The Humans of the Wyss (HOW) series features members of the Wyss community discussing their work, the influences that shape them as scientists, and their collaborations at the Wyss Institute and beyond.
We’re in the midst of an RNA revolution, and Daniel Wiegand and his team are prepared to deliver RNA to the world by making high-quality RNA oligonucleotides cheaper and more easily accessible. After an impactful co-op experience at a pharmaceutical company during his undergraduate years, Daniel understood what it truly meant to be a scientist, and he was hooked. His passion for cutting-edge, impactful science brought him to the Wyss, where he is leading the development of a manufacturing platform for the enzymatic synthesis of RNA oligonucleotides for use in therapeutics. Learn more about Daniel and his work in this month’s Humans of the Wyss.
What are you working on?
As part of Team EnPlusOne, which consists of myself, Jonathan Rittichier, Howon Lee, Dan Ahlstedt, and Ella Meyer as well as our advisor, George Church, I’m working on building a next-generation manufacturing platform for the scaled production of high-quality RNA oligonucleotides using enzymes. Our team name is a play on words that describes the synthesis of an oligonucleotide “one” base pair at a time with an “en”zyme.
An oligonucleotide (oligo) is a string of nucleotides, generally between 10-100 base pairs long. Nucleotides are the basic building blocks of nucleic acids, like RNA and DNA. Oligos are currently used as commodities in a diverse range of applications. However, they probably are most well-known for being a backbone of the oligonucleotide therapeutics and RNA medicine fields, where RNA is programmed by experts to treat disease with great precision.
What real-world problem does this solve?
Currently, the majority of all oligonucleotides are manufactured using a traditional phosphoramidite chemical synthesis method. This chemistry is undoubtedly robust and efficient – there’s a reason why it’s been a staple in the laboratory since the 1980s. However, we are in the midst of an RNA revolution, most recently demonstrated by the mRNA-based vaccines for COVID-19, and the need for RNA oligos is increasing. Researchers and medical professionals are demanding more and more oligonucleotides with increased requirements for yield, product purity, additional modifications, new delivery modalities, and increased oligonucleotide length. These are areas where traditional phosphoramidite chemistry-based synthesis is limited and it won’t be able to keep up with future production demands.
That’s where Team EnPlusOne comes in. My team and I believe that by completely avoiding phosphoramidite chemistry we can eliminate many, if not all, limitations of chemical-based synthesis. By using naturally occurring enzymes, whose job it is to synthesize RNA already, we believe that we can produce oligonucleotides more cheaply at substantially higher purities and commercially relevant scales. We want to meet the new demands of this RNA revolution. We want to deliver RNA to the world; enzymatic synthesis is the key.
What inspired you to work on this project?
I’ve always loved enzymes. Honestly, it’s truly mind-blowing to think about how at this very moment within all of our cells so many different enzymatic reactions are taking place simultaneously to keep our bodies and minds functioning flawlessly. Enzymes are the catalysts of life. They are the product of millions of years of evolution and natural selection. I feel humbled by the fact that I can harness these exceedingly intricate biomolecules to benefit mankind.
Another inspiration for this project is that our enzymatic chemistry greatly reduces the consumption of organic solvents and the generation of toxic waste, which is a by-product of traditional phosphoramidite chemistry. By electing a greener method, we can minimize the impact RNA oligonucleotide production has on the environment.
What continues to motivate you?
I am motivated by the possibility that so many new and interesting applications can be enabled by the development of our enzymatic RNA oligonucleotide synthesis platform. Our synthesis only requires minimal organic solvent consumption, with the majority of all reactions taking place primarily in water. Therefore, we can access new modifications to our RNA. This is because with traditional phosphoramidite chemical synthesis, one must use reagents that are typically not biologically friendly, like strong acids, bases, and organic solvents. So, RNA modifications that are easily broken down or displaced will need to have an extra level of protection throughout synthesis or may not be possible at all. Conversely, performing synthesis in water puts the RNA in a less harsh environment, so less protection is necessary. Some modifications that are completely impossible with chemical synthesis could be possible with our platform.
It is my hope that by collaborating with the experts across the RNA fields we can discover completely new therapeutics, medicines, and tools, as well as initiate a paradigm shift in the way that we commonly access both natural and modified RNA oligos. On Team EnPlusOne, we like to say that our enzymatic chemistry provides a whiteboard for people to use RNA to draw anything they can imagine.
What excites you the most about your work?
It honestly feels great to be working on a project that has so much potential. As we were de-risking the technology in preparation for applying to be a Validation Project, we spoke directly to folks in the academic and industrial spaces who are using RNA oligonucleotides on a daily basis. I can recall my euphoria when I saw other people’s eyes light up as I would explain what we were doing and how our enzymatic synthesis platform might be useful in overcoming the problems and limitations they face daily. It’s quite exciting to think about how this technology may become the next chapter in the history of oligonucleotide synthesis. It’s also humbling to imagine ourselves mentioned in the same breath as all of the amazing researchers, chemists, and engineers who made phosphoramidite synthesis possible. Team EnPlusOne believes that this is possible based on the positive external responses and the gracious support of the entire Wyss Institute, including Angelika Fretzen.
What are some of the challenges that you face?
One of the most interesting challenges we have faced during this project has been deciding which RNA application we should tackle first. Because there were so many possible avenues, it was initially difficult for the team to determine the one that would be most commercially viable. However, with some guidance from the translational technology staff at the Wyss as well as other key opinion leaders in the RNA field, we quickly came to realize that scaled RNA oligonucleotide production was the way to go. That being said, it is my hope that we can revisit some of these other avenues down the road.
What support have you received from Northpond Labs and how has that been helpful to your project?
Our project was the first to be selected for the Laboratory for Bioengineering Research and Innovation at the Wyss Institute supported by the alliance with Northpond Labs. The support we’ve received to commercialize the enzymatic RNA synthesis technology has been tremendous. It really brought the project to the next level – well, maybe up ten levels! On the technology side, the involvement from Northpond Labs has allowed us to significantly increase the number of RNA “inks” we have at our disposal and begin to automate the RNA enzymatic synthesis process. Additionally, working directly with Andrea Jackson, Andrew Lee, and others from Northpond has had a remarkable impact on our team. Their insight and excitement for the project motivates us every day. The fact that they see the vision we are working towards, understand the science, and continually support us means the world. We’ve developed a great relationship with Northpond, it almost feels like we’re a bit of a family and we’re so excited about our future together.
Why did you want to work at the Wyss?
I’ve always been an avid science fiction enthusiast – I grew up reading many of the classics, from Isaac Asimov, to Ray Bradbury, to H.G. Wells, as well as watching television shows like Star Trek: The Next Generation routinely. From these experiences, I always wanted a career at a place where I could blend reality with a bit of science fiction. When I came across some online video lectures on synthetic biology given by George Church, I made it my mission to somehow work for him.
It was at this moment I also discovered the Wyss Institute had some open research positions for high-throughput gene synthesis and now the rest is history. Although we haven’t quite cracked warp drive in space yet, it truly feels great to be a place where I can be a part of important cutting-edge research that could potentially shape entire fields of medicine in the future.
What is unique about the Wyss and how has that impacted your work?
I am humbled and honored to be at the Wyss, leading Team EnPlusOne, and working with Northpond Labs. The Wyss grants you the opportunity to do impactful, cutting-edge research in an environment that is a unique blend of academia and industry, which fosters new and creative ideas and makes for an overall great work experience. Honestly, the best part of being at the Wyss Institute is that one has the chance to work alongside some of the most intelligent, insightful, creative people around. Obviously, ideas are cheap and not everything will stick or be valuable, but the freedom to engage in the organic process of talking a bit of science fiction with your colleagues over coffee may lead eventually to the development of a new RNA oligonucleotide synthesis platform, for example.
How have your previous experiences shaped the researcher you are today?
One particularly impactful experience that shaped me as a researcher occurred during my undergraduate career at Northeastern University. I worked at biotechnology company synthesizing and testing radiopharmaceuticals for the treatment and diagnosis of prostate cancer as part one of my co-ops. During that time, I truly began to understand what it meant to be a scientist and researcher. I’ll be frank here – early on, I was only an average student. I was always unable to connect the dots between what I learned in the classroom and why it was important or useful in the real world. It was only after getting that hands-on experience in the lab that things began to click for me. I always look back fondly on that co-op experience, as it has helped me get to where I am today at the Wyss Institute.
When not at the Wyss, how do you like to spend your time?
I’m an avid outdoorsman, I really enjoy camping, boating, hiking – pretty much anything that can get me out into nature. For me, it’s a requirement to disconnect from the hustle and bustle in the lab, and enjoying some outside time allows me to come back fresh and clear to keep pushing projects along. My fiancée and I also love going to the beach and visiting state parks or places of historical relevance. We recently made it a priority to collect as many patches from the national parks across the United States as possible.
What’s something unique about you that someone wouldn’t know from your résumé?
My first job was working at an old movie theater in Albany, New York – one that was built in the 1920s with a single screen and eventually converted into multiple screens as more and more films started coming out per year. While it wasn’t always the most pleasant experience – I had to clean a lot of spilled popcorn from the theaters – I did have the unique opportunity to learn about and help run the old film projectors. Being an aspiring movie buff, this was such a great experience. I also had the added benefit of seeing whichever movie I wanted for free when not working.
If you had to choose an entirely different career path, what would it be?
I honestly might have stayed in the movie business if it weren’t so tough. At the same time, I’ve always been really into playing video games, and leading the design and crafting a story-driven game would be a great experience. Many of my friends also enjoy games, and it’s just nice having a great group of friends boot up our favorite multiplayer game after a long day at the lab.
What does it feel like to be working on a cutting-edge technology that has the potential to have a real and significant impact on people’s lives and society?
It’s probably one of the most exciting things ever in my entire life. A lot of times folks can end up going through the motions of working on something just to get it done. But for myself, Jon, Howon, Dan, and Ella, the enzymatic RNA oligonucleotide synthesis project is something that gets us out bed every day excited to get to work and keep on moving forward in the hopes that one day we will be able to deliver RNA to the world. Hearing stories of the success of current RNA therapeutics is so inspiring. That is what drives me to work on this technology. The long-term impact that a better way of synthesizing RNA could have on people and society in general is what it is all about for me.