Visions: Susan M. Gasser, Director of the Friedrich Miescher Institute for Biomedical Research, Switzerland
Creating the future of medicine: a role for biomedical research institutes
The medical needs of Western populations are shifting, and scientific developments open new ways to define disease and new avenues for treatment. Here I consider this changing biomedical landscape and describe how the Friedrich Miescher Institute for Biomedical Research (FMI) is orientating itself to rise to some of the challenges.
An ever-changing landscape: the interface of science and medicine
Today's life scientists exist in a world of change, both scientific and societal. One of the most striking changes in Western society has been the extension of lifespan. In Switzerland the average lifespan is already 84 years, and across Europe the fraction of people over 65 is approaching 20%. Life expectancy has risen due to scientific discoveries on the etiology of disease and in many cases the integration of such information into public health policy. This has reduced childhood death rates many fold. But health care faces new challenges, in part due to our aging population. One observes a significant increase in chronic, lifestyle-induced diseases, like diabetes and hypertension, and degenerative states, such as dementia, late-onset blindness, deafness, sarcopenia and arthritis – not to forget cancer, for which the frequency increases exponentially with age.
Biomedical research must embrace this new medical need, and rapidly evolving technologies now provide unprecedented opportunities to study body tissue rejuvenation, the suppression of inflammation, and the restoration of failing sensory organs. These conditions may not fit classic definitions of disease, and indeed the underlying causes of tissue failure are often too poorly understood to allow treatment with existing medicines. But the identification of predisposing genetic factors takes on a new dimension, as one seeks both preventative treatments and to reduce the application of inappropriate therapies. Patient stratification based on both molecular and genetic makeup allows for increased accuracy in diagnosis and in treatment choice, particularly in cancer. So, as medicine changes, biomedical research has a new challenge: to learn to control organ biogenesis, function, homeostasis and tissue dysfunction on a molecular level. Making headway in these domains will allow basic research to contribute significantly to the health of our aging society.
Harnessing the power of quantitative data: 'omics and science-based medicine
No research area has triggered a more vibrant proliferation of relevant data than 'omics-based biology. The production and processing of digitalized information is no longer restricted to sophisticated laboratories, but extends into the lives of individual citizens, who can now obtain a personal database of physiological information on their mobile devices. Inexpensive sources of quantitative molecular information about our genomes, transcriptomes, epigenomes, proteomes and microbiomes may be soon readily accessible. But how will we know which information is of value? How can we provide medically relevant interpretation of massive digital input?
The daunting task before us is to correlate large datasets to outcomes of acute or degenerative disease. One needs information on the evolution of a state over time, and we need to determine which of the many measurable parameters is of value for creating and testing predictive models. More than genomic variants, one needs rapidly quantifiable parameters of cell biology, which are correlated with disease or dysfunction.
So where does this put a biomedical research institute today?
Human genome and epigenome analysis is surely important, but most lifestyle disease is not driven by mutation or predisposition. Rather it stems from chronic abuse or exaggeration of a debilitating lifestyle. How do we study this experimentally? Our bodies are an amalgam of 1000s of distinct cell types, and the development of in vitro organoid systems for studying differentiation and regeneration of cells of specific organ types is a breakthrough of major dimensions. Thus the focus of the FMI has been on new dimensions in quantitative cell biology, applying quantitative molecular genetics and biochemistry to questions of cell fate and differentiation – often in vitro. What exactly does that mean?
Expertise in quantitative live cell imaging, few- or single-cell gene and protein expression, and organoid development are all at the forefront of the biomedical research of the future. Spatial organization, the separation of functions into compartments, be they membrane-bound or aqueous phase separations, are essential for cell function. Learning to identify the integrity of a given cell type, and to recreate pathological outcomes in vitro, will be key to linking cell biology to medicine. Relating cellular phenotypes back to genetically caused model diseases – even rare diseases – gives one the link to human pathology. Finally, linking the phenotypes of rare genetic disease to more common disease phenotypes, which lack genetic alterations but recapitulate the pathology, will be key to redefining disease on a molecular basis.
Interdisciplinarity and extended mathematical training
To move a research institute like the FMI even closer to quantitative biomedicine, one must hire physics- and mathematics-trained group leaders who bring fresh approaches to the description and modeling of biological function. A mathematical understanding of biology will form a bridge from PhDs to MDs, and from model systems to patients, as all of us must interact critically with high-throughput datasets. Everyone must be competent to tweak algorithms to ensure the optimal mining of data patterns, and to correlate it meaningfully with disease outcome. A broad and rigorous mastery of statistics, bioinformatics and simple programming will be crucial. A second clear need will be increased cooperation across Europe, because analyses and new algorithms must be based on large, shared data sets or samples in “biobanks”. Steps towards the coordination of bioinformatics and database management are initiated within 13 life sciences institutes of Europe (see EU-LIFE, http://eu-life.eu/). By cooperation, a critical mass of expertise and biological material can be achieved. The crucial determinants of disease are often only visible once large numbers of samples have been analysed.
In the case of degenerative disorders of the nervous system such as Parkinson’s, Alzheimer’s and other types of dementia, we need first to understand the brain and its disorders, prior to productive intervention. A focus on the cell types and cell networks that drive behavioral functions of the brain is amply vindicated, as neurological disorders are generally not understood. Even how normal memory works is still largely a mystery. Here the FMI is at work.
Experimentation on human brains is difficult, yet there has been dramatic progress in human organ culture over the last few years. This, together with a better understanding of stem cell maintenance and differentiation, has medical potential. Organ or stem cell transplants are within reach if we learn to prevent organ degeneration, and the rebuilding or replacement of missing parts. When combined with genetic repair or virus-mediated gene delivery, in vitro differentiation and implantation may become standard treatments for certain diseases. For example, the use of AAV-mediated gene delivery to the retina to restore light-sensitive photoreceptors has become a plausible way to treat syndromes of late-onset blindness, like retinitis pigmentosa. Perhaps such approaches can be extended to other parts of the nervous system, or to degenerated heart muscle. Hearing loss may be treated by stimulating the regeneration of cochlear hair cells, and of course repopulating the immune system with stem cells taken from a pre-disease or pre-treatment state seems to work, with healthy cells replacing pathological ones.
All in all, the new world of science-based medicine opens the door for some of the most exciting developmental, cell, molecular and chemical biology that we've seen for years. The immediate future of the FMI will require universal mastery of quantitative biology and bioinformatics, expanding molecular imaging, and an outreach to medically trained colleagues, to guide basic research to the unmet medical need of our changing society.