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Evolving how we use DNA through nanotechnological innovations

Three Wyss Faculty members explain how they’re using DNA nanotechnology to shape the future of diagnostics, therapeutics, and sustainability as they work towards the initial vision of the Molecular Robotics Initiative

By Jessica Leff 

Evolving how we use DNA through nanotechnological innovations
From left to right, Wesley Wong, Ph.D., Mingjie Dai, Ph.D., (former Wyss Postdoctoral Fellow), Peng Yin, Ph.D., and William Shih, Ph.D., at the Wyss Retreat in 2018. Credit: Wyss Institute at Harvard University

On April 25, 1953, a group of researchers published papers in Nature detailing the molecular structure of DNA, the building block of the genetic code of all organisms, for the first time. Since then, our understanding of DNA, genes, and genetics has blossomed, enabling the creation of genetic testing, gene therapies, and synthetic DNA.  

In 2018, four Wyss faculty members, William Shih, Ph.D., Peng Yin, Ph.D., Wesley Wong, Ph.D., and Radhika Nagpal, Ph.D., who has since moved to Princeton University, joined forces to explore a new frontier of DNA: not just understanding it, but using it as a building material to solve a whole new set of problems at the nanoscale. This effort became known as the Wyss’ Molecular Robotics Initiative. Over the last nine years, they have developed new diagnostic and therapeutic technologies by pushing the limits of what DNA can do.  

We sat down with Shih, Wong, and Yin to learn more about how they’re using DNA, what problems they can solve with DNA nanotechnology, and their progress towards the ambitious founding vision of the Molecular Robotics Initiative. 

What is DNA nanotechnology? 

WONG: DNA has long been recognized in biology as an information-bearing molecule. Through structural DNA nanotechnology, we’re using DNA, not just as a molecule that can store information, but as an actual programmable structural material.   

Why did you choose to work with DNA? What makes it so appealing? 

SHIH: DNA is a great tool. It’s quite stable and easy to handle – and it’s relatively inexpensive to order DNA with custom sequences. The robustness of the design process has allowed us to fabricate structures of startling complexity, with exponentially greater advances over time.    

YIN: DNA is highly programmable, and we have very simple rules regarding how bases pair with each other that enable us to program very complex behavior. With our understanding of the fundamentals, we can engineer structures and devices with a lot of sophistication and flexibility, which has been useful in developing relevant applications.  

How do you program DNA to do what you want, and how does that differ from the natural function of DNA?

WONG: The natural function of DNA is to base pair in very specific ways. So, once we had the ability to specify the desired sequence of a strand of DNA and have it synthesized, we could really take advantage of this base pairing to position DNA strands very precisely in space. This concept can be built up to create more and more sophisticated devices.  

My lab often combines this DNA technology with proteins and protein engineering to create hybrid molecules that are part DNA, for its programmability and ease of use, and part protein, because of the diversity of functions that can be achieved. 

On a detailed level, our DNA nanostructures appear much different than anything found naturally.

William Shih

SHIH: So, on a detailed level, our DNA nanostructures appear much different than anything found naturally. 

What are the practical applications of building with DNA? What problems could DNA nanotechnology solve? 

WONG: I feel like the list of applications is endless. Sometimes I think that there’s a certain excitement in the air akin to Silicon Valley when people recognized the potential of microchips and transistors. That’s the level of enthusiasm I feel working at the Wyss with pioneers in the field of DNA nanotechnology like my colleagues Peng and William. I believe we’re at a pivotal moment for a transformational technology that has the potential to impact our society in lots of different ways.

SHIH: To treat disease, we can build nanoparticle adjuvants (i.e., vaccines) for cancer and infectious diseases and artificial antigen-presenting cells for low-cost, more effective activation of T cells. Plus, we can create nonviral delivery vehicles for biologics, like mRNA and proteins.   

WONG: We’ve been developing nanoscale devices that we call DNA Nanoswitches, that change their topology and shape in response to mechanical force or to changes in their environment. We’re developing a new screening platform based on these DNA Nanoswitches to discover new therapeutics that are challenging to find with traditional approaches. 

We are also actively developing new diagnostics and proteomics platforms based on topological DNA devices.  

Evolving how we use DNA through nanotechnological innovations
Using the SDC-PAINT method, researchers could visualize a network of cytoskeletal microtubule filaments (green) and their proximity with two additional proteins called TOM20 (red) and HSP60 (blue). Credit: Wyss Institute at Harvard University   

YIN:We can also engineer DNA probes to improve biomarker detection. One example was the technology licensed to 3EO Health, a spinoff from Wyss. During the COVID-19 pandemic, by leveraging DNA-based chemistry, we developed a  sensitive, affordable, and easy-to-use molecular test with the unique positioning of delivering PCR-grade pathogen detection sensitivity at antigen level cost. The first product is now FDA-authorized for home use and commercially available now.

Another useful technology developed at Wyss is SPEAR, which is a protein detection technology. It’s unique because it can detect femtomolar amounts of a protein target in a one microliter sample in a wash-free workflow. It doesn’t require specialized equipment, and only uses a qPCR machine for readout, which is available in common academic and clinical labs. The technology was licensed to Spear Bio, another Wyss spinoff, and now commercially available. The technology can be broadly useful for scientific discovery and future clinical diagnostics.

We also developed various DNA probes for molecular imaging, including DNA-PAINT for super-resolution imaging, DNA-Exchange and Thermal-plex for rapid sequential multiplexed imaging, and SABER for in situ signal amplification. Many of these tools are now well adopted by the community, and can be broadly useful for academic research and drug development in biopharma, for example Wyss spinoff Ultivue Inc.‘s product, and hopefully eventually for disease diagnostics.

SHIH: Plus, we can use DNA to help us build low-power analog optical computers that will bring us closer to a sustainable future.  

There are a lot of problems in the world, and I think it’s incumbent on all of us to do the best we can to try to solve them together, incorporating each other’s developments and strengths while contributing our own creativity and efforts.

Wesley Wong

WONG: There are a lot of problems in the world, and I think it’s incumbent on all of us to do the best we can to try to solve them together, incorporating each other’s developments and strengths while contributing our own creativity and efforts.

What is it that you envision your own work with DNA could lead to? 

YIN: I think it’s an evolution. We can enable much more accurate, sensitive characterization of molecular events in biology. As we iterate on our innovations, I see us making our technologies better and more accessible.  

WONG: A big part of what my lab does is really trying to understand how Nature works at the nanoscale and the role of mechanical force. If we could use this knowledge to, in a sense, replace large instruments with sophisticated, programmable, nano-engineered reagents, it would be a path towards democratizing a lot of these amazing capabilities so they’re accessible to everyone.    

Which applications are already within reach right now?  

SHIH: Imaging and in vitro assays are nearer-term because the FDA regulatory hurdles are lower since they don’t directly interact with the human body.    

Evolving how we use DNA through nanotechnological innovations
A visualization of the DNA Nanoswitch Calipers, a technology that came from a collaboration between Wong and Shih’s groups. Credit: Wyss Institute at Harvard University

WONG: Some of the technologies we developed are ripe for contributing to the world by finding new drugs for pathways that we know about, but haven’t been able to find good medications for. We could find these drugs at significant savings of both time and cost, allowing a wide range of new therapies to be discovered. 

For our DNA caliper project we are inspired by the potential for nanotechnology-based tools to transform proteomics, in a similar way to how nextgeneration sequencing transformed genomics. Right now, proteomics relies on incredibly expensive and complex instruments. If we could develop complementary single-molecule approaches based on accessible nanoscale methods, we could solve current challenges and democratize these amazing capabilities.  

How would you describe your own personal frontier in DNA nanotechnology, the problem that you really want to crack? 

SHIH: How can we achieve highly parallel characterization of single molecules with ever-increasing specificity and sensitivity? How can we achieve “printing without printers” of micrometer-scale devices from molecular components? More specifically, how can we program the growth of micrometer-scale artificial cells with specific nanoscale features? 

YIN: It would be exciting to keep innovating more high-performing, robust, and accessible molecular tools to help study biology, improve testing and diagnostics, and facilitate therapeutics discovery. One exciting direction would be to use DNA tools to help enable spatial, single-cell, and single molecule proteomics including the emerging frontier of single molecule protein sequencing and fingerprinting, as well as ultrasensitive immunoassay for early disease detection. 

WONG: Continuing that Silicon Valley analogy, I sometimes wonder if the people who were around near the beginning felt a sense of satisfaction when they saw how their efforts changed the world. I’m excited see how our groups, our community at the Wyss, and the wider scientific community at large adopt and use DNA nanotechnology to solve pressing problems. 

Can you explain how the Molecular Robotics Initiative was shaped? 

Evolving how we use DNA through nanotechnological innovations
In 2018, the topic of the Wyss Symposium was Molecular Robotics. Experts came to share their progress in this unique area. Credit: Wyss Institute at Harvard University

SHIH: [Wyss Founding Director] Donald Ingber suggested the moniker of “Molecular Robotics.”  

YIN: Don saw the different and synergistic activities the three of us were doing and the opportunity to converge and use DNA technology as part of this larger concept. Initially, we also worked with Radhika Nagpal, who inspired us with her swarm robotic systems before she moved on to a position at Princeton. Working together, we have skills that are very fundamental to innovation and enable us to develop new molecular programming capabilities.  

SHIH: The name itself represents more of a future aspiration, as we cannot yet program molecules to sense, compute, and actuate with the sophistication of a macroscopic robot. But we’re making progress at an exponential pace, so we’ll get there.  

WONG: Some of the devices we’ve developed can respond to changes in their environment and carry out a task. That’s the start of what you might imagine a robot to be. So, the name reflects the journey we’ve been on and indicates what we’re pointed towards.    

Where do you see Molecular Robotics moving in the long-term? 

WONG: One motif that we’ve been exploring as part of the Molecular Robotics Initiative is programmable DNA-based nanodevices that can respond to their environment and report back what they find by changing their topology.  

YIN: For aspirational imaginative future, we could envision groups of “molecular robots”  collectively roaming around, gathering information, and informing us of the otherwise inaccessible molecular landscape, like a web crawler indexing the internet or a Mars rover surveying the planet surface.

It may still sound a lot like science fiction, but we are taking small steps towards making this vision a reality. We recently developed a rudimentary prototype of such “molecular robotic agents” that can basically crawl along a synthetic molecular landscape and remember the molecular cues it encounters sequentially. The information can be read by a machine that sequences DNA. Now, we can imagine that if we had many of these molecular crawlers, we could use their collective sequencing information to reconstruct that molecular landscape. Using a different variant of such a spatial encoding DNA nanodevice, we have been developing a platform that we call a DNA nanoscope to capture molecular images without using a microscope in a process we call “imaging by sequencing.” One specific application for this technology could be to sequence or fingerprint single-molecule proteins. One could envision a molecular crawler crawling along a linearized protein with selected amino acids specifically modified with DNA barcodes, and recording their spatial arrangement for later reconstruction and protein identification.

What sets the Molecular Robotics Initiative apart from DNA nanotechnology work being done elsewhere?  

YIN: At the Wyss, we tend to use our innovations to solve real-world problems, which informs how we focus our research. We often think about how to guide our nanoengineering effort towards an impactful solution for a critical unmet need in a unique fashion. We hope many of our innovations may have the potential to be further developed a useful and commercially available product with broader impact.

At the Wyss, we tend to use our innovations to solve real-world problems, which informs how we focus our research. We often think about how to guide our nanoengineering effort towards an impactful solution for a critical unmet need in a unique fashion.

Peng Yin

WONG: There’s a lot of amazing DNA nanotechnology happening all over the world, and it’s great to be part of this community. People share ideas and support one another.    

One reason I enjoy being part of the Wyss is that here, we’re able to bring together amazing people, resources, and facilities. We’re encouraged to think creatively, collaborate, and take risks. We can have this ambitious vision for how we can change the world along with the scientific maturity and experience to know what concrete steps we need to take to get us there, while making useful tools along the way for real-world impact. 

This interview has been edited for length and clarity.

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