It’s All In The Genes

by | Feb 24, 2015

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Advancing sequencing techniques are set to transform the Healthcare industry says Dr. Jimmy Muchechetere of Investec Wealth & Investment:

In 2012 Roche offered to pay an eye watering 88% premium to the undisturbed share price for a company called Illumina, a relatively small name at the cutting edge of gene sequencing technology. In Illumina’s view a $6.7bn price tag and hefty premium did not accurately reflect the potential of its technology, and it was right to resist Roche’s hostile offer; two years later Illumina is valued at four times this amount ($26.5bn at the close 05/11), all thanks to next generation sequencing (NGS).

Dr Jimmy Muchechetere

Dr Jimmy Muchechetere

The genetic code is the blueprint for the formation and functioning of all living organisms. Each gene is made up of DNA strands that contain proteins called  nucleotides, a combination of four basic molecules called bases – Adenine (A),  Guanine (G), Thymine (T) and Cytosine (C) – a kind of chemical alphabet. These  bases are combined over six billion times in one genome. DNA sequencing is  therefore the process of determining the precise order of the four bases that make  up the building blocks of genes.

One complete human genome has roughly the same number of letters as 2,000  copies of War & Peace. It is therefore unsurprising that the Human Genome  project took 13 years to complete at a cost of $3bn. The method of sequencing  developed in the 1970s by Frederick Sanger, called the ‘chain termination protocol’, has stood the test of time as the gold standard for three decades. Despite being slow, laborious and expensive, it is highly accurate.

In 2004 America’s National Institute of Health (NIH) challenged researchers to find a way of sequencing a genome for $1,000 or less. That opened the door to innovative solutions that either evolved the Sanger sequencing techniques or were completely new. At the same time other essential technologies such as sample preparation, data storage, faster computer speed and bioinformatics became more sophisticated. Some experts argue that the transforming effect of the Human Genome project was not the completion of the sequence itself but the development of technologies that enabled, or were enabled by, sequencing the first reference genome. The NGS market has since exploded in size and is projected to continue growing at a healthy rate.

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The first wave of NGS technologies allowed for several genomes to be sequenced all at once, a process called multiplexing. NGS starts by breaking the reference genome into smaller pieces that are then tagged (with radiolabelled nucleotides called adapters) for later identification.

Although the sample preparation is more complex, once a library of DNA strands is ready for sequencing, things develop quickly thereafter. DNA polymerase is still used but because the strands are amplified then bound to a static surface such as reaction cells, tiny beads or microtubules, it allows for multiple small scale sequencing reactions en masse. Several different genomes can then be copied at the same time in a process called ‘parallel sequencing’. Localisation also aids in identification and there is no chain termination, allowing for continuous reading. Not surprisingly, a lot more data is generated – up to 16 gigabases per run, exceeding Sanger sequencing by many orders of magnitude – but the strands are easily identified and joined correctly.

NGS technologies are still improving. A small company born out of Oxford University had the idea of directly ‘reading’ a DNA strand. The process would force a DNA strand through a cell with a hole in it called a ‘nanopore’, which would disturb a light source. Each of the four bases would affect the light differently and the ‘spectrum’ produced identifies the correct order of the bases. This method can sequence long DNA strands without fi rst breaking them into fragments and negates the need for complex sample preparation, ddNTPs (dideoxynucleotide triphosphates), expensive reagent costs and chain cleavage. Since two thirds of the cost of a sequencing run is spent on reagents and consumables, nanotechnologies have the potential to reduce significantly the cost of sequencing.

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Open source platforms such as Google’s Android have the power to allow independent people to develop elaborate capabilities for the platform that the originators may never have envisaged. Similarly, NGS has proved to be such a ‘platform technology’ allowing a much wider field of researchers and scientists to not only improve NGS technology but also come up with a wide variety of applications both within the field of medicine and outside it.

Despite significant strides having been made in the last decade, NGS remains a niche application in state-of-the-art clinical and research laboratories, and is an area dominated by a few players. Consultants Frost & Sullivan recently suggested that NGS accounts for only 1.6% of all genetic testing products currently available to physicians. As the cost of the technology falls, NGS should increase penetration. The NGS market is dominated by big companies that either pioneered the different NGS techniques or subsumed the more successful smaller players.

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The most exciting thing about NGS is the wide variety of potential applications, healthcare being the most obvious. NGS can be used to enhance diagnosis, treatment and prevention of diseases. Rare and mysterious diseases can be genetically mapped in a matter of days and at low cost. In treatment, NGS has helped spawn a new branch of medicine called personalised medicine. One application is a highly precise treatment of cancer, a disease that is caused by changes to the genome leading to aberrant cell multiplication. Breast cancer for example is caused by more than 2,000 different types of mutations. Roche manufactures a medicine called Herceptin which is used only in those patients with a specific mutation called HER-2. This reduces side effects as well as waste (of valuable time and resources) in not prescribing the treatment to those women with other types of mutations who would not respond to the medicine.

Disease prevention will be a particularly important application for NGS. Currently unborn and newborn babies are tested for genetic diseases and enzyme deficiencies. Catching the problems early helps with optimising treatment, education and social support for the parents. NGS has the potential to screen people for diseases that are little understood today, such as Lou Gehrig’s disease and Alzheimer’s, and identify those at risk so that they can be followed up and receive help without delay. Deadly viral outbreaks such as Ebola can be identified quickly and contained before they spread too far.

It is not just human and animal healthcare areas that are set to benefit from NGS. Archaeologists and forensic pathologists are enthused by the prospect of gleaning more information from a frozen woolly mammoth, fossils of extinct species or a set of ancient dinosaur bones. In the field of food microbiology, NGS has the potential to give plant breeders new insights into crop development which could have significant commercial potential as well as social and economic benefits.

Currently it is thought that NGS will be available to hospital, university and other clinical laboratories over the next three to four years but will take a decade to be commonplace at the point of care. Although significant strides have been made, there remain challenges ahead. The smallest and most efficient NGS machine currently costs more than $100,000. Data security is still an issue with the possibility of sensitive data being illegally obtained and used for criminal/terror purposes. There is a concern that diagnostic companies could sell genomic data to insurance companies who then use it against policyholders who turn out to have defective genes. Finally there are ethical issues to be overcome; for example does genomic data belong to the donor or collectively to biological relatives as they share a lot of similarities in their genes?

Next generation sequencing as a technology has already been validated. Although there are some hurdles and challenges to be overcome, the technologies are well advanced. We expect that as computers get faster and data analytics more sophisticated, NGS technology will make huge strides forward. A positive is that it is not just geneticists that are set to benefit from NGS but other academic disciplines, patients, plants, animals and society at large. It is likely that there will be considerable innovation around the NGS platform with the potential to deepen significantly our understanding of biology, and that could change the world.

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