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Improved molecular targeting via cellular automata

In simplest terms, cellular automata can be thought of as groups of ‘cells’ in which the state of an individual cell will flip depending on the states of its neighbors. A ‘cell’ can be a pixel, a molecule, etc. The mathematical rules associated with cellular automation are complex and have been applied to fields as diverse as computation and cryptography to patterns of pigment in seashells. Now researchers at Hospital for Special Surgery (HSS) in New York City and Columbia University have used an analogous system of molecular cascades to select for particular biological surfaces, taking new steps towards medical therapeutics that use multiple recognition events to improve molecular targeting. The work is published in Nature Nanotechnology, and the press release was reprinted at MedicalXpress.com:

Many drugs such as agents for cancer or autoimmune diseases have nasty side effects because while they kill disease-causing cells, they also affect healthy cells. Now a new study has demonstrated a technique for developing more targeted drugs, by using molecular “robots” to hone in on more specific populations of cells.

Drugs can target disease-causing cells by binding to a receptor, but in some cases, disease-causing cells do not have unique receptors and therefore drugs also bind to healthy cells and cause “off-target” side effects.

Rituximab (Rituxan, Genentech), for example, is used to treat rheumatoid arthritis, non-Hodgkin’s lymphoma and chronic lymphocytic leukemia by docking on CD20 receptors of aberrant cells that are causing the diseases. However, certain immune cells also have CD20 receptors and thus the drug can interfere with a person’s ability to mount a fight against infection.

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.

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, HSS 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.

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. In computer programming language, the molecular robots are performing what is known as an “if yes, then proceed to X function.”

“The automata trigger the growth of more strongly complementary oligonucleotides. The reactions occur fast. In about 15 minutes, we can label cells,” said Maria Rudchenko, M.S., the first author of the paper and a research associate at Hospital for Special Surgery. 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,” said Dr. Rudchenko. “The next step is to test it in animals.”

-Posted by Stephanie C

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