Specialisms

• Cell Biology
• Developmental Biology
• Genetics
• Toxicology

Research Overview

Research in the lab is focused on determining the mechanisms underlying thalidomide-induced teratogenesis; identifying non-teratogenic forms of thalidomide; studying the actions of Primodos (was used as a hormone pregnancy test and alleged to have caused birth defects); screening drugs to identify their function/s and action/s; studying how blood vessels are involved in controlling normal and abnormal limb development; studying the role of the YAP signaling pathway in embryonic development; using the chicken embryo to produce a model of Clubfoot to understand how this common birth anomaly comes about; and understanding how birth defects come about in general.

For a discussion on Primodos and its prior use and history please see the following articles: https://theconversation.com/is-primodos-the-forgotten-thalidomide-50673

https://theconversation.com/why-i-cant-agree-with-the-conclusions-of-the-report-on-primodos-88033

For a recent discussion written for the public about Thalidomide, its history, some of the goals we have as well as potential new uses for thalidomide in treating COVID-19 please see the following articles published in 'The Conversation':

https://theconversation.com/thalidomide-the-drug-with-a-dark-side-but-an-enigmatic-future-50330

https://theconversation.com/despite-thalidomides-dark-past-researchers-are-investigating-it-as-a-potential-covid-19-treatment-136750

For recent discussions written for the public on other topics related to birth defects please see the following articles:

https://theconversation.com/mystery-of-french-babies-born-with-deformed-arms-heres-what-a-developmental-biologist-thinks-112107

https://theconversation.com/proving-that-the-zika-virus-causes-microcephaly-53716

My research interests have also led to requests for scientific advice from the World Health Organisation, the UK Medicines and Healthcare products Regulatory Agency, the Canadian Parliament, the Senate of Australia. My recent research on Primodos, helped contribute to the establishment of an Independent Medicines and Medical Devices Safety Review in 2018, which i contributed to and which concluded Primodos survivors deserve an apology and compensation in July 2020.

Current Research

PRIMODOS:

Primodos was used as a hormone pregnancy test between 1958-1978. It is alleged to have caused birth defects in children exposed to the drug when their mother was trying to confirm they were pregnant. Conflicting research results was obtained from studies in the 1970s and 1980s. We have investigated the actions of the components of the drug in Zebrafish embryos and show Primodos can harm zebrafish embryos.

For a discussion on Primodos and its prior use and history please see the following article: https://theconversation.com/is-primodos-the-forgotten-thalidomide-50673

Our Primodos paper using zebrafish embryos was published in 'Scientific Reports' on 13 Feb 2018 and which received widespread media coverage (Sky News, BBC, ITV, newspapers and online media)
Direct link to paper: www.nature.com/articles/s41598-018-21318-9 can also use http://rdcu.be/GRqS

An example of the media coverage:
https://news.sky.com/story/primodos-study-finds-pregnancy-tests-had-potential-to-deform-embryos-11248682

Some of the Lab's work (prior to publication) looking at the components of Primodos in zebrafish embryos was featured in a Sky News Documentary on 21 March 2017 entitled: “Primodos: The Secret Drug Scandal”. The full documentary can be seen at: https://www.youtube.com/watch?v=7ZRkCNUQvBA&sns=fb

A follow up Sky Documentary in August 2020 featured new research findings from the lab entitled: "Bitter Pill: Primodos". the full documentary can be seen at: https://www.youtube.com/watch?v=HhAJBDdnZBI

Impact:

Our research was discussed in the Houses of Parliament in Feb 2018 and helped contribute to an Independent Medicines and Medical Safety Devices Safety Review in 2018. The Review concluded that Primodos survivors should receive apologies and compensation in July 2020 and received widespread media coverage (nationally and internationally) eg: https://news.sky.com/story/primodos-scandal-relief-for-campaigners-as-review-demands-compensation-for-victims-of-hormone-pregnancy-test-12023127

THALIDOMIDE:
We have demonstrated (Therapontos et al., 2009) how thalidomide can cause limb malformations. The drug was used as a non-addictive, non-barbiturate sedative and was also prescribed to pregnant women suffering from morning-sickness (typically, but not exclusively, between weeks 5-10). Tragically over 10000 children were born with severe birth defects, notably, and commonly, limb malformations.

Using analogs and metabolic byproducts of the drug, we showed that the antiangiogenic action of the drug causes limb defects, through preventing blood vessel migration into the developing limb bud. We further showed how the drug exerts its antiangiogenic effect, through preventing endothelial cell proliferation and migration and thus, preventing vessel tube networks from forming. At the time the limb forms (which in humans is around 5-8 weeks) it has a highly changeable vessel pattern - whereas the rest of the body has a stable vascular network. Thalidomide therefore may prevent new vessel outgrowth, which then causes an increase in cell death and loss of limb signalling pathways, stopping limb formation.
 

Reference:

Therapontos C, Erskine L, Gardner ER, Figg WD, Vargesson, N. (2009). Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation. Proc. Natl. Acad. Sci USA. 106, 8573-8578. DOI:10.1073/pnas.0o01505106.  
 

Our worked received national and international interest. Including interviews on BBC TV, ITV and in a large number of newspapers, including The Independent, The Daily Mail, The Scotsman, The Press & Journal, The Sunday Times, The New York Times (twice), Nature News, several national and international Radio stations including BBC Radio 4 'The Material World', BBC Radio 4 'The Today Programme', The Naked Scientists (twice), German Public Radio and the US National Public Radio Show 'The Diane Rehm Show' (http://thedianerehmshow.org/shows/2010-09-16/thalidomide-and-fda)

Making safer Thalidomide alternatives:

We are also interested in identifying thalidomide alternatives that retain the clinical benefits of the drug (successfully used to treat Leprosy and Multiple Myeloma) with lessened or no side-effect (eg: birth defect, peripheral neuropathy). To this end we have compared the effects of Thalidomide with its structural analogs, Lenalidomide and Pomalidomide. We demonstrated that the minor structural changes in Pomalidomide make this compound more anti-inflammatory (and not teratogenic in chicken and zebrafish embryos) at lower concentrations than Thalidomide and Lenalidomide (Mahony et al., 2013). We have also screened fluorinated thalidomide analogs and demonstrated differences in analog activities (Beedie et al., 2015). These findings validate making structural changes to Thalidomide to try to find safer alternatives.

Following on from this work we have screened over 80 thalidomide analogs in our zebrafish and chicken embryo assays and identified several with actions that retain clinical advantages (ie: anti-inflammatory) with reduced or no observable teratogenic effects in zebrafish and chicken embryos (Beedie et al., 2016). Some of these analogs have been patented.

References:

Mahony C, Erskine, Niven J, Grieg NH, Figg WD, Vargesson N. (2013). Pomalidomide is nonteratogenic in chicken and zebrafish embryos and nonneurotoxic invitro. Proc. Natl. Acad. Sci USA. 110, 12703-8. doi: 10.1073/pnas.1307684110

Beedie SL, Peer CJ, Pisle S, Gardner ER, Mahony C, Barnett S, Ambrozak A, Gütschow M, Chau CH, Vargesson N, Figg WD. (2015). Anticancer properties of a novel class of tetrafluorinated thalidomide analogues. Mol Cancer Ther 14:2228-2237. doi: 10.1158/1535-7163.MCT-15-0320.

Beedie SL, Rore HM, Barnett S, Chau CH, Luo W, Greig NH, Figg WD, Vargesson N. (2016). In vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish and chicken embryo models systems. Oncotarget. 2016 May 31;7(22):33237-45. doi: 10.18632/oncotarget.8909.

Impact:

My research has led to requests to advise the WHO and several international Governments. Including Canada and Australia who have since apologised to thalidomide survivors and offered survivors compensation packages. Moreover my research work has led to meeting thalidomide victims from all over the world and discussing the mechanism of the drugs action.

Some images of my thalidomide work is featured in a Fine Art Exhibition (and subsequent Book) by the renowned artist, Taryn Simon. The Exhibition is entitled: ‘A Living Man Declared Dead and Other Chapters’ and toured the world throughout 2011 and 2012.

For further information:

Knowledge Exchange and Public Engagement

I have also been interviewed by the media on numerous occasions to comment on news stories including Thalidomide (eg: https://www.thetimes.co.uk/article/scots-race-to-develop-safe-form-of-thalidomide-f3gph3blkd5), Primodos (eg: http://news.sky.com/story/primodos-sky-news-exposes-pregnancy-drug-cover-up-10807338; https://www.youtube.com/watch?v=7ZRkCNUQvBA&sns=fb; Sky News Live interview 21 March, 2017) and also on Epilim. Interviewed by Sky News Live (26 Sept, 2017) to discuss the epilepsy drug, Epilim, and how it caused damage to babies born to epileptic mothers, and the new European Medicines Agency inquiry into a lack of information/warnings being given to expectant mum's.

Awards for Public Engagement

Winner, 2017 Principal's Prize for Public Engagement with Research - Senior Award.

https://www.abdn.ac.uk/engage/staff-students/2column-page-152-152.php

Some of the Lab's research on Primodos, a now disused hormone pregnancy test alleged to have also caused birth defects, featured in a Sky News & Sky Atlantic documentary  (https://www.youtube.com/watch?v=7ZRkCNUQvBA) and Neil was part of resulting interviews, including on Sky News Live (21 March, 2017) and news stories in national and international media. Neil also discussed the Primodos research and answered questions from MP’s and Lords at the Houses of Parliament at a special event where the Sky News documentary was premiered. In addition, Neil presented the Primodos research to an Expert Working Group of the UK’s Medicine and Healthcare Regulatory Agency who are determining if Primodos could have caused birth defects – their decision due in late 2017. Neil’s other research interest is understanding how thalidomide caused birth defects and identifying forms of the drug that retain clinical benefit without the spectre of birth defects. This work led to an advisory role to the World Health Organisation in 2014 which has contributed to advisory notices about the diagnosis and causation of thalidomide embryopathy from the World Health Organisation. In addition, Neil gave evidence to the Health Committee of the Canadian House’s of Parliament in 2017 investigating how the drug caused birth defects and the range of damage it induces, as part of the Canadian Government’s scheme of who and how to award compensation for thalidomide damage. Neil has also written several popular articles in 2015 and 2016 for the website ‘theconversation.com’ on Primodos (https://theconversation.com/is-primodos-the-forgotten-thalidomide-50673), thalidomide (https://theconversation.com/thalidomide-the-drug-with-a-dark-side-but-an-enigmatic-future-50330) and the zika virus and how it might cause birth defects (https://theconversation.com/proving-that-the-zika-virus-causes-microcephaly-53716).

Supervision

Research Funding and Grants

2015-2017 PI, Sarcoma UK Project Grant

2012-2016 PI, Wellcome Trust/NIH funded PhD Scholar