When I moved to Germany from India to pursue my masters and graduate studies, the cultural difference was stark. Initially, I was bewildered at cold dinners, succinct chats, and freezing weather, especially coming from a place where warmth is aplenty: in food, weather, and people.

The lab organization differed as well; I almost needed a separate orientation course for the complex reagent labeling system. But just like my other international comrades, I quickly adapted to the local ways, and soon we were pros at lab management and trying glühwein at the Christmas markets. 

My experience is hardly unique. Academia is special; it is perhaps the only profession that normalizes uprooting a life and moving across countries to start afresh every few years. Much like the mutant cells and bacteria we culture in the lab, scientists frequently immerse themselves in new environments, adapt to thrive in them, and emerge stronger from the experiences. 

Travel for academics started as a need when scientific experiments gained popularity. Special equipment and expertise in specific disciplines were rare, so researchers had no choice but to visit research groups across the globe to conduct their experiments. Why is it still a norm today despite the increasing number of world-wide research institutions? Researchers possibly move to work with like-minded experts or to associate with prestigious institutions. But I think that the curiosity of exploring a new place and taking on the associated challenges also contributes to their decisions. 

Since scientists need to always keep open minds and avoid getting stuck in the status quo or traditions, this exercise of acclimatizing to new places, breaking language barriers, and adjusting with diverse people inadvertently broadens their horizons. My hypothesis is that the nomadic life of stereotypically introverted scientists presents a paradoxical situation that pushes them out of their comfort zones in self-experiments that they track throughout their lives. 

How have you navigated moves in your careers?

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Cellular heterogeneity drives many physiological and pathological responses, but conventional analysis methods that sample only in the aggregate can mask signal from rare cell types.^1,2 Achieving single-cell resolution has revolutionized scientists’ understanding of cellular behavior, function, and characterization, helping them advance in many fields.² However, isolating and separating individual cells for downstream single-cell applications can be technically challenging.

     

Numerous techniques for single-cell separation, isolation, and sorting exist, ranging from manual manipulations to high-throughput instruments capable of processing tens of thousands of cells. In all of these, the primary considerations are yield, quality, purity, throughput, and accessibility.² Techniques that rely on manual manipulation, such as limiting dilution, do not require sophisticated instruments, but are inefficient and less accurate. Conversely, fluorescence activated cell sorting (FACS) offers high throughputs, but requires complex instrumentation, can be difficult to master, and applies significant mechanical force upon the cells.²

Microfluidics offers a potential third option to this dichotomy. Microfluidic devices separate cells by passing cellular suspensions through microchannels into distinct chambers, thereby providing throughput and accuracy without exerting mechanical stress upon cells.² While earlier microfluidic devices were complex and highly specialized, newer models are designed with lowering barriers to entry in mind.³ Instruments like the benchtop Uno Single Cell Dispenser™ focus on lower costs, smaller footprints, and greater user-friendliness. None of this comes at the expense of functionality. For example, the Uno can provide 384-well throughput in five minutes with picoliter-level accuracy.⁴ Microfluidic digital dispensing technology can gently isolate viable and healthy cells suitable for a range of downstream applications including mass spectrometry-based single-cell analysis, stem cell libraries, 3D cell research, and cell line development.

Read more about microfluidic digital dispensing technology here.

References

1. Hu P, et al. Front Cell Dev Biol. 2016;4:116. 
2. Gross A, et al. Int J Mol Sci. 2015;16(8):16897-919. 
3. Sanchez-Avila X, et al. J Am Soc Mass Spectrom. 2023;34(10):2374-80. 
4. Uno Single Cell Dispenser™. Tecan Life Sciences. 2023.

William Shih, a biochemist at Harvard Medical School, explores ways to construct tiny structures out of DNA for biomedical applications. By building on DNA origami, a method for programming DNA to self-assemble into nanoscale shapes, Shih plans to manufacture bigger and more complex molecular robots and to deliver DNA origami cancer vaccines.¹  

     

Why is it challenging to build large structures using traditional DNA origami methods? How did you overcome those challenges?

With DNA origami, we are limited to twice the size of the scaffold strand, which is around 10,000 nucleotides long. It's not feasible to find a scaffold strand long enough to build a larger structure.

We developed an elegant solution called crisscross DNA origami to build the biggest asymmetric structure ever programmed to self assemble—two micrometers by two micrometers—and constructed it from more than 1,000 unique DNA origami components, far surpassing the 64 DNA origami structure that another team built and patterned for the Mona Lisa.^2,3 We designed each DNA origami to only interact with specific ports in other DNA origami, akin to a jigsaw puzzle. 

Currently, we can build nanorobots the size of a ribosome, but anything larger, such as a bacterial cell, is difficult. Before crisscross DNA origami, it was hard to imagine how we would do this. Now, we provide a potential route to building larger structures with more sophisticated capabilities.

How do you use DNA origami for therapeutic applications?

Cancer immunotherapy is one of the biggest medical revolutions, but response rates to many life-saving medicines are still low. One reason is that cancer creates an immunosuppressive environment that neutralizes many benefits of these drugs. We developed a DNA origami-based cancer vaccine to help reeducate the immune system to recognize and attack the tumor cells.⁴ To achieve this, we designed a DNA origami pegboard with tumor antigens on one side and precisely spaced adjuvant oligonucleotides designed to raise the alarm to the immune system attached on the other side. This approach enhanced cytotoxic T cell activation, inhibited tumor growth, and worked synergistically with immunotherapy in a mouse model of melanoma. 

This interview has been edited for length and clarity.

References

1. Rothemund PWK. Nature. 2006;440(7082):297-302.
2. Wintersinger CM, et al. Nat Nanotechnol. 2023;18(3):281-291.
3. Tikhomirov G, et al. Nature. 2017;552(7683):67-71.
4. Zeng YC, et al. bioRxiv. 2023.