Humans decoded

But before discussing the past and the future, let’s talk about DNA sequencing. Sequencing simply means determining the order of the base pairs in a segment of DNA. Human chromosomes range in size from about 50,000,000 to 300,000,000 base pairs (National Human Genome Research Institute, or NHGRI).

According to the Telomere-to-Telomere (T2T) consortium’s collection of papers (recently published in Science), the sequence — comprising more than three billion base pairs across 23 chromosomes — is gapless.

When scientists declared the Human Genome Project — an international research effort launched in 1990 to determine the DNA sequence of the entire human genome — complete in 2003, their announcement was a bit premature; they had sequenced 92 per cent of base pairs. They had essentially gained access to the codes to human euchromatin comprising loosely packed protein-coding genes.

Nearly 200 million base pairs of sequence data in the smaller and tightly packaged segment of the genome — heterochromatin (that does not produce protein) — couldn’t be retrieved then.

So, what led to the breakthrough now? “Over the past decade, two new DNA sequencing technologies emerged that can read longer sequences without compromising accuracy. The PacBio HiFi DNA sequencing method can read about 20,000 letters with nearly perfect accuracy. The Oxford Nanopore DNA sequencing method can read even more — up to 1 million DNA letters at a time — with modest accuracy. Both were used to generate the complete human genome sequence,” according to NHGRI, the primary funder of T2T research.

The sequencing is done but the work is far from over as researchers now want to decode full sets of DNA from a larger pool of individuals in a bid to capture all of the variations that exist in humans. “Truly finishing the human genome sequence was like putting on a new pair of glasses,” according to NHGRI’s Adam Phillippy, whose group led the study (www.nih.gov). “Now that we can clearly see everything, we are one step closer to understanding what it all means.”

Already researchers, in a separate project, are building a “human pangenome” representing all the human genetic variations.

T2T researchers, too, used the sequence as a reference to discover over two million sequence variants in the human genome. These included variants within many medically relevant genes. Undoubtedly, this study and related research shall open the door for relatively effective personalised or precision medicine and genome editing in the future.

It’s expected that genome-based research will help develop highly effective diagnostic tools and treatments for diseases. Individualised genome analysis should lead to powerful preventive medication and allow us to learn risks of future illness, besides helping better plan dietary and lifestyle changes.

“Health care will move more toward prevention rather than cure,” according to Kemal Malik, member of the Bayer board of management responsible for innovation (National Geographic). “To date, genomics has had the most impact on cancer... because we can get tissue, sequence it, and identify the alterations.”

The Cancer Genome Atlas (TCGA), a cancer genomics programme in the US, has already mapped genomic changes in 33 cancer types. Such studies are not only helping medical and pharmaceutical experts have deep insight into cancers but also an understanding of what may kill them.

On the treatment side, there are already over 250 US FDA-approved drugs labelled with pharmacogenomic information that can be prescribed based on a patient’s genetics. And as DNA sequencing becomes the norm, it’s likely that medical prescriptions will be based on our genes — minimising side-effects and making treatments relatively effective.

It’s noted that the cost of human genome sequencing has become relatively affordable. According to the NHGRI, which tracks costs associated with DNA sequencing performed at the sequencing centres funded by it, the cost per genome is $562 (August 2021). It was $689 in August 2020 and $942 in August 2019. In India, a person, according to media reports, has to pay between Rs 10,000 and Rs 20,000 for genome sequencing.

The gapless human genome sequencing is likely to have an impact on genetic editing, too, enabling society to select specific embryos to avoid health problems — but it’s a red line in medical science. It may also allow the rise of “superhumans” — another red line. So, what’s needed is strong ethical guidelines encompassing genetic research and editing.

Genomics is providing humans with an instruction manual to fix ourselves. The question is how we fix ourselves.

“We are at a turning point in the study of tumour virology and cancer, in general. If we wish to learn more about cancer, we must now concentrate on the cellular genome.” With these words, Nobel Prize-winning Italian-American virologist Renato Dulbecco first pitched the idea to determine the DNA sequence of the entire human genome, way back in 1984.

Thirty-eight years and billions of dollars later, scientists have completed the first full and seamless catalogue of genetic instructions of humans. And this achievement is seminal: It shall help explain how every cell in a human body is created, which, in turn, may shed light on the treatment, prevention, and cure of diseases.