Designer Proteins: Advances in Bioengineering

Quick Summary of the Economist's report on advances in engineering DNA to produce custom proteins for use in cancer treatment and other applications:

WHO IS INVOLVED?

Dr. Floyd Romesberg, of Scripps Research laboratory in La Jolla, California and his team have developed a new protein engineering technique. Their spin-off firm, Synthorx, is trying to commercialize this technique to produce designer signaling proteins that enhance the body's natural immune response to tumors.

HOW THIS WORKS

Immune System Background

The different types of white bloods cell that make up the immune system signal to each other to coordinate and regulate their immune responses. These signals, in the form of proteins, are secreted from one white blood cell and then bind to another to stimulate or depress activity.

Interleukin-2 Signaling

Interleukin-2 is one such protein that binds to immune system attack cells and regulates their activity. A synthetic version of high doses of this protein has been used as a cancer treatment that stimulates the immune-system-attack-cells to engage with tumors. However, because Interleukin-2 naturally forms a strong bond with the surface of the immune system attack cells, the immune response persists to the point of damaging the walls of blood vessels, causing plasma to leak out. "When this happens in the lungs, the patient may drown. As [Synthorx's boss] puts it, some people have been cured of their cancers thanks to interleukin-2, 'but they have to live to tell the tale'."

Engineering a Better Version of Interleukin-2

Dr. Romesberg and the team were faced with the challenge of synthesizing a version of Interleukin-2 that does not form such a strong bond with immune system attack cells. In order to alter features of the protein, the team needed to alter the DNA blue prints that code for the amino acids, which in turn, form protein (a protein is just a chain of amino acids).

Step 1: New DNA Base Pair Required

Considering that previous DNA-protein altering techniques only succeeded in adding two (2) novel amino acids to the catalog of 20 naturally occurring amino acids, the team needed to add a whole new DNA base pair (outside the two naturally occurring pairs of A (adenine), C (cytosine), T (thymine) and G (guanine) that make up the DNA of all living organisms) that would code for the attachment of novel amino acids to the chain of amino acids that make up a protein.

Dr. Romesberg already had, in 2014, synthesized a new, unnatural, base pair, dubbed X and Y, and successfully added them into the genome of E. coli. A long as a cell was supplied with enough supply of X and Y for cellular reproduction, the cell and its descendants could sustainably produce the novel proteins.

The team used the new X-Y base pair to code for an Interleukin-2 protein that instead of binding strongly on three features of the surface of the immune system cell, binds only to two features plus stray polyethylene glycol (PEG) molecules that are introduced into the cell. This weaker binding takes away the toxicity of the high doses of Interleukin-2 that are needed to produced anti-tumor effects.

"Tested on mice, the modified molecule has exactly the desired anti-tumour effects. Synthorx plans to ask permission for human trials later this year."

Synthorx "sees THOR-707, as the new interleukin is known, as just the beginning. Synthorx already has synthetic versions of several others in the pipeline. And the wider possibilities are endless. The beauty of Dr Romesberg’s system is that it works without disrupting a cell’s normal function, making it possible to hijack cells’ factory-like properties to produce almost any “designer” protein. These might have properties not normally seen in organic molecules—semi-conductor proteins that can be woven into soft materials, perhaps."

The possibilities are tremendous...