Synthetic Biology is on its Way to Treating Human Disease

Synthetic biology has definitely gotten generous helpings of hype recently, so much so that it's easy to confuse speculation with data-backed results. I recently read a review of the clinical applications of synthetic biology¹ and was surprised by how much progress has already been made!

Human health applications are particularly difficult because bringing new technology into the clinic lies at the end of a long, arduous journey involving clinical trials, government certification, and care provider education. Here's a "review of a review" on the most impressive steps synthetic biology has made toward improving human health.*

Bacteria and the human body are both friend and foe. Some bacteria conspire against us to cause severe illness; others live harmlessly inside us, even playing crucial roles in maintaining our health. Perhaps the most pressing challenge in our fight against pathogens is the arms race between modern medicine and antibiotic resistant bacteria. Ordinary natural selection, aided by poor healthcare management and patient noncompliance, has created a global crisis where pathogens are evolving resistance to our treatments.

Part of the problem is that invading bacteria collude to build protective biofilms that create a physical barrier to antibiotics. In a project from Collins's own lab, investigators successfully engineered the T7 phage, a virus that infects E. coli, to degrade biofilms. The viruses invade E. coli cells and hijack their protein synthesis machinery, churning out viral proteins. The engineered version of T7 also contains a gene coding for the enzyme DspB, a molecular wrecking ball that destroys biofilm. With their fortress destroyed, a whopping 99.997% of the E. coli in Collins's experiments were killed by the engineered phages.

Antibiotic resistance is a huge problem, but cancer is undoubtedly one of the most challenging problems facing modern medicine. We are limited to treatments with broad, debilitating side effects, leading the review's authors to call for "new cancer treatments that precisely distinguish between diseased and healthy cells." One enticing possibility is programming bacteria to invade tumors, while leaving healthy tissue alone. Since we already have permanent bacterial populations on and in us (the "microbiome,") maybe we could introduce similar, mutant bacteria programmed to be on the lookout for cancer and, if it appears, destroy the rogue cells.

A lab at UCSF programmed E. coli to invade mammalian cells under hypoxic conditions, a rough tumor indicator. A different study improved on this by programming the invading E. coli to silence a colon cancer gene (CTNNB1), inhibiting tumor growth. The E. coli express a small RNA molecule that binds to the CTNNB1 mRNA, marking it for destruction. Human colon cancer cells grafted under the skin of lab mice were effectively targeted by injecting the engineered E. coli, an intriguing early step.

A third study called on E. coli in their usual environment: the intestines. The authors programmed E. coli to produce signaling molecules recognized by Vibrio cholerae, the bacterium that causes cholera. These signaling molecules prevent the V. cholerae bacteria from producing toxins that cause infection. Mice fed the reprogrammed E. coli were much more likely to survive a subsequent V. cholerae exposure.

Synthetic biologists have become somewhat entrenched in E. coli, not too surprisingly, since it was inherited from molecular biology. Ultimately we want to broaden our horizons, taking advantage of the fact that organisms have carved out particular niches. While we could program E. coli to produce energy through photosynthesis, organisms like algae are much better suited to the task! However, E. coli is quite well suited to operating in the human gut, so charging it with tasks like fighting off cholera makes a lot of sense.

Yet, the holy grail would be to program our own cells directly. As we learn more about human disease-and the loopholes exploited by pathologies-we can devise molecular solutions to combat the problems. It's a long way off, but given the promise of stem cell technologies, there's a lot to be optimistic about.

Image Credits: Figures from Ruder, Lu, & Collins, 2011. In order of appearance: Fig. 2B, Fig. 3, Fig. 1

Reference:

1. Ruder, W. C., Lu, T., & Collins, J. J. Synthetic Biology Moving into the Clinic. Science 333, 1248–1252 (2011).

* Throughout I describe studies as summarized by Ruder, Lu, & Collins (2011). If you are interested in looking at an original paper, you will find the reference there.