A New Step in Targeted Therapies: Molecular Automata Add Surface Labels to Cells

The coming generation of medical therapies will be distinguished from those of the past decades by their specificity: they will target only those cells that need to be destroyed, altered, or reprogrammed, rather than being indiscriminately infused into the body to hit all cells. In a world in which researchers cannot target specific cells, the development of therapies is focused on finding things that won't kill the patient. Treatments are deployed because they are just a bit more harmful to, say, cancer cells than they are to all other cells. This is, needless to say, no walk in the park for the patient.

A targeted therapy, on the other hand, will by design have few side effects. The method of destroying or altering targeted cells can be ramped up to optimal levels of effectiveness because it won't bleed over to impact many other cells. Indeed, with the addition of some form of targeting and delivery mechanism such as nanoparticles even the old chemotherapies for cancer can be turned into highly effective, low impact treatments that kill only cancer cells and don't make the patient sick at all.

This is the future, and not just for cancer treatments. So it's worth keeping an eye on research in the field of targeting and delivery, as any new methodology with a broad application has the potential to greatly impact the effectiveness of many types of medical therapy over the next ten to twenty years.

I noticed an example of this sort of thing today, wherein researchers are engaged in the first steps of building a generic cell labeling platform. Instead of incorporating the ability to detect surface markers into a delivery mechanism, it might be possible to standardize delivery systems to identify cells by a small set of constructed labels. Labeling technologies would perform the work of identifying specific cell types by their (very varied, very complex) surface chemistry, and then applying labels to those cells. So a treatment would be a two-step process in which cells are labeled, that result is validated, and then the therapy is applied, targeted to those labels. With these technologies, a standard set of labels becomes an API of sorts, enabling specialization of research and development into labeling and delivery camps, something that always speeds progress and reduces costs where it occurs.

Molecular robots can help researchers build more targeted therapeutics

In the new study, scientists have designed molecular robots that can identify multiple receptors on cell surfaces, thereby effectively labeling more specific subpopulations of cells. The molecular robots, called molecular automata, are composed of a mixture of antibodies and short strands of DNA. These short DNA strands, otherwise called oligonucleotides, can be manufactured by researchers in a laboratory with any user-specified sequence.

The researchers conducted their experiments using white blood cells. All white blood cells have CD45 receptors, but only subsets have other receptors such as CD20, CD3, and CD8. In one experiment, [researchers] created three different molecular robots. Each one had an antibody component of either CD45, CD3 or CD8 and a DNA component. The DNA components of the robots were created to have a high affinity to the DNA components of another robot. DNA can be thought of as a double stranded helix that contains two strands of coded letters, and certain strands have a higher affinity to particular strands than others.

The researchers mixed human blood from healthy donors with their molecular robots. When a molecular robot carrying a CD45 antibody latched on to a CD45 receptor of a cell and a molecular robot carrying a CD3 antibody latched on to a different welcoming receptor of the same cell, the close proximity of the DNA strands from the two robots triggered a cascade reaction, where certain strands were ripped apart and more complementary strands joined together. The result was a unique, single strand of DNA that was displayed only on a cell that had these two receptors.

The addition of a molecular robot carrying a CD8 antibody docking on a cell that expressed CD45, CD3 and CD8 caused this strand to grow. The researchers also showed that the strand could be programmed to fluoresce when exposed to a solution. The robots can essentially label a subpopulation of cells allowing for more targeted therapy. The researchers say the use of increasing numbers of molecular robots will allow researchers to zero in on more and more specific subsets of cell populations.

"The automata trigger the growth of more strongly complementary oligonucleotides. The reactions occur fast. In about 15 minutes, we can label cells." In terms of clinical applications, researchers could either label cells that they want to target or cells they want to avoid. "This is a proof of concept study that it works in human whole blood. The next step is to test it in animals."

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