Photo by Alyssa Stone/Northeastern University
Since the Human Genome Project first produced the genetic instructions for a human being by sequencing DNA 22 years ago, scientists have been focused on roughly 2% of the genome producing proteins.
But what about the rest?
Northeastern University professor Sudhakaran Prabakaran says this “dark genome” is not only actively making “dark proteins,” but its secrets could provide the future for the pharmaceutical industry and modern medicine.
“If biology and evolution are known to keep things simple and efficient, if it is just using 1% or so of the genome, why would it keep the remaining 98%? There must be some reasons for it,” says Prabakaran, associate professor of biotechnology and chemistry and chemical biology at Northeastern. “Now we are discovering those reasons.”
Prabakaran is the author of the upcoming book “Eclipsed Horizons: Unveiling the Dark Genome,” an account of the scientific investigations into the so-called “junk” or non-coding DNA of the human genome. He has also recently reviewed the scientific literature in this field in new research.
It’s an expansive area to research — the human genome consists of 3.6 billion nucleotides that make up our DNA and have accumulated over our evolutionary journey. Moreover, this dark genome — and the dark proteins it encodes — has only recently become visible due to technological and computational advances.
“Think about the analogy of flying over the Himalayas at 30,000 feet,” Prabakaran explains. “We only see the tallest peaks, but as we come down to 20,000 feet and 10,000 feet we start seeing other things in the landscape — more proteins, more regions that we know as functional or active or both.”
But the common notion that the dark genome is inactive or inconsequential is wrong, Prabakaran says.
Scientists in Prabakaran’s lab have already cataloged around 250,000 new “dark proteins,” learning about the biological processes they are involved in and whether they are dysfunctional in various diseases. Algorithms, meanwhile, have predicted at least 2 million more.
In fact, the dark genome has spawned a new focus for research.
“We look at just the protein aspect of it,” Prabakaran says of his particular focus. “Some look at repeating regions, some look at just the viruses that are encoded in those regions, some look at how modifications in those regions affect the known proteins.”
Biotech and the pharmaceutical companies are also expressing interest, with companies investigating the dark genome and its dark proteins for therapeutic purposes.
But Prabakaran says harnessing the dark genome will require a new approach in the “conservative” pharmaceutical industry.
Prabakaran says that while billions of dollars have been spent trying to cure diseases over the last 50 years, the pharmaceutical industry has only looked at 20,000 proteins and — of those — selected 812 to investigate for treating illness. Add in a high likelihood of failure — 95% of clinical trials fail by the time they reach phase three, at which point roughly $2 billion has been already spent, Prabakaran says — and you get, say, five pharmaceutical companies competing to produce the best weight-loss drug rather than five companies each working on five more revolutionary treatments.
“The target space is very small and we keep looking at it again and again,” Prabakaran says.
But Prabakaran is hopeful.
The pharmaceutical industry soon faces a “patent cliff,” where blockbuster drugs will lose their patent and become available to all manufacturers.
“So, there’s no revenue, we need to make new drugs and we need to identify new targets,” Prabakaran says.
The dark genome may hold the solution.
“It took a long time for academic people to open up to this idea that other proteins are playing a role in the genome and that they’re dysfunctional in different diseases and you can modulate them,” Prabakaran says. “But now, because of this patent cliff and our need to scramble for new targets, people are waking up and seeing the potential. There’s a lot of excitement.”