DNA nanotechnology's Oscar season

'Tis the season. Movies are released year round, but November and December are when the Oscar buzz starts. A slew of movies, made for such awards, storm the theaters. This season saw such a surge in research articles in the field of DNA nanotechnology, where four articles featured in one issue of Nature, and one more article in Science. There were many other papers in DNA nanotechnology that were published in top journals earlier in the year, but the media storm around these were abounding. Specifically, these papers contributed an advancement in the assembly of DNA nanostructures and scaling them up to size ranges not achieved before. I'm not going to discuss these papers in detail here, but just point out what was done.

Lulu Qian's group from Caltech made a Mona Lisa using DNA origami fractal assembly. The group made square tiles with specific surface patterns that can connect via controllable DNA interactions.

Peng Yin's group at Harvard used the DNA bricks they already developed, and extended the concept to construct large scale sculptures (including a teddy bear).


 A gigadalton sized dodecahedron made from DNA origami parts.  Source:  Nature publishing group.

A gigadalton sized dodecahedron made from DNA origami parts. Source: Nature publishing group.

Hendrik Dietz's group at Technical University of Munich assembled DNA origami parts into a gigadalton polyhedron, the largest of origami objects ever made (~450 nm). In a double feature, Dietz's group also report a strategy to mass-produce the DNA strands required for such feats, by utilizing bacteriophages (a type of virus) to create the staple strands. This method reduces the cost of DNA origami structures 1000-fold.

Read the perspective by Fei Zhang and Hao Yan in Nature for an overview of these research reports.

Another paper in Science - a collaboration between Peng Yin and Hao Yan at Arizona State University - showed that DNA origami can be done using single stranded DNA and RNA. The "traditional" DNA origami strategy is double stranded: one long 'scaffold' strand is folded into desired shapes by hundreds of short complementary 'staple' strands. It is to be noted that Dietz's group had, earlier in 2017, showed the creation of DNA origami using proteins as staples (which used double stranded DNA as scaffold), also published in Science.

Many such novel techniques have advanced the construction of DNA nanostructures in larger scales and bridging the gap between bottom-up and top-down assembly. The applications the field promised is still elusive, but with every new research article coming out, the effort is gaining traction.

How my paper went from rejection to being the cover feature

DNA nanoswitch concept_bg.png

I started a side project during my post doc days at Albany, and called it the DNA memory device. We were working with DNA nanoswitches, which can bind specific nucleic acid sequences, resulting in specific bands on a gel. We were using this as a biosensing technique. My "just for fun" side project was to use the same strategy to encode data into such DNA nanostructures and read it out using agarose gel electrophoresis. We designed a multi-input nanoswitch that can bind up to 5 different DNA input strands. Each input creates a loop and the different-sized loops migrate differently on a gel resulting in a 5-bit output (design is shown in the figure on the right). We showed that we can store alphanumeric characters as 5-bit codes in these nanoswitches. By using a process called DNA strand displacement, we also made this a rewritable system. That is, once you encode the information, you can add DNA "eraser" strands that remove the input strands from the nanoswitches, and thus erase the pre-written bits (the loops revert back to the linear state). We were also able to re-write information in the same set of nanoswitches. My favorite result from this project is where we wrote HELLO WORLD, erased it completely, and rewrote GOOD BYE using the same nanoswitches (see figure).

Hello World_bg.png

Then came the time to publish this. The once cheesy, half-baked idea now took a full form as a well-characterized concept, with complete results showcasing the efficiency of the memory system. I was happy that I convinced my post-doc advisor that this was now a worthy project that could be published. We even made a bet as to whether we will succeed in publishing this in a journal with an impact factor >5 (let's save the impact factor importance argument for later). This was my first research paper as a corresponding author and I was characteristically exuberant about getting this in a top journal (and willing to go through multiple rejections). So I did what I think most academics do: I started at the top of the food chain of journals and went down the ladder as I got rejected. After three rejections from first-tier journals, I submitted the article to a well-known "Nano" journal. I was so excited to see that the paper was sent out for peer review. I just wanted this to get past the editor so we have a real chance to know what our peers think of this paper. Three weeks went by and we received the decision email: "Rejected". I went through the reviewers' comments and they were all positive but the paper was still rejected. One reviewer mentioned this was suitable after minor changes but indicated a different journal name (not the one we submitted to). We wrote to the journal about the apparent mistake, and they reversed the decision. While we waited to see a reversed "accepted" decision, the journal sent us a "revise and resubmit" option saying it will be considered as a new manuscript with further peer review.


While it seemed like the straight forward option to go back and submit again to the same journal, I was "delirious" and wanted to submit the paper to a different journal, a higher level one at that. Journals do not always have to get the upper hand at authors and I did not want to succumb to that trend. After hours of discussions and arguments with my advisor, I convinced him of submitting this to a different journal. It was sent out for peer review, and three weeks later, the paper was accepted with minor revisions! It was the best moment of my academic life! I knew I would tell people about this for years to come, how I decided to ditch a potential acceptance for a better journal, to show authors don't always have to bend down to journals, and succeeded in that. And to top it off, I submitted a cover figure for our paper and that was accepted too! Our paper came out in all its glory in the journal Nucleic Acids Research, and was featured on the cover of the October issue of 2017.

Read the article here to find out more.

Academic publishing: Time wasted in formatting and resubmission


A universal manuscript submission page is the need of the hour to save precious time for researchers that can be spent in doing actual research instead.


As a researcher, one's first priority is to do science without having to worry about the next grant deadline or having enough publications to keep them afloat in the academic system. These two desk work items (as opposed to the bench work many scientists love to do) are tied in to one another, with publications serving as a currency or track record for grant applications. In this 'publish or perish' scenario, it might seem a simple process to do research and publish, but there is a limbo phase in scientific communication that takes away precious time from researchers. This is the time when new scientific results are written up for publication and submitted to a journal. Some of the thoughts that go into this process are which journal to submit to, what kind of a manuscript category does the paper fit into and the publication time involved in the chosen journal. According to a news feature in Nature, while the average time between acceptance and publication has dropped in recent times, the time taken for review and eventual acceptance (or rejection) is still frustratingly long. These metrics show the wait times that are part of the publication process, but what it does not show is the time spent behind the scenes when scientists "window shop" for journals before the paper eventually gets accepted and published in one.


Manuscript formatting

Academic researchers are probably used (and adapted) to the process of rejection from a journal and resubmission to another. But it is not a streamlined process and researchers lose time in such a phase. Every journal has its own style and formatting (striving to stand out in a competitive publishing business) and in most cases, recommend submitting the manuscript already formatted according to the journal's requirements. But content is more important that style. As Quanmin Guo says in his correspondence to Nature, “Cosmetic treatments should instead be reserved for enhancing the clarity of a manuscript's content.”

Time spent on formatting their manuscripts is time lost on doing research or writing grants. If a paper is rejected from a journal and is submitted to another, that's another few hours to format it again! There is no advantage to spending time formatting an article without knowing if it will be accepted for publication in that journal. If rejected, authors have to format the manuscript again to make it suitable for a different journal. In this era of online publishing, it is high time that journals work together to agree on a particular format (or format free) submission prior to acceptance and save time for authors. Authors could possibly format the manuscript according to journal requirements after acceptance. This does not burden the publisher, while saving a lot of time during submission (and resubmission) for the authors. Publishing giant Elsevier has taken a right step in this direction, introducing “Your paper, your way”, so that “authors can focus on what really matters: the science”. Authors can simply submit a PDF version of their manuscript without any formatting requirements. A free-form submission does not in any way impact the current publishing process, as long as a manuscript is written well for editors and reviewers to comprehend. Desktop publishing work like formatting and styling manuscripts should be taken over by publishers, especially those which charge authors (publication charges, figure charges, or open access charges).


Manuscript submission page

In today's academic world, for a paper to be accepted in its first submission has become a rarity. Authors whose papers are rejected lose more time in resubmission of the paper to other journals, especially when it requires reformatting to suit the second journal, making this a frustrating process. Submission process even between journals belonging to the same publisher is not streamlined as they treat each journal as an independent entity. It takes quite a while to enter author names and emails, abstract, title, funding, reviewer suggestions, and so on for every submission. Some journals provide a manuscript transfer service for the convenience of authors: If a paper is rejected, the journal suggests an alternative in the same publishing family so that authors can transfer all pertinent information and save time. However, this is not a default option, and if editors do not recommend another journal, authors cannot use manuscript transfer service unless the option is provided in the decision letter. Moreover, in most cases, the journals provide a transfer to one of their new journals or a new open access journal they have started. This only helps the publisher promote their new journals rather than helping the author. Journals should attempt to create a submission page where authors can easily submit to different journals of the publisher with the click of the button.

 A universal manuscript submission platform where authors can upload a file and choose which journal they wish to submit to, without having to enter the information over and over again in multiple websites for different journal resubmissions.

A universal manuscript submission platform where authors can upload a file and choose which journal they wish to submit to, without having to enter the information over and over again in multiple websites for different journal resubmissions.

The ideal solution to all these publishing woes is to create a single webpage for manuscript submissions to all journals. This might take some time to become a practical solution, but it is definitely a possibility, at least within the same publishing family. While a drop down menu of journals now exist, authors cannot choose another journal in the same family and use the same information he or she entered in the prior submission. Journals belonging to the same publisher use the same website, but yet do not allow information transfer between journals even if they specifically ask “has this manuscript been previously considered by any journal in this family”. The publication arena has seen many changes in recent years, and hopefully it will change for the better, and help authors spend less time on menial formatting and meta data input.

DNA nanowires, with a ‘silver lining’

A DNA double helix, stabilized by silver ions forms a long, thin nanowire.


We are surrounded by so many electronic gadgets every day. Everything from your favorite iPod to that miniaturized digital watch contain microchips and very thin wires and circuits. Scientists are always on the exploration for materials on the order of nanometers so they can use it to build futuristic devices, where a full computer can be jam-packed into a needle head. In a recent study published in Nature Chemistry, researchers report a silver nanowire created using a DNA template. In their study, the DNA double helix contained non-canonical base pairs (i.e. base pairing except the traditional A:T/G:C) stabilized by silver ions. The "metallo base pairs" have provided a strategy to create silver/DNA hybrid nanowires, much longer than any nanowire previously reported. This study adds to the development of molecular electronics, one of the current focuses of bottom-up nanotechnology.

In recent years, DNA has been used for drug delivery, biosensing, molecular computation, and in the development of nanoelectronics. DNA, in its natural form, lacks electrical conductance and is unsuitable for applications in nanoelectronics. So scientists use DNA as a template for creating metallic nanowires, as a means to increase its electrical conductance while creating thin nanowires (on the order of a few nanometers). Up until this study, nanowires based on DNA duplexes with metallo base pairs were short, with around ten contiguous metallobase pairs. It remained a challenge to create long nanowires containing such metal ions.

  Left : The pseudo-continuous duplex stabilized by silver ions.  Right : The non-canonical metallo base pairs seen in the crystal structure. From: J Kondo et al,    Nat. Chem.  doi:10.1038/nchem.2808 (2017).

Left: The pseudo-continuous duplex stabilized by silver ions. Right: The non-canonical metallo base pairs seen in the crystal structure. From: J Kondo et al, Nat. Chem. doi:10.1038/nchem.2808 (2017).

Tanaka and coworkers now address this challenge by creating DNA nanowires in which the duplex contains metal-mediated base pairs. In their study, they used a DNA dodecamer (a DNA strand with 12 nucleotides) and crystallized it in the presence of silver nitrate. The crystal contained DNA duplex units composed only of silver-mediated base pairs. They used X-ray diffraction to study the crystal structure of metal-containing DNA duplexes: the duplexes in this crystal was much similar to the traditional, and well known, B-form conformation, except that the base pairs were not A:T or G:C. What they found was four types of silver mediated base pairing: C–Ag–C, G–Ag–G, G–Ag–C and T–Ag–T. Tanaka's group had earlier reported the silver-mediated C-Ag-C metallo base pair, but the other three were observed for the first time. One other observation was that the duplex was stabilized by exclusive silver-mediated base pairing causing the adenine residues in the dodecamer to bulge out from the duplex. In the crystal, the DNA duplexes were connected end-to-end by the guanine overhangs that formed a G-Ag-G base pair between the duplexes. This "continuous" duplex thus is a long silver nanowire within the DNA duplex. The aspect ratio of these nanowires are in the order of 50000 (diameter of the largest crystals was 0.1 mm and width of the continuous duplex DNA is 2 nm) which is larger than most reported nanowires. We have to wait to see if these nanowires can actually support electron transport either in solution or in crystallo.

The metal-mediated base pairs also lead to interesting options for DNA nanotechnology and molecular circuits. One, it opens up more sequence design options: we might be able to use metal-mediated non-canonical base pairs. Second, the metallized DNA itself imparts additional characteristics on to such DNA nanostructures (electrical and optical properties, for example). The inter-duplex connection in this study is also provided by metal mediate base pairing. DNA arrays depend on base pair hybridization, and many motifs are designed with sticky ends as structural glue. So one could envision a “metallo sticky end” by using silver-mediated interactions between connecting units. With developments in DNA nanotechnology and the new results of metal-mediated base pairs, newer possibilities are awaiting the field of nanoelectronics.

Discussion paper: J Kondo, et al, A metallo-DNA nanowire with uninterrupted one-dimensional silver arrayNat. Chemdoi:10.1038/nchem.2808 (2017).

This post is based on my highlight in ChemBioChem: AR Chandrasekaran, DNA arrays with a silver lining. ChemBioChem. doi:10.1002/cbic.201700367 (2017).