Population genomics: A scientific leap in treating cancer and rare diseases

Population-wide gene sequencing helps map disease patterns and variations in generic makeup to offer customised cancer therapy and help treat a host of rare and hitherto incurable ailments

Earlier this year, Jay T Flatley, Executive Chairman, Illumina Inc, was on a quick and first-ever visit to India. The company, with a market cap of $45 billion, is a leader in genome sequencing products and services. While the company has not made major inroads into India yet, the country's immense population presents a huge opportunity that Flatley wants to tap.

Founded in 1998, at the height of the dotcom bubble, Illumina was taken public in 2000 by Flatley, who led it as CEO for 17 years. It raised $100 million and used that money to develop its product line. Now with 22 offices around the world, it has a revenue that is growing in double digits and stands at $3.3 billion currently. 

India, with its huge pool of scientists and its population, presents an opportunity to study genomics and move into the genomic medicine era. Though commercially some amount of screening is done by private companies who have taken consent from patients, the science needs to be taken to a mass level, as it would be a powerful tool for the future of medicine in India.

How sequencing works

Illumina’s main business is providing next-generation machines that sequence the DNA. 

We have 23 pairs of chromosomes—22 autosomes and one pair of sex chromosomes, with one coming from the mother, and the other from the father. This gives a base DNA of 3.2 billion, according to Flatley. So if  you started reciting your base genome at the rate one one base every second, 24X7, it would take a century to read your genome. 

All this means that it is a big set of letters, which the machines developed by Illumina can sequence extraordinarily quickly. 

The first sequencing of a single human genome cost $3 billion and took more than a year. 

Today, a genome is sequenced per hour using Illumina's high-end instruments. The price point is about $800. Illumina had launched a new system six years ago that sequences six tera bases, or six trillion DNA, in a single run and can read 50 genomes in a single time span of three days, or 8,000 genomes a year, says Flatley. 

Illumina has indicated to the market that it can offer a product that sequence a genome in under an hour and for less than $100. The company still has to fix the date of product launch. According to Flatley, the market has to be ready for it, and there have to be enough samples going through the machine to be able to justify genome sequencing at $100.

Genomes are big, take enormous horse power and generate a lot of data which is stored in cloud. Illumina has its AWS Base Space in cloud, to which 5,000 of its 13,000 customers are directly connected. Since it has a repository in cloud, companies can compute locally using 85 applications developed by Illumina. 

In 2018, it uploaded 25 petabytes of data that was uploaded to Base Space. 

Why does sequencing matter?

Once genome sequencing is done, it throws up variations and errors that occur through reproduction. There is a whole different class of variants called SNIPs, or single nucleotide polymorphisms. These are single-base changes in the DNA molecule. The DNA sequence of a gene can be altered in a number of ways. A single-base change is a mutation in one DNA base pair, which results in the substitution of one amino acid for another in the protein made by a gene. There are also other changes in the DNA molecule, such as insertions and deletions, block substitutions, trans versions or inversions. And then there are copy number changes which help in non-invasive pre-natal testing when an extra copy of a chromosome is the cause for down syndrome, a genetic disorder that impairs physical growth and moderately impacts intellectual ability. 

These variations or errors allow for non-invasive testing using body fluids. Liquid biopsies are the most efficient and popular among these procedures.

Population genomics means large-scale sequencing of genomes across a population. 

Populations may have variations that are genetic as well as those affected by environment. Countries are focusing on mass screening of their populations.

Genomics England, with the consent of participants and the support of the public, is creating a lasting legacy for patients, the NHS and the UK economy, through the sequencing of 100,000 genomes. This flagship project will sequence 100,000 whole genomes from NHS patients with rare diseases, their families, as well as patients with common cancers.

The 100,000 Genomes Project is mainly funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research, UK and the Medical Research Council have funded the research. Apart from benefitting patients, it will also kick-start the development of the UK genomics industry.

In the United States, the rebranded “All of Us” initiative aims to collect data on one million people. China is spending $9-10 billion on similar projects. There are two projects in India, One by IIsc on brain research, the other being Genome Asia 100 K, which is looking at screening 100,000 people in an attempt to make information about Asian populations open source.

How it benefits the population

Sequencing genomes hold immense progress and promise in personalised medicine. 

Currently, 25 approved drugs are tailored to patients' genetic profiles. “About 40 per cent medicines in clinical trials could be classified as precision therapeutics,” says Flatley. In oncology, the figure rises to 75 per cent. Recently FDA expanded approval of Merck’s lung cancer drug Keytruda (pembrolizumab), based on patients’ genetic signature. With this, the drug has become the companion therapeutic to what will be a universal genetic test. 

Other areas of excitement include liquid biopsies (blood tests that identify cancer as efficiently as traditional biopsy, which needs a part of tumor to be cut out and checked) and consumer genomics. 

GRAIL, a diagnostic company spun out of Illumina, is developing a cancer-screening test by collecting data from hundreds of thousands of patients in what would likely amount to “the world’s largest clinical trial.”

Flatley paints a picture of the future era of personalised genomic medicine, where every baby is sequenced at birth, and its health record maintained electronically, so that it can be used to manage the individual's health through his lifetime. This screening would begin for early childhood diseases, including failure to thrive. Autism would be discovered at the early stage. 

The world would be a bit surreal, where screening could lead to using in-vitro fertilisation and pre-implantation genetic diagnosis would allow the implantation of a healthy embryo. reducing the burden of disease. 

Opportunity for the future

DNA sequencing, if done on patient populations. can give insights into the gene of various sub-populations. 

Rare diseases: This is a major market where next-generation sequencing is becoming the standard of care at least in the US. Many rare diseases are undiagnosable using traditional techniques. There are at least 7,000 such disorders in a million and many kids may also have spontaneous mutations. Even though many of these diseases are rare individually, collectively they represent over four per cent of the rare variant. 

Children with rare diseases are usually seriously ill and 30 per cent die by age five. Sequencing is an incredibly powerful tool to diagnose genetic mutation in kids. It avoids at least seven years of diagnostic ordeal involving at least eight different physicians, which many of these kids would otherwise have to go through, even in a country like the US.

Theranostics: This new field of medicine uses specific targeted therapy based on specific targeted diagnostic tests. With a key focus on patient-centered care, theranostics provides a transition from conventional medicine to a contemporary, personalised and precision medicine approach. The technology is able to sequence both liquid and solid tumors, and  prescribe drugs accordingly.

Finally, genomics helps monitor patients both during and after treatment. It sequences to monitor cancer cells and dump their DNA in the blood during treatment, and also monitor for recurrence.  

In India, patients are usually detected with cancer in advanced stages, due to low screening. Taking screening to populations could help with understanding the mutations and variations which cause diseases.

Cancer has been the preferred targeted diagnostic focus but sequencing could ultimately be used for many other diseases.