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Courtesy: Shawn Douglas

Science


The term “cancer killing nanorobot” could conjure up all sorts of images, the best involving teeny tiny laser eyebeams.

What you wouldn’t expect is the illustration that pops up in Shawn Douglas’ slide deck, which looks more like a colorful rope basket split in half.

The fresh-faced assistant professor at the UC San Francisco School of Medicine is seated in his tidy office in Genentech Hall, the grand centerpiece of the university’s young Mission Bay campus, patiently walking me through the art and science of DNA design.

The software rendering in question actually represents coiled strands of DNA, nearly 200 of them twisted into just the right shape and texture to latch onto certain types of cells. Antigens on the surface that signal the cells are cancerous act as a kind of key that unlocks the structure, flipping it open like a clam shell and unleashing a drug that can bind with the aggressor cells and instruct them to self-destruct.

The promise is a highly targeted method of drug delivery, precision guided missiles that leave healthy cells alone — as opposed to the kill-everything-cluster-bombs of chemotherapy.

And here’s the interesting part: Douglas and his peers have actually produced the nanorobots and they appear to work. At least in cell culture flasks.

How they did it says a lot about where we are and where we’re going in synthetic biology, an emerging field that allows scientists to custom design DNA, proteins and organisms to carry out specific tasks. The tools and techniques have already delivered cheaper versions of drugs like Artemisinin and promise a long list of novel therapeutics, vaccines, biofuels, nano materials and more.

“You can almost run that question in reverse and say ‘what won’t (synthetic biology) affect?’” said George Church, a professor of genetics at Harvard Medical School and co-author of “Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves.”

‘Nature’s building blocks’

UCSF assistant professor Shawn Douglas

UCSF assistant professor Shawn Douglas

Douglas said that the ability to program “nature’s building blocks” the way we code computers represents the early stage of a revolution that could have more profound effects than information technology.

“We already have a proof of concept that exists,” he said, noting that billions of years of evolution have produced “examples of the power of self-assembly an order of magnitude more sophisticated and complicated than anything anyone has ever built with silicon.”

“We’re doing the really low-level, basic building blocks now,” he added. “But once we get tools in place to make it easier to program matter then things will really take off.”

Of course, there are plenty of scarier scenarios as well, where bad actors use the same technology to release deadly new viruses into the world or other sorts of bio-weapons. So science’s improving capabilities also prompt important questions about appropriate boundaries, procedures and regulations.

Stars and smiley faces

Douglas is soft-spoken, exceedingly precise in describing his work and quick to credit collaborators and fellow scientists.

He began drawing in DNA around 2005, as a graduate and then doctoral student at Harvard. He said he was following in the footsteps of pioneers like Nadrian Seeman and Paul Rothemund, who seized media attention after creating self-assembling “DNA origami” like stars and smiley faces.

See Rothemund’s TED Talk here:

Douglas collaborated with peers such as Hendrik Dietz and his advisor William Shih to construct increasingly complex, three-dimensional shapes like stacked crosses, railed bridges and gears with teeth.

Designing in DNA is every bit as complicated as it sounds, but basically it works like this: The double helix familiar from biology books folds and twists in predictable ways based on the order of nucleotides, the base pairs of adenine (A), cytosine (C), guanine (G) and thymine (T) that make up the genomic code. Those strands of DNA will, in turn, interact with other strands in equally predictable ways, at least under set conditions.

Once researchers figure out the order of nucleotides for the strands, they can simply order them from a DNA synthesis company, which will overnight them in vials. When the strands are allowed to intermingle in a kind of warm broth, they eventually bend, link and otherwise “self assemble” into the desired shape. Some strands act as scaffolding; others like staples.

To say these structures are microscopic doesn’t really get you there (unless you’re talking about the electron variety). There is a million times more DNA in every human cell than is contained in one of these shapes.

This animation approximates the self assembly process:


Ad hoc design

A critical challenge for the Harvard researchers was the growing complexity of the design process — and the mind-numbing task of translating three-dimensional images into thousands of As, Gs, Ts and Cs.

Some hacked through the work with open source digital drawing tools like Inkscape; other actually went with pen and paper.

“What we had in the lab was just an ad hoc design process,” Douglas said.

He decided to briefly set aside his PhD projects in favor of building an open source software tool, known as Cadnano, that automatically translates shapes into DNA code — effectively a compiler for biology. He previously studied computer science as an undergraduate at Yale, but had to teach himself how to program graphical user interfaces to create the application he wanted.

“I convinced myself I would break even on that effort eventually and if I shared it with the lab and the world, a lot of time would be saved on that tedious process,” he said.

Cadnano, design software for drawing in DNA.

Cadnano, design software for drawing in DNA.

It did pay off. In fact, researchers in the lab went from completing about one design a month to cranking out dozens. More importantly, it allowed them to take on much more ambitious structures, built for very specific purposes.

For his postdoc work, Douglas joined Church’s famed lab at Harvard. There he partnered with Ido Bachelet, who had earned his PhD in experimental pharmaceutics at Hebrew University in Israel. Together they began investigating the potential for using DNA structures for medical purposes — including those cancer killing nanorobots.

In early 2012, the researchers published their findings in Science, and the promising results caught the attention of synthetic biologists and the scientific press.

They had studied the impact of the structures in the presence of six types of cancer cells, including Burkitt’s lymphoma, T-cell leukemia and Neuroblastoma. The robots selectively targeted cancer cells in all cases, working particularly well with myeloid leukemia cells. And critically, they were generally more than 99 percent effective at remaining shut in the presence of healthy cells.

The next challenge

Whether or not these structures are, in fact, robots forces us to ask: what is a robot? The researchers’ point in using the term — beyond it being catchy — was that they are programmed and act autonomously. The key difference from the popular conception of robots, constructed from metal and coded in 1s and 0s, is that these versions are made out of DNA and told what to do with As, Cs, Gs and Ts.

But whatever you call the structures, researchers around the globe are now studying their potential in medicine.

Scientists at Duke University, the University of Rome and Aarhus University in Denmark recently created a “DNA nanocage” that could encapsulate and release an active enzyme. A team at Chonnam National University in South Korea developed a “Bacteriobot” that could target cancer cells in mice.

And just last month, researchers at the Wyss Institute at Harvard and Bar-Ilan University in Israel, including Bachelet, were able to get “DNA origami robots” to interact with each other inside living cockroaches. At Google’s “Solve for X” conference in February, Bachelet had discussed the potential of coordinated nanorobot teams to perform noninvasive surgery.

Douglas joined UCSF as an assistant professor in the fall of 2012, and continues his work on the nanorobots and Cadnano.

He has collaborated with design software giant Autodesk to improve the three-dimensional functionality of the tool by, among other things, allowing it speak with the company’s popular Maya 3D-animation application.

Seeing great promise in the field, Autodesk has been partnering with many researchers in synthetic biology, nano design and related areas, in a broad effort to develop a design software platform and interoperability standards.

“The programming of living things with digital tools is the most important technology humanity has created,” said Andrew Hessel, a distinguished researcher with San Rafael, Calif. company’s Bio/Nano Programmable Matter group.

The challenge that Douglas, and his team at UCSF’s Douglas Lab, are now tackling with the nanorobots is cost and quantity.

Synthetic DNA is expensive and they need a lot of it before they can consider studying the treatment’s safety and efficacy in animals. Specifically, they need to be able to produce about 1,000 times more of the material with the same amount of effort.

Douglas is the first to stress that until their nanorobots are tested on animals, much less humans, it’s impossible to say what they can really do. What happens in test tubes may or may not indicate what occurs inside warm bodies. So considerable work remains.

“It doesn’t mean anything until we have a patient who was terminally ill and can now say that they’re fine,” he said.

To learn more, check out Douglas’ video explainer of “bionanotechnology” below:

Update: This story has been updated to correct when Shawn Douglas began designing DNA and the name of his collaborator, Hendrik Dietz.

 



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