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DNA: From blueprint to blank slate

In the half-century since its structure was identified, DNA has become one of the most powerful and versatile tools in biotechnology

By Lindsay Brownell

DNA has come a long way since it was first described in 1896 by Swiss chemist Friedrich Miescher. So much so, in fact, that in 2003 the US Congress designated April 25th National DNA Day to commemorate the successful completion of the Human Genome Project that year, and the discovery of DNA’s double helix structure in 1953.

Since then, DNA has become an incredibly valuable tool for a wide variety of uses, including healthcare, agriculture, and even data storage. Despite all that we have learned about DNA’s structure and functions, we still do not fully grasp all of its idiosyncrasies. We know that the letters of its “alphabet” (A, G, C, and T) are the genetic code that contains all the instructions for creating and maintaining a functional living organism, and we have uncovered what many of the “words” (genes) that can be created with those letters mean. But many mysteries about DNA remain, and scientists are continuing to probe and solve them.

Nonetheless, what we have discovered about DNA so far has been sufficient to enable a host of groundbreaking insights and technological discoveries that have improved and will continue to improve quality of life and solve difficult problems. While humans have been using biotechnology in various forms since the dawn of civilization (such as fermentation and selective animal breeding), unlocking the genetic code galvanized the rise of the biotech industry as a global powerhouse of innovation. Read on to learn about how the Wyss Institute’s leaders are harnessing the power of DNA to shape our future.

Cracking the genomic code cheaply

DNA: From blueprint to blank slate
Sequencing molecules of DNA to determine the order of As, Gs, Cs, and Ts along their length was time-consuming and expensive when the Human Genome Project began in 1984. Now, thanks to innovations created by Wyss Core Faculty members George Church and David Walt, it’s cheap and commonplace. Credit: Shutterstock

The task of sequencing the 3.2 billion base pairs in the human genome seemed like a Herculean task until George Church, Ph.D., now a Core Faculty member at the Wyss Institute and Professor of Genetics at Harvard Medical School (HMS), developed the first direct genomic sequencing method. This method was used to generate the first full genome sequence of an organism (the infectious bacterium Helicobacter pylori) in 1984. He helped initiate the Human Genome Project the same year, capitalizing on this innovation to allow the first draft of the human genome to be completed in 2000.

While human genome sequencing was now possible, it was still astronomically expensive. That changed when David Walt, Ph.D., Wyss Core Faculty member and Hansjörg Wyss Professor of Biologically Inspired Engineering at HMS and Brigham and Women’s Hospital, invented a self-assembling bead technology that could be used to create microwell arrays for single-molecule detection and analysis. In 1998 he co-founded Illumina, Inc. to commercialize the technology, which has revolutionized the process and established next-generation sequencing (NGS) as the new gold standard method. This advance, along with Church’s ongoing innovations in fluorescent, nanopore, and in situ imaging for NGS, has dropped the cost of DNA sequencing and genotyping nearly a millionfold over the last 20 years. Illumina’s NGS platform is now the most widely used worldwide.

But cheap, easy sequencing was just the beginning. Scientists could “read” a full human genome, but didn’t know what most of it actually said. Since then, countless hours have been spent in labs around the world decoding those 3.2 billion letters, revealing some surprises. For example, the ~20,000 distinct genes in the human genome represent only about 1-2% of the total number of pairs in human DNA. The vast majority of our entire genome doesn’t directly produce the proteins our cells need to function. To figure out what it does do, the Human Genome Project initiated ENCODE, or the Encyclopedia Of DNA Elements, in 2003, which is still ongoing. Thanks to ENCODE and other efforts, scientists have begun to make real strides in understanding the function of our DNA.

Editing the book of life

DNA: From blueprint to blank slate
Bacteria can be genetically engineered so that they produce a signal, such as a color change, in response to the presence of a target molecule. These microbes could be used to monitor and report on the health of the human gut. Credit: Wyss Institute at Harvard University

But, as scientists are wont to do, they wondered if they could not only read existing DNA, but “write” their own genetic instructions as well, a process that became known as synthetic biology. The discovery of the CRISPR-Cas9 system revolutionized synthetic biology by enabling DNA to be edited quickly and precisely, and it has been used by Church’s group to modify the pig genome in 62 places at once in an effort to create transplantable organs that are more compatible with the human body. While many people are rightfully wary of the idea of rewriting the genes of humans and animals, synthetic biology today is largely focused on microbial DNA, and has the potential to create many useful tools and products.

One of the major benefits of DNA is that it is the “language of life,” allowing researchers to harness the many advantages of living systems. Wyss Core Faculty members Pam Silver, Ph.D. and Jim Collins, Ph.D. have been instrumental in the development of synthetic biology, and their labs are recognized as leaders in efforts to engineer biological systems to perform useful tasks. Among the Silver group’s more recent projects is Circe, a Wyss Institute project that is genetically tweaking the metabolism of bacteria to allow them to consume greenhouse gases rather than their normal food source of sugar, and use those gases to produce fatty acids that form the basis of plant-based fats and biodegradable plastics. Her lab at HMS, where she is the Elliot T. and Onie H. Adams Professor of Biochemistry and Systems Biology, has also engineered the genes of microbes found in the human gut so that they can sense and respond to inflammation, providing real-time monitoring of intestinal health.

DNA: From blueprint to blank slate
Freeze-dried cell-free reactions are shelf-stable and functional at room temperature, and can be activated with the simple addition of water. Here, they are embedded into paper to create a cheap, sensitive diagnostic device that can be used without the need for expensive lab equipment. Credit: Wyss Institute at Harvard University

While modifying the DNA inside of living organisms has its advantages, several Wyss faculty members are experimenting with what it can do outside of its normal environment. Collins and his group at MIT, where he is the Termeer Professor of Medical Engineering & Science, have invented a way to extract the molecular machinery that cells use to read and express their own DNA to create freeze-dried cell-free biological reactions. These reactions, when combined with a fragment of DNA and water, produce the proteins that the DNA fragment encodes – no living cell needed. Collins’ lab has created synthetic genetic circuits that allow them to detect the presence of a given piece of DNA or RNA (such as SARS-CoV-2), and use the freeze-dried cell-free components to create a signal in response. These sensors can identify a wide variety of biological substances of interest without the expensive equipment required to keep cells alive, eliminating much of the cost and complexity of microbe-based technologies. Their technology has been licensed to Sherlock Biosciences, which used it to create the first FDA-authorized CRISPR-based diagnostic for COVID-19.

In addition to their ongoing work to optimize genomic sequencing and use synthetic biology to change the functions of microbes, Church’s lab is pushing DNA beyond the biological realm and exploring its use as a digital data storage device. While it might seem strange, DNA is actually a very good storage medium: it takes up virtually no space, is extremely resistant to degradation, and can store a lot of information relative to its size. The lab even used the now-famous CRISPR-Cas9 gene editing system to encode a short film into the DNA of bacteria, then extracted and sequenced the DNA to recover the data and played the film back.

Postdoctoral Fellow, Henry Lee, presents a Wyss Institute Validation Project that is developing a sustainable, low-cost approach for writing large amounts of digital information in DNA. This could one day replace current data storage methods, which are energy intensive and use large amounts of nonrenewable resources. Credit: Wyss Institute at Harvard University

Molecular-scale machines

DNA: From blueprint to blank slate
DNA is capable of self-assembling into a variety of shapes based on its sequence of nucleotides, and can be used to create various shapes for completing tasks at the nanoscale. Credit: Wyss Institute at Harvard University

Not only is DNA useful as an orchestrator of biological processes and a medium for information storing, its unique physical properties are also being harnessed by Wyss Institute members working in a new field called molecular robotics. Each nucleotide base always binds to its complementary base when given the opportunity, and single-stranded (unbound) DNA strands tend to fold in predictable patterns, meaning that DNA molecules can be programmed to self-assemble into specific shapes. In these experiments, the DNA sequences do not code for proteins, but are used to construct customized nanoscale machines that can perform a variety of tasks too tiny to be done by human hands.

Core Faculty member and Professor at HMS and Dana-Farber Cancer Institute, William Shih, Ph.D. and his lab are using DNA’s self-assembling capabilities to construct three-dimensional shapes made from folded strands of DNA, including nanostructures that can encapsulate and deliver drugs. They have created DNA-based nanoparticle vaccines that display tumor antigens and immune-boosting adjuvant molecules with specific shapes to maximize their efficacy. His team has also been able to weave strands of DNA together to create long “nanoribbons,” which can grow up to tens of micrometers in length, with a mass almost one hundred times larger than a typical DNA origami. These ribbons could be used to detect minute amounts of a target molecule for diagnostics.

DNA: From blueprint to blank slate
DNA-PAINT (left) creates much more detailed microscopy images than standard methods (right), allowing scientists to peer more closely into the phyiscal structure of life. Credit: Wyss Institute at Harvard University

Another Core Faculty member of the Wyss Institute’s Molecular Robotics Focus Area and HMS professor, Peng Yin, Ph.D and his team are harnessing DNA’s base-pairing structure for a number of different applications. One of their technologies, called DNA-PAINT, produces a flash of fluorescent light whenever a single “probe” strand of DNA binds to its complementary “target” DNA strand in a sample. DNA-PAINT dramatically improves the accuracy of microscope images, and has been licensed to Ultivue. Another technology called toehold probes, enables the detection of DNA sequences down to the single nucleotide level, and is being commercialized by Torus Biosystems and NuProbe to help diagnose cancer and infectious diseases.

Gel electrophoresis, a common laboratory process, sorts DNA or other small proteins by size and shape using electrical currents to move molecules through small pores in gel. The process can be combined with novel DNA nanoswitches, developed by Wyss Associate Faculty member Wesley Wong, to allow for the simple and inexpensive investigation of life’s most powerful molecular interactions. Credit: Wyss Institute at Harvard University

To allow researchers around the world to reap the benefits of DNA-based analysis methods without expensive equipment, Associate Faculty member and Associate Professor at HMS and Boston Children’s Hospital Wesley Wong, Ph.D. and his colleagues have created DNA nanoswitches. When DNA nanoswitches bind to a target biomarker, such as a protein or mutated DNA fragment, they change their shape. This shape change can be observed using simple and inexpensive gel electrophoresis, yet provides rapid and highly sensitive detection. This approach can be used to engineer diagnostic tests that work in a variety of different settings, including low-resource areas. The Wong lab has recently been adapting their nanoswitch detection technology to meet diagnostics challenges posed by the COVID-19 pandemic. DNA nanoswitches can also allow researchers to analyze individual molecules’ mechanical properties using a benchtop centrifuge, making single-molecule force measurements accessible to more scientists.

The explosion of uses for DNA over the last half-century since its double-helix structure was discovered is a testament to the power of harnessing billions of years of evolution to solve some of humanity’s most pressing problems. Whether in research labs, pharmaceutical companies, or hospital settings, it is clear that DNA will drive technological innovation for decades to come, and the Wyss Institute looks forward to continuing to help uncover DNA’s secrets and abilities.

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