Using computational genetic engineering, researchers at the Technical University of Munich (TUM) say they have invented a method of killing any type of virus. The researchers say they have demonstrated their solution on previously incurable hepatitis-B viruses, and are next aiming at the coronavirus.
The deoxyribonucleic acid (DNA) origami base-pair key-in-lock method they devised yields sphere-like icosahedral shells that kill viruses by clamping around each virion (the complete, infective form of a virus outside a host cell) until it is dead, dead, dead.
"Computational methods are an integral part of our work, from the initial design phase to the data processing for the final cryogenic electron microscopy," explains Hendrik Dietz, a professor of biomolecular nanotechnology at TUM. "In one way or another, all members of my team are using computer modeling."
Shawn Douglas, a professor of molecular engineering at the University of California at San Francisco, said the work by Dietz and his team "is a remarkable demonstration of the power and versatility of DNA origami hierarchical assembly by non-covalent shape complementarity, a method that was also pioneered by the Dietz Lab. These new icosahedral shells are beautiful and inspiring artifacts of molecular engineering. I am excited to see how the team and their collaborators can adapt this system for in vivo applications in the coming years."
The method uses a combination of software engineering, computational chemistry, and complementary DNA base-pair key-in-lock scaffolding to create icosahedral "traps" that snap shut around a target virus, isolating it harmlessly from both infecting and duplicating, and resulting in its eventual death.
The genetic engineering involved in the process does not tamper with human DNA; instead, the researchers use the universal building blocks of DNA—synthetic versions of the nucleotides cytosine, guanine, adenine, and thymine. A "virus trap" composed of locked-in-place isometric triangles is constructed in a spherical shape. A specific combination of nucleotides is first modeled in simulation to be the correct size to handle the target virus, then constructed using synthetic DNA from scientific laboratory suppliers. A coating is then inserted into the shell's interior to trap the virus inside, and a cap is added to block its exit. In practice, the virus victim's blood is flooded with the traps, which safely capture the individual virions and destroy them.
Dietz' TUM lab used a battery of software to model, simulate, validate, construct, and test prototype traps, the first of which were designed for hepatitis-B. The virus traps were tested in vitro (in a test tube or elsewhere outside the body) and were observed to be capable of trapping a targeted virus through the use of single-particle cryo-electron microscopy, which harnesses computationally intensive machine learning algorithms, according to Dietz. Subsequent in vivo (within a living organism) testing on mice showed the DNA-origami traps were capable of targeting individual virions inside the body, disarming them without disrupting bodily functions, and finally destroying them with natural immunological mechanisms. Human trials, however, are years away.
Dietz said the interior of the shells were coated with "antibodies specific for the hepatitis-B virus. You can think of the shells as a generic platform; depending on your selection of inner coatings, you can 'program' them to be specific for a user-defined target virus."
To ease the future work of applying this virus-killing methodology to all the viral strains that plague the human condition, the researchers "pre-engineered" a computer library of shell designs with different internal diameters. Depending on the size of the next target virus, the appropriate shell designs are available on hard disk, ready to be constructed with synthetic DNA, then functionalized with the appropriate antibody coating.
In addition to hepatitis-B, the researchers have already tested the methodology on viruses associated with maladies such as adenocarcinoma, a type of cancer for which viruses are a major risk factor, albeit only in vitro cell cultures. Aside from tackling coronaviruses next, there are many other acute viral infections that today can only be prevented by vaccines, but for which there are no sure-fire treatments after infection has occurred. The flexibility of the virus-killing method holds promise for the treatment of even the most dangerous viruses.
The Dietz Lab is working with Brandeis University's Fraden Lab to move from proof of concept to mass-production capabilities for constructing traps for all sorts of virus.
"Dynamical simulations of our model made predictions for how the assembly kinetics (shells assembled as a function of time) depends on the subunit concentration and strength of interactions between subunits. The simulations show that overly strong interactions lead to poor assembly (incomplete or malformed shells), as was seen in the experiments," said computational scientist Michael Hagan, a professor at Brandeis University. "The simulations also predict that certain sets of subunit interactions lead to highly efficient assembly pathways in which subunits assemble hierarchically (into small multi-subunit clusters, which then assemble into complete shells). We are working with the Fraden lab and the Dietz Lab to experimentally test this prediction."
R. Colin Johnson is a Kyoto Prize Fellow who has worked as a technology journalist for two decades.
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