A Blog by Ed Yong

Genetic logic circuit makes cells self-destruct if they look cancerous

It is easy enough to make software do what you want it to. You could tell your email client to recognise and immediately delete any unwanted messages – say, any from your mother-in-law that contain the word “visit”, but not the word “cake”. Now, Zhen Xie from Harvard University and MIT has found a way of filtering undesirable human cells – in this case, a specific type of cancer cell – with similar ease.

Xie has developed a genetic “logic circuit” that prompts cells to kill themselves if the levels of five molecules match those of a cancer cell. Yaakov Benenson, who led the study, says, “In the long term, the circuits’ role is to act like miniature surgeons that can identify and destroy cancer cells.” That is a very long way off, but the study is a promising step in the right direction.

Xie worked with HeLa cells, a common line of cervical cancer cells taken from a tobacco farmer called Henrietta Lacks in 1951. Since then, they have become one of the most important tools in modern medicine. Xie identified five small molecules called microRNAs that act as a signature for HeLa cells, separating them from healthy ones. Two of the microRNAs are unusually common  in HeLa; three are unusually rare.

Next, Xie created five genetic switches that would only flip if their respective microRNAs were found at the right levels. The switches control a gene called Bax, an executioner that compels a cell to kill itself. If the circuit is introduced into a cell that carries the molecular signature of HeLa, all five switches flip, Bax is roused into action, and the cell automatically self-destructs.

Xie rigged his circuit so that Bax could be restrained by each of the three microRNAs found at low levels in HeLa cells. The gene would only activate if all three molecules were largely absent; any one of them could stay the executioner’s hand. Meanwhile, the two microRNAs that are common in HeLa actually lift restraints on Bax, by blocking genes that keep it in check. Again, the circuit needs high levels of both of these molecules. If either is absent, Bax is held back.

This clever set up means that all five switches must to be flipped before the executioner carries out it bloody work. The cell only dies if it meets every one of five conditions.  And Xie found that his circuit worked in practice. It activated Bax at far higher levels in HeLa cells and selectively killed them while leaving other lineages of laboratory cells unharmed.

It is a fascinating concept: tweaking cells so they self-destruct if they go too far down the road to cancer. Ehud Shapiro, who has worked with Benenson on “DNA computers”, says, “This work is an important step towards realizing the vision of a “doctor in a cell”, of programmable molecular-sized devices that can roam the body, equipped with medical knowledge.”

Xie now plans on testing the circuits in animals. But there’s still a long way to go before this approach could ever be used in practice to diagnose, treat or prevent actual cancers. For a start, the circuit isn’t perfect. It kills some healthy cells, and misses some HeLa ones, so Xie has some work ahead of him to minimise these false positives and missed cases.

There are other problems. Getting the circuit into a cell in the first place is a challenging technical problem. The standard approach is to use a virus to shunt the relevant genes into a native genome, but that could ironically increase the risk of cancer if the genes ended up in the wrong place.

It is also very hard to find groups of molecules that can accurately separate cancer cells from healthy ones. Cancer isn’t a single disease; there are hundreds of types and subtypes, each with its own characteristics. HeLa cell, for example, are indeed cervical cancer cells but they’re just one cell line. A panel of HeLa-specific microRNAs won’t necessarily single out all cervical cancers. For every type or subtype, scientists would need to discover another set of molecular markers.

Many people are working towards that goal , but the quest is fraught with problems.  People have identified many “biomarker panels” but few of them stand up to repeated studies, or have the accuracy necessary for a decent cancer test. However, Benenson points out that most of this research has focused on levels of molecules in blood or other bodily fluid, while he has focused on levels within cells themselves. That might make it easier to find consistent sets of molecular markers, although he admits that finding these will not be easy.

Despite these challenges, Xie’s study proves the principle that cells can be “programmed” with logic circuits that respond to combinations of molecules within them. You can imagine a future where our cells are loaded with simple biological computers that monitor our health at a molecular level. It’s a far-off future, but not an unreachable one.

Reference: Xie, Wroblewska, Prochazka, Weiss & Benenson. 2011. Multi-Input RNAi-Based Logic Circuit for Identification of Specific Cancer Cells. Science http://dx.doi.org/10.1126/science.1205527

6 thoughts on “Genetic logic circuit makes cells self-destruct if they look cancerous

  1. I love this. It’s stuff like this that explains so much at so many levels. Carl Zimmer wrote about cellular circuitry in E. coli cells in Microcosm, which explains how they grow their flagella, but only when needed. I think that was the biggest insight I had into cellular biology since reading a few chapters of The Blind Watchmaker by Dawkins.

    Of course, the next question in cellular programming has to be: can they run Doom?

  2. “It is easy enough to make software do what you want it to. ”

    Oh, that’s a good joke. Making software correct is notoriously difficult and almost always fails.

    If this new “genetic logic” really lives up to that comparison, I’m terrified.

  3. @Antti

    Thats not really a very fair comparison. Simple logic gates in computers do in fact work, all of the time. And this system is effectively equivalent to that – its no where near as complex as the high level software we have on our computers. Complexity does arise in this system as it obviously has to deal with fuzzy logic systems, but luckily we have the rest of molecular biology to give us tips on dealing with that.

    The delivery method is the other kink that will need a lot of work.

  4. The potential for this technology is huge, but the software analogy makes me uneasy. The company I work for once invested in spam-protection software. The software immediately deleted all the e-mails from my boss. After I made several attempts to program the software with rules, to make sure I received my messages, I had to turn the software off because it was still deleting the wrong things. It occurs to me you would need a high level of trust in the “software” marketer for gene therapy. For their own protection, people will need to start self-educating on a high level in the field of genetic engineering. Either that, or trust the marketers that the product will do what it says it will.

  5. @Myles

    Sure they work, now. Sixty years ago when they were new, they didn’t, not particularly reliably. And writing correct software has always been hard, even in the early days when the programs and the problems solved were trivial compared to those of today. But I take your point – the comparison offered in the article is not far. Which is, truly, a relief.

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