Through the collaborative efforts of computer scientists and bioengineers hailing from Harvard University, it has been found that chemical reactions can be used as a form of code, especially in a class of artificial intelligence algorithms. Using this knowledge, “smart molecules”, can be programmed to perform specific functions. Researchers at Aarhus University have taken the first steps toward developing “nanorobots” able to deliver payloads of biomolecules. However, before we delve into the aspects of nanorobots, we have to talk about the basics.
So, What is Programming?
Computer programming can be best defined as “a vocabulary and set of grammatical rules for instructing a computer to perform specific tasks. It is composed of unique sets of keywords and a special syntax for organizing program instructions”. These programs have allowed humans to use millions of lines of code to do amazingly complex tasks with minimal amount of work required from the user. Now, similar things are happening with information-bearing molecules such as DNA and RNA. These can be used to control cell metabolism or to control biological development, which is when a single cell becomes an entire organism. Decision making will be carried out by chemical processes themselves.
In computer science, a programming language is used to detect an input, decide what the computer wishes to do with the given information, and return information that the user expects or needs from the input. A similar thing can be done with chemicals: a program can be written to help design chemical-reaction networks which will describe how chemicals, when synthesized, behave. Thus, molecules can be formed with specific responses to specific environments.In the therapeutic field of science, these networks can serve to deliver “smart” drugs, or to detect diseases at the cellular level and react accordingly to it. In order to achieve this, molecular control circuits need to be engineered to perform integrated sensing, computation and actuation.
|An example of a chemical program. A, B and C represent different chemical species.|
How Does “Programming Molecules” Work?
An example of a “smart drug” would be programmable chemical controllers made from DNA done byYuan-Jyue Chen and others. They report “a DNA-based technology for implementing the computational core of such controllers. [They] use they formalism of chemical reaction networks as a programming language and [their] DNA architecture can, in principle, implement any behavior that can be mathematically expressed as such”. These behavior are close to those that are exemplified in our bodies.
Organisms already have molecules that regulate cells and keep the body in check. These man-made programs are made to copy these functions, but to the programmer’s specific orders. Although not completely ready to be implemented in the medical field, this technique can be used to create molecules that self-assemble within cells and serve as sensors in the near future. If there are irregular or atypical changes within a cell, the input signals will warn the programming language. This in turn will try to modify the state until the cell starts to behave as the program originally intended it to.
|An example of how a Nucleic acid nanocontroller would respond to a change in input signals. A programming language determines whether or not the system has reached its target behavior, and if not satisfied, will try to modify the system until it reaches the target state. This target behavior is experimentally actualized.|
This method of “programming” molecules was utilized by Birgitta R. Knudsen and her group in “Temperature-Controlled Encapsulation and Release of an Active Enzyme in the Cavity of a Self-Assembled DNA Nanocage.”
How is the cage formed?
With this method, they were able to “program” DNA molecules such that they self-assembled into a specific shape, a truncated octahedron. Self-assembly is the result of a number of noncovalent forces, such as hydrogen bonds or van der Waals forces, taking place between molecules and forcing them to bond in certain ways. By creating DNA strands with specifically ordered structures, the intermolecular interactions could be manipulated in such a way as to create the desired product.
How does the cage open/close?
|Model of nanocage when closed (far left), open with
enzyme loaded (left), closed with enzyme loaded (right), and open with enzyme released (far right).
As can be seen in the figure, the shape of the nanocage varies with temperature. As deduced by the researchers, at 4 degrees Celsius the nanocage “closes”, whereas at 37 degrees Celsius it opens. One corner of the octahedron is held shut by four elements while at 4°C. However, as the temperature is raised towards 37°C, energy is added into the system, exciting the atoms of these elements. As these atoms gain energy and begin moving about frantically, their energy begins to overcome the intermolecular forces retaining their solid shape. At 37°C, the “melting point” of these elements, the four become liquid, losing their solid form. As a result, there is nothing left to hold the cage closed.
Due to the shape of these elements in their closed formation, they are referred to as “hairpin-forming regions.”
It’s no coincidence that the activation temperature of these cages is the same as the core body temperature for humans. The “melting” of the hairpin-forming regions is spontaneous only at 37°C. Thanks to this controllable property the nanocages can effectively hold biomolecules and release them in desired locations within the human body.
In hopes of learning more about this topic, we emailed the main director of this research project. Luckily we managed to get some answers from Oskar Franch, a student working on the project under Professor Birgitta R. Knudsen. The group is comprised of experienced researchers from across the globe, ranging from the Department of Biomedical Engineering of Duke University to the Department of Biology of the University of Rome to the Departments of Molecular Biology, Genetics, Pathology, and the Interdisciplinary Nanoscience Center of Aarhus University. Here is a sampling of our exchange.
What inspired you to develop these nanocages?
“The appealing thing with this nanocage is that in contrast to many other nanocages, this nanocage has a small and rigid structure. This means that nanocage retains its shape and material [and] can selectively be excluded or included.”
What was your [Oskar’s] part in this project?
“My primary work in this project so far has been to elucidate how many hairpin-forming regions are required to facilitate encapsulation. The next step in the project is to investigate the possibility of using the nanocage for drug delivery.”
What are some future goals/applications you have in mind for these nanocages?
“The primary hope for the nano-cage is to employ the cage for drug-delivery purposes. But there are multiple applications, another being to facilitate structural analysis. Most recently the cage has also shown promise as a mean of retaining proteins in a native [natural/unaltered] state, and this is indeed a very exciting prospect.”
In our next blog post we will address how intramolecular forces play a role in tricking the body into accepting prosthetic bones.
*Special thanks to Oskar Franch, a grad student working on this project, for answering some of our questions regarding the nanocages.