Fellowship case studies
Case studies for the 10th BBSRC Fellows’ Conference
To coincide with the 10th BBSRC Fellows’ Conference, case studies have been prepared from fellows who between them have attended every BBSRC Fellows’ Conference since the first one in 1999. These case studies describe the research the fellows conducted and the ways in which the fellowship helped to advance the fellows’ careers.
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Lynda Harris, David Phillips Fellow at The University of Manchester
How does BBSRC fund your work?
I'm supported by a BBSRC David Phillips Fellowship, which funds me to identify specific homing peptides that bind to the surface of the placenta. I did the initial work screening for the peptides, and both my PhD students are taking that work further by building different carriers and testing different drugs in animal models.
What research do you carry out under your fellowship?
The idea is to synthesize liposomes, which are like small bubbles that can be modified to display the placental-homing peptides on their surface. This creates a little drug carrier and when you introduce it intravenously it binds only to the placenta, and doesn't accumulate in any other organs so you don't get off-target side effects from the drugs you are administering.
It's an idea developed originally for delivering chemotherapy to tumours. Because cancer drugs are toxic and you don't want them accumulating around the body, this method of targeting reduces the side effects as well as the amount of drug you need.
Why target the placenta?
A poorly functioning placenta is the cause of many pregnancy problems, so by targeting the placenta we are treating the problem rather than treating the symptoms. You can either give drugs that increase blood flow into the uterus and placenta, to supply more nutrients and oxygen to the tissue, or you can give drugs that encourage placental growth.
We know from evidence from a lot of animal studies – mice, rats and sheep – that either increasing placental size or function or increasing blood flow improves outcomes for the baby. And this can relieve maternal symptoms too.
What inspired you to look at this field?
I started with in interest in human biology and did a degree in pathobiology, which is basically biomedical science, then did a PhD in vascular biology. And then I accepted a post-doc up in Manchester looking at how the placenta interacts with blood vessels in the uterus – that got me interested in the placenta.
Then it became evident there was no safe way of delivering drugs to pregnant women. That seemed to be a big gap. When I found out that it was possible to target delivery of drugs to tumours, I thought that this technology would work well for the placenta, because you can consider placenta as a big tumour. That's when I applied for the David Phillips Fellowship to do the screening for novel peptides that bind to the placenta.
When did you start DP Fellowship?
I started that in October 2010 and spent first year in big cancer lab in the US, working with Professor Erkki Ruoslahti's at the Sanford Burnham Medical Research Institute, California. It was there that I did the screening for placental peptides and learnt their technology.
What was working in the US like?
The US was a great experience – it was a big lab with lots of funding, the average age was mid-30s so quite a mature environment with people with specialised knowledge who were really excited about science.
Dr Jackie Ferguson, Daphne Jackson Fellow at The National Institute of Biological Standards
Erythropoietin (EPO) is a protein hormone produced in the kidneys which stimulates cells in the bone marrow to develop into red blood cells.
Since 1988, preparations of EPO produced in genetically engineered cell lines have been approved for the treatment of anaemia. In rare cases, therapeutic EPO has elicited an immune response in patients, resulting in the generation of anti-EPO neutralising antibodies. These inhibit the activity of EPO resulting in the development of pure red cell aplasia (PRCA ), a severe anaemia characterised by a drastic decline in red blood cell production.
Jackie aims to develop a cell-based bioassay to detect anti-EPO antibodies by using EPO-stimulated gene expression as a measure of EPO bioactivity.
Jackie is nearing the end of her fellowship and has identified that the Egr-1 gene, which is involved in co-ordinating the cellular response to EPO, is expressed in a dose-responsive manner to EPO. She explains: “Egr-1 is rapidly and robustly induced by EPO, such that we routinely measured a maximal fold-change in Egr-1 gene expression of >30 fold over unstimulated cells after 50 minutes of stimulation with EPO.”
Furthermore, Jackie has found that gene expression was inhibited by dilutions of serum from a patient with PRCA , suggesting that the inhibition of EPO-stimulated Egr-1 gene expression could provide a widely-available, rapid and automatable bioassay to monitor patients for the development of neutralizing antibodies to EPO.
In the remaining time of the project, Jackie hopes to further investigate the potential of this assay method using patient samples and purified antibodies which exhibit varying degrees of binding and neutralisation of EPO activity.