Dodging a silver bullet; preventing infectious disease
David Baulcombe, Head of Gene Expression Group, and Regius Professor of Botany Emeritus
The problem
The third certainty of life – ignored by Benjamin Franklin who emphasised only death and taxes – is infectious disease. In plants, including crops, we often use disease resistance genes or pesticide chemicals as “silver bullet” measures to control disease. Unfortunately, these ‘single shot’ solutions are often short term. The pests and pathogens have short life cycles and there is often rapid selection for strains with just one or two mutations that have adapted to these control measures. In response, the breeders must find new resistance genes and the agrochemical companies need new pesticides.
The solution
To overcome this lack of durability in current disease resistance strategies we have been developing nature-based solutions, with additive small measures of protection provided by multiple layers of defence. Our approach, informed by our understanding of the molecular biology and genetics of immunity in plants, is to fine-tune the existing systems of immunity. By avoiding silver bullets, we make it difficult for the pathogens because they would need more than just one or two mutations to overcome the resistance.
Why Cambridge, why now, and history of working in this area
Our research over the last several decades has identified interacting layers in plant immune systems that either increase or, surprisingly, decrease the level of disease resistance. Our current understanding of the counter-intuitive suppression is based on the well-established finding that activation of immunity often reduces the vigour of the plant: there is a cost of disease resistance. In nature the oppositely acting regulation of immunity allows the plant to counterbalance the costs and benefits of immunity.
The current projects were originally independent. In one set of experiments, we were investigating Nod-Like Receptors (NLRs) in tomato and other species. These proteins are encoded by families of genes and the conventional view is that each family member determines strong resistance against one or a few pathogens.
A second project involved small ribonucleic acid (sRNA) regulators of gene expression in plants. Since the Covid pandemic we are all familiar with RNA vaccines but, less well known is that plants use RNA to protect against disease. My research group had discovered these sRNAs in GM plants more than twenty years ago but, more recently, we have found that they also regulate viruses and genes encoded in the nuclear genome including NLRs. The two projects had converged and the sRNAs emerged as suppressor of NLRs.
What is the research – what is it, how does it work, what resources are used and who is involved?
To investigate this finding we used gene editing to mutate the genes for the sRNA regulators of NLRs in tomato. We found, as expected, that there was more expression of NLR genes in these mutants because the sRNA suppressors were absent. The plants grew normally but, by testing with bacterial and viral pathogens, we have confirmed that the mutants have enhanced resistance against multiple pathogens.
Any outputs, outcomes or impact that is measurable. Has this or can it translate to clinical, society or industry uses?
Our research can be extended to further explore the offsetting hypothesis about the benefits vs costs of disease resistance. In the shorter term, however, there is potential benefit for growers of tomato and other crops due to the enhanced disease resistance in our mutants. Due to the recent “Precision Breeding” Act it is now possible to grow gene-edited plants for crop production in the UK and we hope to test our enhanced resistance tomatoes to see whether they perform better than the plants without the mutations.
What are the milestones, timelines and what happens next?
We hope to complete the laboratory testing of our plants in the next few months and to carry out field or glasshouse testing within the next year both in the UK and in China. The Chinese experiments will be carried out by former postdocs who have returned to their home country and are continuing the work they started in Cambridge.
If we solve the problem, what can we expect?
The silver bullet fallacy tells us that there are no simple solutions to disease resistance. With our exploration, however, of natural systems that fine tune the immunity of plants we expect to develop an integrated pest management strategy as part of sustainable and productive agriculture and horticulture.
Although this research is based on molecular biology and genetics it is part of a tradition of phytopathology research from Cambridge botanists including H. Marshall Ward. Ward was Professor of Botany from 1895 until 1906 and he is well known for promoting protection of coffee from disease by avoiding monoculture. He also advocated mixing coffee and trees in the plantations to prevent spread of spores from diseased coffee plants: an early type of integrated pest management. I like to think that, if he was working now, he would embrace our molecular avoidance of silver bullets to be used alongside his approaches for preventing infectious disease in crops.