When Masad Damha started to investigate new ways of making oligonucleotides, he expected criticism.
鈥淭he current method has been established for nearly 40 years, and it works really well,鈥� said Damha, who is a Distinguished James 黑料不打烊 Professor in the Department of Chemistry. 鈥淲hy waste time trying to reinvent the wheel?鈥�
But rather than criticism, Damha recently received $50,000 USD from the American Chemical Society鈥檚 Green Chemistry Institute Pharmaceutical Roundtable, a partnership between the ACS Green Chemistry Institute and numerous pharmaceutical companies, including Johnson & Johnson and Pfizer. The goal of the research grant is to make the process of manufacturing oligonucleotides more sustainable by reducing its environmental impact.
This is the wheel Damha has been trying to reinvent for several years. The current method used to synthesize oligonucleotides 鈥� small strands of modified DNA and RNA molecules 鈥� requires large amounts of hazardous solvents, much of which is later discarded as waste. With more than a dozen oligonucleotide drugs now on the market to treat a range of genetic diseases, and hundreds more in clinical trials, the cost and risks associated with this process are rapidly becoming unsustainable.
鈥淣ow that we know oligonucleotide therapeutics are here to stay 鈥� with some requiring many kilograms manufactured every year 鈥� we need to find better ways to make them,鈥� Damha said. 鈥淲e need to be responsible, both environmentally and economically.鈥�
The alternative Damha has been exploring is mechanochemical synthesis, a technique that applies mechanical energy through grinding or milling to create a chemical reaction. In collaboration with Professor Tomislav Fri拧膷i膰, who just for outstanding advancements in the field of mechanochemistry, Damha first tested this approach with funding from the 黑料不打烊 Sustainability Systems Initiative (MSSI).
Using a vibration ball mill, the team managed to synthesize DNA fragments up to six nucleotides long while reducing the amount of reaction solvents needed by 95 percent. They also developed a method for coupling these fragments to build oligonucleotides more efficiently than the current process of reacting one nucleotide at a time. In addition to , Damha and Fri拧膷i膰 submitted a report of invention and filed a patent in May 2021.
鈥淭he funding we received from the MSSI was critical. It gave us the opportunity to test our theory and prove there was merit to our idea,鈥� Damha said. 鈥淲ithout it, we wouldn鈥檛 have received the ACS grant.鈥�
With the backing of the ACS Green Chemistry Institute, Damha and his team now have a year to test a different type of mechanochemical synthesis to see how its compares to vibration ball milling.
鈥淥ur industry partners are going to need some convincing to change their manufacturing process,鈥� Damha said. 鈥淪o it鈥檚 up to us to find the most effective option and show them it works.鈥�
He will also be meeting every six weeks with representatives from the ACS Green Chemistry Institute as well as from the pharmaceutical companies Amgen and Roche to exchange ideas and, hopefully, increase the prominence of nucleic acid research in the field of green chemistry.
鈥淚 think all scientists have a responsibility to think about how their projects can impact society,鈥� Damha said. 鈥淎nd this grant is a pivotal moment when we can make sustainable oligonucleotide research a priority.鈥�
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Photo caption: From left, PhD students Julian Marlyn and James Thorpe, along with Prof. Masad Damha, are developing new ways to synthesize oligonucleotides using mechanochemical instruments like this vibration ball mill.
