In one of my recent conversations with Prof. Pawan Dhar I found out about a library of over 500 novel molecules that his group has constructed in a span of six years. Prof. Dhar is a synthetic biology pioneer in India. His work on lab-made genes from DNA sequences historically considered “junk” has led to a novel drug discovery platform.
Did you know: Nearly 80 percent of human DNA only codes for RNA and stops there. Nobody knows why rest of the DNA (15 percent or more) exists? Welcome to the “dark matter of genome” — historically considered junk.
What is junk DNA?
In the 1970s, the term junk DNA was originally proposed by geneticist Susumu Ohno to describe the non-functional DNA sequences that do not code for proteins. For years this notion kept many scientists from spending their time studying these sequences. In 2001, the Human Genome Project revealed that a minority of our DNA comprises protein coding genes and majority of DNA sequences are RNA coding. In addition, sequences were found that were protein coding in the past but were retired into what we call, pseudogenes.
Unraveling the mystery of non-expressing regions in DNA has been the key focus of research for the last few years.
Imagine making user-defined genes and proteins from this dark matter of genome
Like humans, bacteria also undergo genetic mutations. They are capable of developing defense mechanisms as well. In the last few years the antibiotic resistance crisis has emerged around the world. The rise of antibiotic resistance is often attributed to the misuse and overuse of medications. Given the current scenario, the existing therapeutics are rapidly becoming ineffective. There is a need to develop new and bold ways of thinking to develop more effective therapeutic strategies.
But — is this junk an untapped goldmine?
Prof. Dhar presented this idea of cooking up brand new genes from “junk’ DNA to his team at RIKEN, Japan. Unfortunately, nobody showed interest. Students were afraid of failure as there was no prior publication in this area. He hired a lab technician from Myanmar to perform experiments and teamed up with collaborators from Singapore to perform bioinformatics work.
The “eureka moment” came when his team found a clear evidence of “junk gene” expression and its impact on the cell survival.
Buoyed by this initial success, Prof. Dhar dedicated the next few years in mining “junk DNA” of various model organisms and developing a large computational inventory of “junk” DNA sequences towards therapeutic applications. His recent experimental work (unpublished) at the School of Biotechnology, JNU, New Delhi, has led to development of a new drug discovery platform. Specifically, his group has reused “junk” DNA sequences to make anti-malarial, anti-microbial, anti-leishmania and anti-cancer peptides. Furthermore peptides against Alzheimers’ and Parkinson’s disease are currently going through experimental validation.
From junk to jewel
The current armour of anti-malarial drugs are beginning to prove ineffective due to the emergence of resistant plasmodium strains. But, if one uses synthetic/non natural peptides coming from “junk” DNA sequences to treat malaria, it would be very interesting to see how parasites react over time, as they do not have a prior history of natural exposure towards these molecules and may take time to develop resistance.
Likewise, conventional antimicrobial and anti cancer treatment strategies merit a major revision, as resistant strains/cells have started showing up in the natural environment. We need a fresh look at the scale and depth of the problem vis-a-vis existing solutions.
Junkomics as his students, fondly call it, has opened up new avenues of research as the strategy of lab-made genes can be used to synthesize custom designed proteins and RNAs towards pre-defined therapeutic outcomes. One of the most attractive features of the lab-made genes approach, is that every molecule comes with an assured IP (Intellectual Property). Before synthesizing and testing the molecule, one can do the prior art search and only then go ahead.
Paradigm shifts in finding novel drugs are urgently required as the traditional drug discovery pipeline has almost dried up. Perhaps, in future pharmaceutical sector will use unique strengths of several strategies to develop combinatorial solutions. Only time will tell whether “junk DNA”-based therapeutic solutions will survive clinical trials. However, the idea seems to be novel and very interesting to merit a closer look.
After all, the Junk DNA is not all that much junk! Maybe it’s time to rewrite our high school and graduation books.
The information presented here is a brief overview of the work carried out at the School of Biotechnology, Jawaharlal Nehru University, India. I would like to thank Prof. Dhar for taking out time and giving me a gist of his past and unpublished work.
Eshna Gogia works as a business developer for Helixworks. Follow her on Twitter @eshna_gogia.
This article originally appeared at Medium under as Junkomics: Diggin’ through genomic ‘garbage’ for the hidden treasure and has been republished here with permission from the author.
