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Gang-yu Liu Discusses The Construction of DNA Nanostructures

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At A Glance

Gang-yu Liu

Associate Professor, Department of Chemistry, University of California, Davis

Experience: Associate Professor, Department of Chemistry, Wayne State University

PhD, Princeton University: Atomic scattering from thin film surfaces

Postdoctoral fellow, University of California, Berkeley: Scanning probe microscopy

Recently published a paper in Nano Letters entitled “Production of Nanostructures of DNA on Surfaces”

 

You recently published a paper on producing nanostructures of DNA on surfaces. How do you go about creating these nanostructures?

The idea is actually very simple. We have a very flat surface, we cover it with an organic monolayer, and you use that as the resist layer or “sacrificial” layer. Then we take an atomic force microscope, or AFM tip, which is like a very sharp needle, and shave some of the sacrificial layer away using very high shear force. It’s like shaving, but we do it in a reactive environment.

We either put the whole surface in a solution containing reactants [such as DNA or proteins], or we put it in a low vapor pressure chamber. We prefer solution — because most chemical and bioreactions occur in solution phase. As we shave away the molecules from the sacrificial layer, the new reactant from the solution will come in and fill the void space. Thus you get nanostructures of your new molecule; the new molecules are embedded in the old matrix of the sacrificial layer.

This molecule can be DNA, or it can be a molecule with a bioadhesive group at the very end. In the latter case, we can inject proteins or other biomolecules to react with the nanostructure that we generated, so you can deposit molecules of your choice. We call the entire approach nanografting.

The smallest dots we have made so far, of 32 hydrocarbonthiols, are 2 by 4 nanometers in size. With proteins, we have been able to position as few as three molecules at a time on the surface. For DNA, the smallest dots we can make are about 7 by 12 nanometers; they contain about 26 single-stranded DNA molecules.

How do you apply these nanostructures?

If you can position molecules individually, you can control subsequent polyvalent interactions, which people cannot do very well right now. Using this nanoengineering approach, you can study these types of reactions very systematically.

In terms of technology, the reason people want to make DNA nanostructures is to create a new generation of DNA chips with nanometer dimensions and to explore DNA-based devices for quantum computing. Right now, a spot on a typical DNA chip is 50 micrometers or larger. Hopefully, we can miniaturize them by a couple of orders of magnitude.

What is the technical challenge?

You have to control the local force very well. If it’s not enough, you cannot shave molecules away; if it’s too much, you cannot obtain small enough structures and run the risk of deforming the substrate. That’s the greatest technical difficulty, the sharpness of the tip and local force control. Another issue is the drift — you need to maintain the tip-location up to molecular-level precision.

Have you taken any steps to commercialize the technology?

Being in California certainly puts us in a good position. But since I am brand new [in California], I have not gone out to contact anybody. But we probably will in the near future try to see if a DNA chip company or a protein chip company is interested. I have been contacted by a company [based in Palo Alto], but I haven’t taken any steps yet. In any case, I think the technology still needs on the order of three to 10 years of development.

Can this work with microarrays?

Industry probably does not think this approach is mature yet, because we create the nanostructures sequentially. We have to do scanning probe lithography in parallel for industry to be interested, because of their high-throughput requirements.

To make nanostructures in parallel, you probably need to make a tip array rather than a single tip. IBM Zurich has already made tip arrays for data storage — I think their largest is about 1,000 tips, and the regular one is about 400 tips. That would increase the speed tremendously, but how to control this tip array will be another issue.

What would be the main advantage in comparison with current microarray manufacturing methods?

Nanografting is certainly superior because it’s a pure engineering approach: it will have higher precision, be smaller, and have higher reproducibility. The current gene chip arrays run into the difficulties of non-reproducibility. But if you engineered with molecular precision, you could very effectively avoid that. This would be a good selling point to the industry, but right now the speed and the cost is what holds it back.

How reactive are DNA and protein molecules once they have been deposited?

Now you are getting into our unpublished results! Proteins, as you probably saw in our PNAS paper from April [entitled “Positioning protein molecules on surfaces: A nanoengineering approach to supramolecular chemistry”] are active; they can react with a secondary antibody.

We have also been able to hybridize complementary strands of DNA to DNA on the chip, but we haven’t published that yet. What we have published is that DNA reacts with an enzyme that digests it base by base.

As a result of these experiments, we are very confident that the DNA is active, and the proteins are alive and well. But you cannot keep the proteins for as long as DNA, as you know.

Can you control the orientation of the proteins?

In the experiments you saw in the PNAS paper, the orientation was not controlled very precisely. Each protein has a certain number of primary amines which can react with aldehydes on the surface, so the orientation will have multiple choices, and we saw almost all of them.

But people have used biospecific immobilization, such as biotin-streptavidin pairs. With that, you can control the orientation.

What have you done since your publication?

What we have been doing actively is building all kinds of DNA architectures. That’s probably going to be our focus in the next couple of years. If you want to do DNA chips or computing, you need more complicated structures than squares or dots.

This is the fundamental step: You get all kinds of building blocks, for instance triangles. You can build all kinds of nice architectures like this.

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