A single fertilised cell must divide trillions of times to build a human brain, and this fellowship asks what happens when that process goes wrong. The researcher focuses on rare genetic disorders that cause extreme growth restriction and microcephaly—conditions where the DNA-copying machine, the replisome, malfunctions. Despite being caused by mutations in genes found in every cell, these disorders produce tissue-specific effects, such as a small brain but normal-sized limbs. The project will investigate how defects in DNA replication lead to growth failure and why different organs respond differently. This is fundamental science: there is no immediate clinical application. However, understanding how the replisome controls cell number and fate during development could eventually inform cancer therapies—where uncontrolled proliferation is the problem—and strategies for tissue repair and regeneration. It may also shed light on neurodevelopmental disorders. The work addresses a basic biological question that Haldane posed nearly a century ago: why are organisms the size they are, and how do they get that way?
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The biggest mammal is 75 million times larger than the smallest; hence, the greatest difference between species is organism size. This intellectual problem is best articulated by Haldane’s essay On Being the Right Size: “The most obvious differences between different animals are differences in size, but for some reason the zoologists have paid singularly little attention to them”. While cell number is the major determinant of body size in mammals, the mechanisms regulating cell number during development remain poorly understood. Yet, proliferative disorders underlie some of the most devastating human health conditions including cancer, affecting 1 out of 3 individuals in their lifetime. In addition, loss of stem cell renewal and tissue repair capacity are hallmarks of aging and degeneration. Humans develop from a single cell into a complex organism containing 1015 cells, and the human brain contains the largest number of cortical neurons in the animal kingdom. With the highest number of specialized cell types, and a complex degree of functional specialization exemplified by neuronal connectivity and function, it is highly prone to neuropsychiatric and neurodevelopmental disorders, and very difficult to repair. While of basic biological significance, understanding how cell number is determined during development to achieve appropriate organ and organism size and function is an important and pressing question for society. This fellowship work is inspired by human disorders of extreme growth restriction, which surprisingly produce tissue-specific manifestations such as microcephaly, despite being caused by mutations in ubiquitous genes. These single-gene conditions provide direct causal links between genes and phenotypes, with large and tractable biological effects. From these studies, the replisome, the machine replicating DNA, emerges as growth and cell fate determinant during development. Informed by these Mendelian conditions, I will address how DNA replication and cell cycle dysfunction determine organism and brain growth and development. Precisely how defects in DNA replication lead to growth failure, as well as the reasons for organ-specific phenotypes in microcephalic dwarfism, remain to be defined. Central to these questions is how perturbed DNA replication acts in primary cells, and how this differs in different tissues. Hence, this proposal will investigate: 1. The molecular and cellular mechanism of Replisome progression defects in microcephalic dwarfism 2. How DNA replication controls cell fate and brain development This work will shed light on the relationships between DNA replication, growth, and development to advance our understanding of human-disease mechanisms and improve our understanding of the cell cycle determinants of brain development. Emerging results therefore have the potential to inform cancer therapies, neurodevelopmental disorders, and future strategies for tissue repair and regeneration.
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