Synthetic “Alien” DNA Provides Opportunities for Disease Diagnostics and Treatment
NASA-funded research offers clues to life on Mars and new technologies for enhancing disease detection.
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Diagnostic tests for infectious diseases often involve identifying “alien” life – in the form of viral DNA – within a patient. Detecting life on Mars may also rely on DNA detection strategies but, unlike Earth-borne viruses, this alien DNA may look quite a bit different to what we are used to.
To help understand how DNA may have evolved on other planets, Dr. Steven Benner, director of the Foundation for Applied Molecular Evolution (FfAME) and Firebird Biomolecular Sciences, and his partners went into the laboratory and synthesized DNA-like molecular systems with more than four nucleotides. This research was funded in part by NASA’s Astrobiology Program.
The resulting synthetic or “alien” DNA can encode proteins, replicate and even evolve under laboratory-controlled conditions. This controlled evolution can be used to develop synthetic DNA molecules that bind to targets important to diseases, such as COVID-19 viruses or cancer cells.
Technology Networks spoke to Benner to learn more about what synthetic DNA can tell us about life on other planets and how this technology could be harnessed to improve disease diagnostics and treatment.
Blake Forman (BF): Can you tell us more about synthetic “alien” DNA?
Dr. Steven Benner (SB): Natural DNA is built from four nucleotide building blocks. These are adenine (A), cytosine (C), guanine (G) and thymine (T). DNA molecules can bind to complementary DNA molecules by simple rules: A pairs with T, and G pairs with C. DNA thus encodes information that is translated into proteins that determine every feature of our biology. DNA can also evolve by swapping nucleotides in its four-letter code with other nucleotides. This leads to proteins built from different amino acids – mutations that can improve or damage fitness. Those that improve fitness allow an organism to evolve in response to changing environments, and this evolution is at the center of natural biology.
The structure of natural DNA emerged by a process constrained by prebiotic chemistry; the chemistry that occurred before life emerged on Earth.
Furthermore, the structure of DNA was influenced by 4 billion years of evolution since life emerged. Thus, there is no reason to believe that the DNA that supports Earth's life is the same in its chemical details as the DNA that might support alien life.
We have questioned for some time what DNA might look like if it were created by intelligent designers who are free from the constraints of prebiotic chemistry and natural history. Asking that question has led to synthetic forms of DNA that are built from more than four building blocks.
We have shown that as many as 12 building blocks are possible in DNA made in the laboratory, adding the letters P, Z, S, B, K, X, V and J to the DNA "alphabet”. We have also shown that these can encode proteins, be replicated, and evolve in laboratory-controlled conditions to create new functions. Pairs are also formed in this "artificial evolvable genetic information system" following simple rules: P pairs with Z, S pairs with B, K pairs with X and V pairs with J.
BF: What are the benefits of synthetic DNA over traditional DNA in disease detection?
SB: Synthetic DNA can be used across medicine. Here are just three of the applications of synthetic DNA:
1. As a molecular recognition system that does not interact with natural DNA
Because of its simple rules, DNA has been used to assemble structures that signal the presence of the DNA of a bacterium or a virus. However, these signaling structures, because they are built from A, T, G and C, can interact destructively with DNA and RNA that are present naturally in a patient. Thus, when people tried to use nanostructures built from A, T, G and C to signal the presence of nucleic acids from HIV, hepatitis B, hepatitis C and other viruses, the patient's DNA interfered. Synthetic DNA built from extra building blocks can signal without interference. This allowed the detection of eight HIV virus particles per milliliter of patient blood, a very sensitive assay. The same is true when trying to detect molecules from a coronavirus, or mutated molecules from the human genome where the mutations have caused cancer.
A re-invented DNA placed into the hands of researchers, diagnosticians and physicians gives them all the power of molecular evolution without the constraints of prebiotic chemistry and natural history.
2. As an evolving system
An evolving system with 12 building blocks has many more capabilities than an evolving system with 4 building blocks. Thus, if we place our expanded DNA under selective pressure to bind, for example, to specific cancer cells, the binders that emerge from 12-letter DNA evolution are much better than those that emerge from 4-letter DNA evolution. Evolution gives us better receptors, ligands, catalysts and drugs when the evolving system is designed intelligently by chemists, rather than relying on prebiotic chemistry followed by random evolution during a particular natural history.
3. In drug targeting as a delivery system
Synthetic DNA can evolve under selective pressure to do specific tasks. Here, the synthetic biologist chooses the task, challenging collections of synthetic DNA molecules to compete to perform the task better and better. One of these tasks is to get synthetic DNA to bind selectively to specific cancer cells. The combination of drugs and targeting synthetic DNA molecules could deliver instructions to certain cancer cells, killing them specifically.
BF: What were some of the challenges faced when creating this synthetic DNA and how did you overcome these?
SB: We had to develop chemistry to make the extra letters in the expanded DNA alphabet.
We then had to create enzymes that would replicate the expanded DNA so that it could make copies of itself and evolve. This required campaigns of protein engineering.
We also had to develop new tools to sequence DNA with 12 letters. We have been working with groups from the University of Washington to do this, as well as doing work in our laboratories.
Lastly, we had to develop a system where synthetic DNA can evolve to get molecules that, for example, bind to specific cancer cells, inactivate specific RNA molecules or prevent toxins from acting. This required the skills of many talented coworkers working at the Foundation for Applied Molecular Evolution.
More difficult than all these technical challenges has been getting peers to understand the potential of synthetic DNA. Even though our synthetic DNA has delivered over $1.3 billion in diagnostics applications, National Institutes of Health (NIH) peer reviewers still hesitate to recruit these new materials to address problems in human medicine.
BF: How has being part of NASA’s spinoff program helped to enable the research and development of this technology?
SB: None of this medical potential would have been realized without NASA. NASA is charged with setting missions to discover alien life in the cosmos, on Mars, Europa, Enceladus and other locations in our solar system, as well as in the galaxy on planets circling other stars. These other planets may have had different prebiotic chemistry and different natural history. Accordingly, DNA that supports life that we might find in the cosmos may not have the same structure as the DNA in our bodies. Synthetic biology allows us to explore the universe of possible genetic molecules that NASA missions might find.
It has also led us to develop new theories about what genetic molecules look like in general. Of particular importance has been the polyelectrolyte theory of the gene, which holds that the information needs of life in water anywhere in the cosmos will be met by a polymer as a repeating backbone charge.
Had we relied solely on NIH funding, very little of this technology would have been developed. By pursuing this basic science activity, the result has been a technology with broad implications for health and disease.
BF: What impact do you hope synthetic DNA technology will have on disease diagnostics in the next two years?
We have developed this and other technology platforms that will allow clinicians to detect 100 or more different pathogens in a single sample. This "all diseases in one sample" diagnostics platform is being developed now with the help of the National Institute of Allergy and Infectious Diseases. We are presently looking for commercial partners to help us bring this to the market to help patients.
However, we expect in the next two years to do far more than have an impact on disease diagnostics. Because of the evolving nature of synthetic DNA, we can create synthetic DNA with therapeutic potential. Again, we are looking for commercial partners who will help move this technology through what is prosaically called the "valley of death" that separates advanced basic research from products that help patients and cure diseases.
Dr. Steven Benner was speaking to Blake Forman, Senior Science Writer for Technology Networks.
About the interviewee:
Credit: Photo by Brian Cory Dobbs.
Dr. Steven Benner obtained his BSc and MSc in molecular biophysics and biochemistry at Yale University and his PhD in chemistry at Harvard University. He has been a professor at Harvard University, ETH Zurich and the University of Florida, where he was the V.T. & Louise Jackson Distinguished Professor of Chemistry.
In 2005, Benner founded the Foundation for Applied Molecular Evolution and The Westheimer Institute of Science and Technology (TWIST). He also founded several biotechnology companies, and his work has delivered diagnostics products that are widely used in medicine and ways to produce new classes of therapeutics. He has also been active in the fields of paleogenetics and astrobiology.
