Researchers at the UK’s national synchrotron facility, Diamond Light Source, have just published the 5000th scientific paper using data from the facility. This milestone marks a significant step for the synchrotron that is used by over 8,000 scientists each year. Diamond accelerates electrons to produce powerful light, 10 billion times brighter than the sun. This allows scientists to investigate the molecular and atomic nature of matter. The 5000th paper, published by an international scientific collaboration reveals the discovery of one of the genetic triggers behind a range of birth defects, including congenital heart disease. The group from the UK, USA and Japan published their findings in PLOS Genetics.
Andrew Harrison, CEO at Diamond, said: “Our 5000th paper represents a significant milestone for the facility. As we move towards the tenth anniversary of Diamond in 2017, this work underscores the vital human impact that synchrotron research can have. “If we can uncover more about the intricate processes at the heart of embryonic development, we may eventually be able to prevent some of the birth defects that can occur as a result. These findings are a tangible step forwards towards that goal.”
The new research reveals the genetic pathways by which proteins in the body help to align a developing embryo in the very early stages of development at just 19-22 days after conception. During this period, a developing embryo begins to take shape by adopting a left and a right hand side. Major organs, like the heart and liver, exist only on one side of the body, whilst our left hand lung is shaped slightly different to our right hand lung so as to make space for the heart. The orientation of our internal organs is vital for the body to correctly function, so when the alignment process goes wrong it can cause serious genetic defects, the most common being congenital heart disease.
The process of early-stage alignment has not been previously well understood, as the genetic pathways behind it are highly complex, containing many different proteins and cell reactions. However, these findings help to shed light on the interactions that determine our organ alignment – and resulting personal health – at such an early stage of development. Using the powerful light produced at Diamond, the researchers were able to study a pocket inside mouse embryos. This pocket, known as the ‘node’, is where the process of organ alignment originates.
Fluid begins flowing through the embryo at a very early stage of development. This research shows that it is the physical direction of this flow that helps to shape the young embryo, determining the development of the foetus at a later stage. The group were able to show, for the first time, that cilia – minute hair-like structures on the surface of the embryo’s cells – are able to detect the direction of fluid flow within the node, triggering a genetic chain reaction that leads to the correct alignment of the embryo. There are many different proteins involved in this process, and if just one of them contains a mutation that causes them to read the signals coming to them incorrectly, it can lead to misalignment of the young embryo, sometimes resulting in birth defects.
Rohanah Hussain, Senior Beamline Scientist on Diamond’s B23 beamline, where the work was carried out, said: “Now that we have identified the complex processes involved in embryonic alignment, we are better equipped to investigate exactly how and why things go wrong, and potentially develop ways of preventing these issues and the birth defects that result. “There is still some way to go before we fully understand the delicate and highly intricate processes that govern embryonic alignment, but this work constitutes a major step forwards in efforts to understand developmental milestones that take place at a very early stage.”
This research has emerged from an international collaboration that has made it possible to combine genetics, biophysics and structural biology. In the UK, Dominic Norris and colleagues from Medical Research Council (MRC) Harwell who conceived the research together with Rohanah Hussain and colleagues at Diamond Light Source, the UK synchrotron science facility, made it possible to understand the nature of structural changes caused by a point mutation in PKD1L1. This work took place on Diamond’s B23 beamline for Circular Dichroism. beamline, B23. Surya Nauli and colleagues at Chapman University, USA, allowed the role of PKD1L1 in flow detection to be assessed in cells. Hiroshi Hamada and colleagues in Osaka, Japan, provided novel techniques that allowed the team to more precisely analyse ‘nodal flow’.