar set of cells and proteins to fight off infections, although of course, there are a few notable exceptions.

Importantly, mice are small and can thus be studied housed in large numbers in the laboratory, under homogeneous and controlled housing – and dietary – conditions, removing the environmental challenges that confound many human genetic studies.

They also reproduce rapidly – pregnancy lasts 21 days – which means transmission of genetic traits can be studied over a few months.

How do you look for unknown genetic links to human disease?

There have been several “mouse to human” approaches utilised in the past to look for unknown genetic causes to human disease.

These included identifying the genetic lesions that caused spontaneous disease in certain strains of laboratory mice, introducing random mutations in the mouse genome using chemicals like ENU and screening for diseases of interest followed by identification of the causative mutation, and genetically manipulating mice to remove a particular gene predicted to be involved in disease.

These approaches, while successful in their ability to improve our understanding of gene function, have generally failed to translate into improved clinical outcomes for patients, because in essence, the specific mouse lesions failed to recapitulate the human disease.

Our Centre for Personalised Immunology has now taken a “human to mouse” approach: we start by identifying all the putative genetic lesions that may cause disease in an individual through sequencing the entire genome.

Then, we can introduce these specific lesions in mice to test whether they indeed cause the disease, to understand how disease develops, and to trial new or existing drugs that may specifically target the affected pathways.

Could you please outline the project you are working on to understand how the immune system work?

We have established a Centre for Personalised Immunology, co-directed by Prof Matthew Cook and myself, in collaboration with clinicians, scientists, bioinformaticians, educators, and policy developers from Australia, US and Europe.

We adopt a circular approach to understand human disease by starting from an individual patient, identifying rare genetic variants that may cause disease, testing the individual variants in the laboratory, introducing them into mice to develop bespoke mouse models of disease to prove and understand causation, and returning to the patient to trial therapies that target the affected pathway.

We take advantage of a cutting edge technological platform comprised of a state-of-the art bioinformatic analysis pipeline, large-scale and highly parallel flow cytometric analysis of immune cell subsets and CRISPR/Cas9 gene editing of human cell lines and single mouse zygotes.

How will this research help people with conditions such as rheumatoid arthritis?

Rheumatoid arthritis is one of over 80 autoimmune diseases, which, as a whole, affect 3-5% of individuals, can cause serious morbidity, and for which there are no curative therapies to date.

We have had early successes in identifying the genetic lesions that cause disease in individuals with autoimmune and other immune diseases.

For example, we recently discovered why a 3 year old girl suffered a stroke as a complication of a severe form of lupus – the prototypic systemic autoimmune disease: she harboured a homozygous novel mutation in the gene TREX1 that causes accumulation of pro-inflammatory molecules known as type 1 interferons; blocking these interferons with existing monoclonal antibodies may prove an effective therapy for this disease, for which current therapies are not very effective and cause serious side effects.

Investigators in our centre have also elucidated novel genetic causes of common variable immune deficiency, haemolytic uremic syndrome etc, and some patients have already benefited from specific treatments as a consequence of precise identification of their genetic defect.

What role do bioinformaticians play in phenomics research?

Bioinformaticians play a central and key role in phenomics research. The process of identifying the putative causative genetic lesions in humans starts with state-of-the art bioinformatic analysis, that could not take place without the development of sophisticated pipelines that can identify, rank and filter the over 20,000 coding mutations that each individual harbours.

We are fortunate in our Centre of Personalised Immunology to count with the expertise of two bioinformatic geniuses, Dr Dan Andrews and Matt Field, who have developed and are continuously improving our pipeline.

What do you think the future holds for phenotyping human diseases in mice?

The future is bright. We anticipate we will soon have personalised mouse models for many human diseases, which will accommodate the diversity and heterogeneity of causative pathways.

Through careful phenotyping of these mouse models and detailed understanding of how disease develops, we will be able to generate an array of novel diagnostic tools with which to stratify patients according to molecular causes of disease rather than the tissue or organ affected.

These mouse models will also enable us to run pre-clinical trials on drugs predicted to be effective for each specific pathway.

The corollary is the implementation of personalised medicine, which will not only treat patients more effectively, but also bring significant savings to national health systems by rationalising the use of expensive drugs to the most appropriate patient groups.

Where can readers find more information?

Readers can visit our Centre for Personalised Immunology website to find more information: and Australian Phenomics Facility

About Carola Vinuesa

Carola Vinuesa was born in Spain and obtained a medical degree at the University Autonoma of Madrid. She undertook specialist clinical training in the UK and in 2000 was awarded a PhD by the University of Birmingham. A year later she was the recipient of a Wellcome Trust International Travelling prize Fellowship to do postdoctoral work at The John Curtin School for Medical Research in The Australian National University.

In 2006 she became leader of the Humoral Immunity and Autoimmunity Group at ANU supported by a Viertel Senior Medical Research Fellowship.

She has been the recipient of prestigious prizes including the Biogen-Idec prize (Spain, 2007), the Prime Minister’s Prize for Life Scientist of the year (Australia, 2008), the Gottschalk Medal of the Australian Academy of Sciences (2009) and the inaugural CSL Young Florey Medal (2014).

She is currently Professor of Immunology, The John Curtin School of Medical Research at the Australian National University and Head of the Pathogens and Immunity Department, and Director of the Centre for Personalised Immunology.

Her work has led to the discovery of genes important for immune regulation and memory and the identification of a novel pathway of posttranscriptional control of gene expression to prevent autoimmunity.

Her group identified a critical role for follicular helper T (Tfh) cells in autoantibody-mediated autoimmune diseases and discovered novel follicular T cell subsets important for antibody responses.

Her current effort focuses at understanding quality control checkpoints during antibody responses, and connecting genetic variation in humans to autoimmune disease with the goal of implementing personalised medicine.

April Cashin-Garbutt

Written by

April Cashin-Garbutt

April graduated with a first-class honours degree in Natural Sciences from Pembroke College, University of Cambridge. During her time as Editor-in-Chief, News-Medical (2012-2017), she kickstarted the content production process and helped to grow the website readership to over 60 million visitors per year. Through interviewing global thought leaders in medicine and life sciences, including Nobel laureates, April developed a passion for neuroscience and now works at the Sainsbury Wellcome Centre for Neural Circuits and Behaviour, located within UCL.


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