For British Science Week 2019, we are looking back at how Great Britain has shaped different scientific fields through its research and innovation. First, we are delving into genetics and molecular biology – from Darwin’s legacy, to the structure of DNA and now modern molecular techniques.
The theory of evolution by natural selection is one of the most famous scientific theories in biology to come from Britain. Before Charles Darwin famously published this theory, several classical philosophers considered how some traits may have occurred and survived, including works where Aristotle pondered the shape of teeth.
These ideas were forgotten until the 18th century, when they were re-introduced by philosophers and scientists including Darwin’s own grandfather, Erasmus Darwin.
Darwin used birds, particularly pigeons and finches to demonstrate his theories. Image: Pixabay
In 1859, Darwin first set out his theory of evolution by natural selection to explain adaptation and speciation. He was inspired by observations made on his second voyage of HM Beagle, along with the work of political economist Thomas Robert Malthus on population.
Darwin coined the term ‘natural selection’, thinking of it as like the artificial selection imposed by farmers and breeders. After publishing a series of papers with Alfred Russel Wallace, followed by On the Origin of Species, the concept of evolution was widely accepted.
Although many initially contested the idea of natural selection, Darwin was ahead of his time, and further evidence was yet to come in the form of genetics.
Gregor Mendel first discovered genetics whilst working on peas and inheritance in the late 19th century. The unraveling of the molecular processes that were involved in this inheritance, however, allowed scientists to study inheritance and genetics in a high level of detail, ultimately advancing the field dramatically.
A major discovery in the history of genetics was the determination of the structure of deoxyribose nucleic acid (DNA).
DNA was first isolated by Swiss scientists, and it’s general structure – four bases, a sugar and a phosphate chain – was elucidated by researchers from the United States. It was a British team that managed to make the leap to the three-dimensional (3D)structure of DNA.
Using x-ray diffraction techniques, Rosalind Franklin, a British chemist, discovered that the bases of DNA were paired. This lead to the first accurate model of DNA’s molecular structure by James Watson and Francis Crick. The work was initially published in Nature in 1953, and would later win them a Nobel Prize.
The age of genetic wonder. Source: TED
By understanding the structure of DNA, further advances in the field were made. This has lead to a wide range of innovations, from Crispr/CAS9 gene editing to targeted gene therapies. The British-born science has been utilised by British pharmaceutical companies – pharma-giants GlaxoSmithKline (GSK) and AstraZeneca use this science today in driving new innovations.
The European Court of Justice (ECJ) ruled in July 2018 that onerous EU regulations for GMOs should also be applied to gene edited crops. The ECJ noted that older technologies to generate mutants, such as chemicals or radiation, were exempt from the 2001 GMO directive, but all other mutated crops should be regarded as GMOs. Since gene editing does not involve foreign DNA, most plant scientists had expected it to escape GMO regulations.
‘We didn’t expect the ruling to be so black and white and prescriptive,’ says Johnathan Napier, a crop scientist at Rothamsted Research. ‘If you introduce a mutant plant using chemical mutagenesis, you will likely introduce thousands if not millions of mutations. That is not a GMO. But if you introduce one mutation by gene editing, then that is a GMO.’
What is genetic modification? Video: The Royal Society
The ECJ ruling will have strong reverberations in academe and industry. The European Seed Association described the ruling as a watershed moment. ‘It is now likely that much of the potential benefits of these innovative methods will be lost for Europe – with significant economic and environmental consequences,’ said secretary general Garlich von Essen.
In 2012, BASF moved its plant research operations to North Carolina, US, because of European regulations. ‘If I was a company developing gene editing technologies, I’d think of moving out of Europe,’ says Napier.
‘The EU is shooting itself in the foot. Its ag economy has been declining since 2005 and it has moved from net self-sufficiency to requiring imports of major staples,’ says Maurice Moloney, CEO of the Global Institute for Food Security in Saskatchewan, Canada. ‘Paradoxically, it still imports massive quantities of GM soya beans and other crops to feed livestock.’
Stem cells with shared genetic information aid in the study of human disease. Image: Kyoto University/Knut WoltjenSingle nucleotide polymorphisms (SNPs) are the most common form of genetic mutation, with more than ten million currently identified, and are often found in hereditary diseases – from Alzheimer’s to diabetes.
Due to the precise nature of SNPs, researchers need to compare genetic differences with isogenic twins – two cells which differ in their makeup by only a single gene.
To do this, scientists in Japan have used induced pluripotent stem (iPS) cells to create a novel gene editing technique that can modify DNA to a single gene.
iPS cells are unique in that they retain the genetic makeup of a donor and can be converted into any cell type. These characteristics mean the cells are perfect for testing new treatments in a laboratory setting.
The team – led by Dr Knut Woltjen and based at the Centre for iPS cell Research and Application at Kyoto University, Japan – use the method to insert an SNP modification along with a fluorescent report gene as a marker for the modified cells.
As adding the reporter gene is another modification to the genome, the researchers created a duplicated DNA sequence that flanks the gene in order to remove it.
These strands hang over the sequence of the reporter gene so that once the latter is removed, the two resulting strands can join together – a method known as microhomology-mediated end joining.
In the Alzheimer’s affected brain, abnormal levels of the beta-amyloid protein clump together to form plaques (seen in brown) that collect between neurons and disrupt cell function. Image:NIH Image Gallery
Unique target sites were also added to remove the gene using the enzyme CRISPR, which cuts DNA. As a result, only the modified SNP is left in the genome of the cell.
One of the isogenic twins receives the mutant SNP and the other receives the normal SNP, allowing for a comparison to be made.
Dr Woltjen calls the new technique Microhology-Assisted eXcision, or MhAX. ‘To make MhAX work, we duplicate DNA sequences which are already present in the genome. We then let the cell resolve this duplication. At the same time, the cells decide which SNPs will remain after repair,’ said Woltjen. ‘One experiment results in the full spectrum of possible SNP genotypes.’
The team have already collaborated with other Japanese universities on the application of their novel method, using the HPRT gene – a mutation that can lead to gout – as the first example of its potential use in therapy.
Their work shows that cells with the HPRT mutant SNP had similar issues with metabolism associated with gout patients, while the isogenic control cells had no problems.
Following on from this success, Woltjen and his team are now applying the technique to different diseases associated with SNPs, including diabetes.