What is sequencing and where is it headed?

Sequencing, the art of deciphering the DNA code into A, T, C and G's, is increasingly in the limelight. Public opinion and debate on sequencing needs to happen to help drive political, legal and economical movements in a way that is aligned with our social ethics and norms. In parallel, rapid strides in technological advancements will continue to completely revolutionise this field and we seem to be running behind in terms of regulations and standards. The potential of sequencing is enormous and the future is full of hope, but we need to clearly define the extent to which this technology could and should be utilised.

We need to clearly define the extent to which this technology could and should be utilised.

The understanding, and public debate, of these new technologies is already lagging behind research progression. Examples such as the engineering of HIV-free twins, demonstrate this. Scientific evolution and progression will continue, whether we as lay-people want it or not, and we have an urgent obligation to ensure that the right regulations and laws are constructed. 

Is genomics a great potential or a great threat?

The field of genetics has always been eminent because the DNA code is our human blueprint. Within the past 10 years, sequencing technologies have rapidly evolved (NGS, for instance, is a revolution in this field). Sequencing is now so sophisticated that it can be used, for instance, in cancer diagnosis through “liquid biopsies” using ctDNA, in NIPT and in ancestry & health profiles. We are now even seriously considering engineering DNA as data storage! We can use or misuse powerful genetics and sequencing technology to copy and paste genes, as demonstrated by the recent CRISPR baby scandal or use CRISPR Immunotherapy in cancer treatment. The advancement of this technology has been so rapid, that ethical and fundamental issues are still being investigated.

Where do we draw the line for genetics?

US measures including GINA and HIPAA ensure, that no discrimination is allowed based on genetic profile in insurance and employment, and guarantee patient confidentiality. These acts are important in protecting our rights as humans and patients. We as a society along with research associations such as ASHG and ESHG are part of stipulating these. There is an urgent need for partnerships within countries in regulating genetics. One of the consequences of lack of discussion in this field might include events such as the controversial gene editing of new-born twins in China. Only after this happened, there was increased public awareness of germ line editing and the consequences thereof.

Sequencing to become a commodity?

In 2003 the human genome project, i.e. sequencing of the entire human genome, was completed. It took 15 years and cost $95 million. Whereas, current sequencing of the human genomes takes a couple of days and costs around $1,000.

As a result of increasingly competitive and cost effective sequencing prices, and continued technological advances, there is a possibility that sequencing will become a routine diagnostic tool. The contest to provide the most affordable, quickest and most accurate technology will continue with the global sequencing market estimated to rise from an estimated $4.5 billion to $8.9 billion in 2022.

Sequencing is a powerful tool to better inform treatment selections and is coupled with personalised healthcare, where patients access specific treatments according to their individual setup. The power of sequencing, is that it provides with rich data. However, the question is, whether this additional data adds more value.

The power of sequencing is that it provides with rich data. However, the question is, whether this additional data adds more value.

Do we care?

As cheaper technology is made available, it is possible to market sequencing for non-medical purposes. For instance, nutritional and ancestry testing can be achieved with ease - a 23andme home testing kit costs a mere $99. However, the consumer's general understanding of what they are consenting to in terms of usage of their sequencing data seems partially lacking. In fact, less than two weeks ago it was announced that 23andme is collaborating [read: making good money] with pharmaceutical companies to develop drugs based on intelligence from customer's DNA. One could agree with Forbes that if it's for free, you're probably the product.

If it's for free, you're probably the product.

Others fear that sequencing will control our lives like something out of the film GATACA i.e. that personal information is abused. Indeed many ethical issues remain unresolved.

For example, using genealogy to solve crimes that would otherwise be unresolvable raises concerns about privacy and the use of genetic information by the government. Another example is the Texas lawsuit, where newborn infant screening has been used for research purposes without explicit parental consent. A last example are the first immortalized cancer cell lines, that are the most important cell lines in medical research to date. These cells were harvested from Henrietta Lacks without her consent. Institutions profited through these so-called HeLa cells (worth $3 Billion) whilst Henrietta’s family lived in poverty. 

What's next in sequencing technology?

Since the advent of Sanger sequencing in the 70's, sequencing has evolved into a plethora of different sequencing techniques. The main sequencing techniques include the present gold standard, sequencing by synthesis (SBS) (Illumina), and two third generation sequencing (TGS) methods; single molecule real time sequencing (Pacific Biosciences) and Oxford nanopore technologies (minION).

The companies target different sectors, for instance, Illumina has many different models depending on throughput and price. Illumina’s devices are mainly used for (clinical) research purposes. The drawback of this technology is that read (DNA) lengths are short, meaning that many bioinformatics tools are needed to patch together the DNA sequences. Some competitors capitalise on this, including Pacific Biosciences that has focused on long reads to target basic research. Oxford Nanopore Technologies have higher error rates, but nevertheless, useful in the field for species confirmation where less accuracy might be tolerated.

The preparation steps prior to sequencing and the following analysis are as important as the sequencing itself. They involve the extraction of the sample from the patient, to preparation of the DNA by shearing, to ligation to adaptors, to library preparation and to PCR amplification, and then performing the sequencing run.

Likewise, the following bioinformatics, includes many steps of assembly of gene fragments and looking at variations in the genome, and deciding whether they are of significance. Indeed, the sequencing field is increasingly about bioinformatics and computing.

Moreover, continued innovation and an increase of competitors within the industry suggest that more cost effective and efficient technologies will be developed.

My Crystal Ball predicts...

• Prices for sequencing will decrease as technology improves.
• Patients will have easier access to sequencing and higher health literacy, including increasing self-diagnosing and self-monitoring.
• Genetic counsellors will be of increasing importance to explain health risk profiles and kinship situations.
• NGOs, rights groups and patient organisations will increase in number to protect and speak up for patients' rights and privacy.
• Sequencing will become a commodity. The quickest and highest quality vendor to achieve a low-cost genome will dominate the market, since it will no longer be profitable to enter this market. Existing players will leave the market or may choose to horizontally expand into pre- or post-sequencing sectors, giving them a potential competitive advantage.
• There will be a continued infiltration of technology companies into this field, as Google, Uber, Amazon and Apple have.