For Masad Damha, falling in love with science was easy. Growing up in Managua, Nicaragua, his high school teachers encouraged scientific exploration, curiosity, and experimentation, such as processing vegetable oil into soap, producing hydrogen and oxygen from water via electrolysis, and determining the gravitational force constant using a pendulum. The students also visited industries that use geothermal energy for electricity production and participated in national science fairs, where they created a solar BBQ and a spacecraft. Ultimately, Damha says he owes this passion to his parents for enrolling him in such a great school.

After finishing high school in 1978, Damha traveled to Montreal, Canada, to learn English and, later that year, began his undergraduate degree in Chemistry at McGill University. It was the right time to leave Nicaragua, Damha explains, as the country was experiencing a turbulent political climate marked by the collapse of a dictatorship and the rise of a socialist party.

At McGill, Damha enrolled in an introductory organic chemistry course taught by Kevin Ogilvie and David Harpp and soon learned that Oglivie and his research group were working on constructing a “gene machine” to assemble short strands of DNA.

“I found that fascinating, and upon completion of my BSc Chemistry degree, I joined Ogilvie’s laboratory to pursue a PhD degree,” he says. “Together with other members of the group, I worked on the chemical synthesis of RNA, which was more challenging than DNA synthesis.”

Damha also prepared RNA molecules with 2′,5′-branching (1), which had recently been identified as intermediates during RNA splicing, specifically in the formation of lariat structures.

“I was forever hooked to the field of oligonucleotides!” he says.

Professorship and Scientific Discoveries

After finishing his PhD in organic chemistry, Damha started an Assistant Professorship at the University of Toronto’s Erindale College, which has a world-class chemistry department. Here, he and other scientists worked on developing methods for the synthesis of 2′,5’-linked RNA and branched RNA on solid supports, which ultimately culminated in the characterization of the Lariat Debranching Enzyme (2) and the synthesis of hyperbranched polymers made from DNA.

“These nucleic acid “dendrimers” (3) were among the first “chiral dendrimers” ever made from DNA, which has since become popular in DNA nanotechnology,” he explains, adding that ongoing collaborative studies have resulted in several inhibitors of the lariat debranching enzyme that hold promise as therapies for viral infections and neurodegenerative diseases like ALS.

In 1992, Damha returned to his Alma Mater, where he teaches and continues to work on RNA analogues. A key finding from this work was that arabinose nucleic acid (4) (ANA, the 2’-epimer of RNA) and its close cousin, 2′-fluoroarabinonucleic acids (5) (FANA), could elicit RNase H activity to cleave an RNA target, just like DNA. This discovery made FANA and ANA the first modified oligomers lacking 2-deoxy-D-ribofuranose that could mimic DNA and support RNase H activity. Damha notes that it was a timely discovery, as ribonucleotides with 2′ modifications were being extensively investigated in second-generation antisense oligonucleotides (ASOs).

“We learned that FANA gapmers were as potent as RNA gapmers and that FANA would also work in other configurations,” he says.

They also found that FANA could stabilize noncanonical DNA structures (6), like G-quadruplexes, i-motifs, Z-DNA, and triple helices, by virtue of fluorine’s inductive effects and its ability to engage in stabilizing F-H interactions. Additionally, they found that DNA polymerases could synthesize FANA strands (7) from DNA templates. Based on this property, other groups engineered polymerases to efficiently transfer genetic information from DNA to FANA and retrieve it back into DNA, demonstrating that FANA, like DNA, can store hereditary information. From this research, a drug candidate of 2’F-ANA to treat COPD was pursued by Topigen Pharmaceuticals and received approval to start Phase 1 clinical trials in 2008.

“This area, known as Xenobiology, has been gaining considerable attention as it seeks to find life forms that evolve and replicate from artificial genetic materials,” he says, adding that the research promises a deeper understanding of human biochemistry for innovative therapeutic avenues.

Damha co-founded Anagenis Inc., a start-up company with proprietary antisense technologies. Additionally, numerous research laboratories and industries are utilizing his FANA technology to create modified oligonucleotides targeting various biological entities, including cancer and different infectious diseases. Additionally, Damha and students have developed the “ALE chemistry” (ChemGenes) for long RNA synthesis, making it possible to synthesize strands over 200 nt in length in a single run.

Nobody makes it alone: mentorship and collaboration

While Damha is proud of his FANA research, he considers his most significant contributions to be the students he has worked with over his career, with whom he has authored more than 230 publications and received several patents worldwide.

“Collaboration is a key driver of science and innovation. I have worked with over 70 graduate and postdoctoral students and over 60 undergraduate students,” he says. “Many of them have developed remarkable academic, industrial research, and management careers in the life sciences, medical technologies, and oligonucleotide therapeutic sectors.”

Damha says he’s also had the privilege of working with outstanding colleagues who are innovators in the oligonucleotide field, including Alan Gewirtz (ASOs), Cy Stein (Gymnosis), Jeff Boeke, John Hart and Shuman Stewart (branched RNA), Carlos Gonzalez (Nucleic Acid Structure), Keith Gagnon (CRISPR/Cas), David Corey (ASOs), Mano Manoharan (siRNA), Annemieke Aartsma-Rus (splice switching ASOs), Anastasia Khvorova (new chemistries), Mark Somoza (RNA synthesis on microarrays), Nahum Sonenberg (mRNA translation), Jerry Pelletier and Sidong Huang (mRNA synthesis), John Rossi (antiviral ASOs),  Hanadi Sleiman (Delivery), Philippe Gros (ASO/siRNA to treat neuroinflammation), Bruce Sullenger and Maureen McKeague (Aptamers), Tracy Bryan (Telomeres, G4s, i-motifs), Modesto Orozco and PI Pradeepkumar (computation).

“Together, we leverage different capacities and expertise to solve a scientific problem,” he says, adding that students also benefit from these collaborations by working and learning from them and completing internships in their laboratories.

He explained how he has overcome challenges by quoting Oprah Winfrey, “Nobody makes it alone; nobody has made it alone. And we are all mentors to people even when we don’t know it.” Damha expanded on this by sharing that to be successful in academia, a strong support system of people who can mentor and guide you is essential. For him, this included colleagues at the University of Toronto and McGill, as well as his parents and immediate family.

Damha believes there has never been a better time to work in the oligonucleotide field and encourages his graduate students to pursue postdoctoral studies to refine specialized skills or transition to an academic role. However, he notes it’s not a one-size-fits-all path, and depending on each student’s aspirations, he tries to guide them and direct them to lab alumni in different fields who can also provide advice.

“In the job market, having a strong professional network and staying connected with colleagues and contacts over the years is extremely valuable for career advancement,” he says, noting that he’s remained close with his mentors and friends, Ogilvie and Harpp, throughout his academic career. “And it goes without saying that I encourage them to join the Oligonucleotide Therapeutics Society. The way the OTS can benefit their career is immeasurable; I certainly speak from my own experience as a faithful member and as a Past President of the OTS.”

Artificial Intelligence and the future of the oligonucleotide field

As the oligonucleotide field continues to grow, Damha believes the role of artificial intelligence and machine learning will revolutionize drug discovery in several ways.  The technologies’ ability to accelerate the identification of novel targets, predict drug behavior and toxicity, choose the chemical modification for a particular application, predict the effectiveness of molecules for nucleic acid delivery, and speed up the development process are all possibilities with artificial intelligence and machine learning.

“The potential to predict toxicity, especially at high doses, would be an enormous benefit to oligonucleotide medicines,” he explains. “However, this requires large and reliable data sets to accelerate the drug discovery process.”

As for the obstacles the field needs to overcome to advance oligonucleotide therapeutics to mainstream clinical use, Damha says a recent publication by David Corey, Muthiah Manoharan, and himself, highlights some of the challenges and opportunities (8) for advancing to the clinic more quickly. Some of the questions the paper brings up include determining if other ligands can replicate the success of GalNAc; how RNA-based therapeutics impact cancer; if the success of systemic mRNA parallels the success of mRNA vaccines; if RNA medicine can be manufactured at a large scale and supplied worldwide; can endosomal escape be harnessed to enhance drug potency; can effective oral drug delivery be achieved; and will nucleic acid medicine cross the blood-brain barrier effectively. Regardless of the answers, Damha says these past years have seen significant advances in all stated areas.

“I am very optimistic about the future of our field,” he says.

On that note, he views work such as N-of-1 therapy for ultra-rare diseases as an exciting direction for the oligonucleotide field. He is a big fan of Sonia Vallabh and Eric Minikel, who are researchers at the Broad Institute of MIT and Harvard working to find a cure for genetic prion disease. Damha says their story, which includes the pair switching from non-scientific fields after Vallabh’s mother passed away from the disease and she was found to carry the same gene, is truly inspirational.

“They are fully committed to developing treatments and preventative strategies, including lowering prion protein levels in the brain,” he says.

From a curious high school student to a McGill professor

Outside of academia, Damha enjoys chess, photography, mixology, and being a grandad. If he could choose what to be remembered for, it would be as a “FANA-tico of nucleic acid chemistry” and as an imperfect husband, dad, and grandpa.

“I am immensely proud of my three amazing daughters, Vanessa, Catherine, and Melissa; my son Jean Philippe; my two (so far!) grandchildren, Thomas and Liana; and my wife of 40 years, Sylvie Coallier, whom I met at the Montreal Olympic Stadium while watching a baseball game.”

Masad Damha’s journey from a curious student in Nicaragua to a pioneering chemist in the field of RNA research illustrates the profound impact of education, collaboration, and mentorship in scientific discovery. To stay updated with Damha’s latest research and contributions, visit his Damha Lab website or Google Scholar. To read Damha’s studies that were mentioned, and some additional ones that weren’t, see the citations below.

1. Habibian, S. Harikrishna, J. Fakhoury, E. Ageely, M. Barton, H. H. Fakih, A. Katolik, R. Cencic, M. Takahashi, J.J. Rossi, J. Pelletier, K.T. Gagnon, P.I. Pradeepkumar, and M.J. Damha (2020) Effect of 2′-5’/3′-5′ phosphodiester linkage heterogeneity on RNA interference, Nucleic Acids Research 48, 4643-4657. doi: 10.1093/nar/gkaa222
2. Clark NE, Katolik A, Roberts KM, Taylor AB, Holloway SP, Schuermann JP, Montemayor EJ, Stevens SW, Fitzpatrick PF, Damha MJ, Hart PJ. Metal dependence and branched RNA cocrystal structures of the RNA lariat debranching enzyme Dbr1. Proc Natl Acad Sci U S A. 2016 Dec 20;113(51):14727-14732. doi: 10.1073/pnas.1612729114. Epub 2016 Dec 6. PMID: 27930312; PMCID: PMC5187747.
3. H.E. Hudson and M.J. Damha (1993). Nucleic acid dendrimers: Novel biopolymer structures. Journal of the American Chemical Society 115, 2119-2124. doi: 10.1021/ja00059a004
4. Noronha AM, Wilds CJ, Lok CN, Viazovkina K, Arion D, Parniak MA, Damha MJ. Synthesis and biophysical properties of arabinonucleic acids (ANA): circular dichroic spectra, melting temperatures, and ribonuclease H susceptibility of ANA.RNA hybrid duplexes. Biochemistry. 2000 Jun 20;39(24):7050-62. doi: 10.1021/bi000280v. PMID: 10852702.
5. Wilds CJ, Damha MJ. 2′-Deoxy-2′-fluoro-beta-D-arabinonucleosides and oligonucleotides (2’F-ANA): synthesis and physicochemical studies. Nucleic Acids Res. 2000 Sep 15;28(18):3625-35. doi: 10.1093/nar/28.18.3625. PMID: 10982885; PMCID: PMC110742.
6. El-Khoury R, Roman M, Assi HA, Moye AL, Bryan TM, Damha MJ. Telomeric i-motifs and C-strands inhibit parallel G-quadruplex extension by telomerase. Nucleic Acids Res. 2023 Oct 27;51(19):10395-10410. doi: 10.1093/nar/gkad764. PMID: 37742080; PMCID: PMC10602923.
7. Peng CG, Damha MJ. Polymerase-directed synthesis of 2′-deoxy-2′-fluoro-beta-D-arabinonucleic acids. J Am Chem Soc. 2007 May 2;129(17):5310-1. doi: 10.1021/ja069100g. Epub 2007 Apr 10. PMID: 17419631.
8. Corey DR, Damha MJ, Manoharan M. Challenges and Opportunities for Nucleic Acid Therapeutics. Nucleic Acid Ther. 2022 Feb;32(1):8-13. doi: 10.1089/nat.2021.0085. Epub 2021 Dec 17. PMID: 34931905; PMCID: PMC8817707.
9. F. Deleavey, J.K. Watts, F. Robert, T. Alain, A. Kalota, J. Pelletier, A.M. Gewirtz, N. Sonenberg and M.J. Damha (2010). Synergistic effects between analogs of DNA and RNA improve the potency of siRNA-mediated gene silencing. Nucleic Acids Research 38, 4547-4557. doi: 10.1093/nar/gkq181
10. Carriero S, Damha MJ. Inhibition of pre-mRNA splicing by synthetic branched nucleic acids. Nucleic Acids Res. 2003 Nov 1;31(21):6157-67. doi: 10.1093/nar/gkg824. PMID: 14576302; PMCID: PMC275466.
11. El-Khoury R, Damha MJ. 2′-Fluoro-arabinonucleic Acid (FANA): A Versatile Tool for Probing Biomolecular Interactions. Acc Chem Res. 2021 May 4;54(9):2287-2297. doi: 10.1021/acs.accounts.1c00125. Epub 2021 Apr 16. PMID: 33861067.
12. Thorpe JD, Marlyn J, Koenig SG, and M.J. Damha MJ. Synthesis of Short DNA and RNA Fragments by Resonant Acoustic Mixing (RAM), RSC Mechanochemistry, 2024 March 28;1, 244-249. DOI https://doi.org/10.1039/D4MR00009A
13. Hear from our RSC Mechanochemistry authors: Masad Damha, James Thorpe and Julian Marlyn