Tag Archives: chemistry

Now in 3D: Video of virus-sized particle trying to enter cell (Nature Nanotechnology)

Video of virus trying to enter cell

3D movie (below) of virus-like nanoparticle trying to gain entry to a cell

By Catherine Zandonella, Office of the Dean for Research

Tiny and swift, viruses are hard to capture on video. Now researchers at Princeton University have achieved an unprecedented look at a virus-like particle as it tries to break into and infect a cell. The technique they developed could help scientists learn more about how to deliver drugs via nanoparticles — which are about the same size as viruses — as well as how to prevent viral infection from occurring.

The video reveals a virus-like particle zipping around in a rapid, erratic manner until it encounters a cell, bounces and skids along the surface, and either lifts off again or, in much less time than it takes to blink an eye, slips into the cell’s interior. The work was published in Nature Nanotechnology.

Video caption: ‘Kiss and run’ on the cell surface. This 3D movie shows actual footage of a virus-like particle (red dot) approaching a cell (green with reddish brown nucleus), as captured by Princeton University researchers Kevin Welcher and Haw Yang. The color of the particle represents its speed, with red indicating rapid movement and blue indicating slower movement. The virus-like particle lands on the surface of the cell, appears to try to enter it, then takes off again. Source: Nature Nanotechnology.

“The challenge in imaging these events is that viruses and nanoparticles are small and fast, while cells are relatively large and immobile,” said Kevin Welsher, a postdoctoral researcher in Princeton’s Department of Chemistry and first author on the study. “That has made it very hard to capture these interactions.”

The problem can be compared to shooting video of a hummingbird as it roams around a vast garden, said Haw Yang, associate professor of chemistry and Welsher’s adviser. Focus the camera on the fast-moving hummingbird, and the background will be blurred. Focus on the background, and the bird will be blurred.

The researchers solved the problem by using two cameras, one that locked onto the virus-like nanoparticle and followed it faithfully, and another that filmed the cell and surrounding environment.

Putting the two images together yielded a level of detail about the movement of nano-sized particles that has never before been achieved, Yang said. Prior to this work, he said, the only way to see small objects at a similar resolution was to use a technique called electron microscopy, which requires killing the cell.

“What Kevin has done that is really different is that he can capture a three-dimensional view of a virus-sized particle attacking a living cell, whereas electron microscopy is in two-dimensions and on dead cells,” Yang said. “This gives us a completely new level of understanding.”

In addition to simply viewing the particle’s antics, the researchers can use the technique to map the contours of the cell surface, which is bumpy with proteins that push up from beneath the surface. By following the particle’s movement along the surface of the cell, the researchers were able to map the protrusions, just as a blind person might use his or her fingers to construct an image of a person’s face.

“Following the motion of the particle allowed us to trace very fine structures with a precision of about 10 nanometers, which typically is only available with an electron microscope,” Welsher said. (A nanometer is one billionth of a meter and roughly 1000 times smaller than the width of a human hair.) He added that measuring changes in the speed of the particle allowed the researchers to infer the viscosity of the extracellular environment just above the cell surface.

The technology has potential benefits for both drug discovery and basic scientific discovery, Yang said.  “We believe this will impact the study of how nanoparticles can deliver medicines to cells, potentially leading to some new lines of defense in antiviral therapies,” he said. “For basic research, there are a number of questions that can now be explored, such as how a cell surface receptor interacts with a viral particle or with a drug.”

Welsher added that such basic research could lead to new strategies for keeping viruses from entering cells in the first place.

“If we understand what is happening to the virus before it gets to your cells,” said Welsher, “then we can think about ways to prevent infection altogether. It is like deflecting missiles before they get there rather than trying to control the damage once you’ve been hit.”

To create the virus-like particle, the researchers coated a miniscule polystyrene ball with quantum dots, which are semiconductor bits that emit light and allow the camera to find the particle. Next, the particle was studded with protein segments known as Tat peptides, derived from the HIV-1 virus, which help the particle find the cell. The width of the final particle was about 100 nanometers.

The researchers then let loose the particles into a dish containing skin cells known as fibroblasts. One camera followed the particle while a second imaging system took pictures of the cell using a technique called laser scanning microscopy, which involves taking multiple images, each in a slightly different focal plane, and combining them to make a three-dimensional picture.

The research was supported by the US Department of Energy (DE-SC0006838) and by Princeton University.

Read the abstract.

Kevin Welsher and Haw Yang. 2014. Multi-resolution 3D visualization of the early stages of cellular uptake of peptide-coated nanoparticles. Nature nanotechnology. Published online: 23 February 2014 | DOI: 10.1038/NNANO.2014.12

When scaling the quantum slopes, veer for the straight path (Physical Review A)

Research image

Princeton University researchers found that the “landscape” for quantum control (above) — a representation of quantum mechanics that allows the dynamics of atoms and molecules to be manipulated — can be unexpectedly simple, which could help scientists realize the next generation of technology by harnessing atoms and molecules to create small but incredibly powerful devices. Scientists achieve quantum control by finding the ideal radiation field (top of the graphic) that leads to the desired response from the system. Like a mountain hiker, a scientist can take a difficult, twisting path that requires frequent stops to evaluate the next step (right path). Or, they can opt for a straighter trail that cuts directly to the summit (left path). The researchers provide in their paper an algorithm that scientists can use to identify the starting point of the straight path to their desired quantum field. (Image courtesy of Arun Nanduri)

By Morgan Kelly, Office of Communications

Like any task, there is an easy and a hard way to control atoms and molecules as quantum systems, which are driven by tailored radiation fields. More efficient methods for manipulating quantum systems could help scientists realize the next generation of technology by harnessing atoms and molecules to create small but incredibly powerful devices such as molecular electronics or quantum computers.

Of course, controlling quantum systems is as painstaking as it sounds, and requires scientists to discover the ideal radiation field that leads to the desired response from the system. Scientists know that reaching that state of quantum nirvana can be a long and expensive slog, but Princeton University researchers have found that the process might be more straightforward than previously thought.

The researchers report in the journal Physical Review A that quantum-control “landscapes” — the path of a system’s response from the initial field to the final desired field — appears to be unexpectedly simple. Although still a mountain of a task, finding a good control radiation field turns out to be very much like climbing a mountain, and scientists need only choose the right path. Like a hiker, a scientist can take a difficult, twisting path that requires frequent stops to evaluate which step to take next. Or, as the Princeton researchers show, they can opt for a straighter trail that cuts directly to the summit.

The researchers observe in their paper that these fast tracks toward the desired control field actually exist, and are scattered all over the landscape. They provide an algorithm that scientists can use to identify the starting point of the straight path to their desired quantum field.

The existence of nearly straight paths to reach the best quantum control was surprising because the landscapes were assumed to be serpentine, explained first author Arun Nanduri, who received his bachelor’s degree in physics from Princeton in 2013 and is working in the laboratory of Herschel Rabitz, Princeton’s Charles Phelps Smyth ’16 *17 Professor of Chemistry.

“We found that not only can you always climb to the top, but you can climb along a simple path to the top,” Nanduri said. “If we could consistently identify where these paths are located, a scientist could efficiently climb the landscape. Looking around for the next good step along an unknown path takes great effort. However, starting along a straight path requires you to look around once, and you can keep walking forward with your eyes closed, as it were.”

Following a straighter path could be a far more efficient way of achieving control of atoms and molecules for a host of applications, including manipulating chemical reactions and operating quantum computers, Nanduri said. The source of much scientific excitement, quantum computers would use “qubits” that can be entangled to potentially give them enormous storage and computational capacities far beyond the capabilities of today’s digital computers.

If the Princeton research helps scientists quickly and easily find the control fields they need, it could also allow them to carry out improved measurements of quantum systems and design new ones, Nanduri said.

“We don’t know if our discovery will directly lead to futuristic quantum devices, but this finding should spur renewed research,” Nanduri said. “If straight paths to good quantum control solutions can be routinely found, it would be remarkable.”

Read the abstract.

Nanduri, Arun, Ashley Donovan, Tak-San Ho, Herschel Rabitz. 2013. Exploring quantum control landscape structure. Physical Review A. Article published: Sept. 30, 2013. DOI: 10.1103/PhysRevA.88.033425

The work was funded by the Program in Plasma Science and Technology at Princeton University, the Army Research Office, and the U.S. Department of Energy.

Serendipity Pays Off (Science)

By Catherine Zandonella, Office of the Dean for Research

Serendipity –­­ the act of finding something good or useful while not specifically searching for it – can sometimes pay off. Now Princeton University chemistry researchers report that this non-specific type of searching has yielded a new method of building molecules for use in new drugs, new agricultural chemicals and even new perfumes.

In a paper published today in the journal Science, Princeton’s David MacMillan and his team describe the discovery of a new chemical reaction – not noted before in nature or in any lab – that could assist pharmaceutical chemists and others who routinely create new chemicals for a variety of industries.

Until now, no one realized this chemical reaction – which involves adding atoms to a specific carbon atom on a molecule – could occur, according to MacMillan, the James S. McDonnell Distinguished University Professor of Chemistry at Princeton. “If you show this chemical reaction to most chemists, they immediately say ‘that’s impossible,’” MacMillan said.

In this case, the team discovered this “impossible” reaction using an approach MacMillan pioneered that he calls “accelerated serendipity.” The researchers use robotic arms to conduct thousands of reactions per day by combining in test tubes different combinations of chemicals along with catalysts that spur the reactions. When the investigators find a reaction that makes an interesting product, they study it to understand how the reaction occurs.

“We didn’t invent this new reaction – nature did that,” MacMillan said, “but we figured out how to get the reaction to happen in the lab.” said MacMillan. His team, which included graduate student Michael Pirnot, postdoctoral researcher David Martin and former postdoctoral researcher Danica Rankic, uses ordinary light bulbs as catalysts, a technique developed in MacMillan’s lab and published in Science in 2008, to spur the reactions.

Going forward, chemists can add this new reaction to their tool box of methods for building up molecules, which they do in a way analogous to joining together pieces of Kinex or Tinker Toys, by swapping in new parts to increase the function of the molecule. In the new reaction published today, the team discovered a way to join so-called “functional groups” to a specific carbon atom (see diagram) in larger structures known as ketones and aldehydes. The ability to add functional groups to that carbon atom was thought impossible until now.

macmillan

Caption: Upper and lower left: Green spots indicate carbon atoms known to undergo reactions. Right panel: Purple spot indicates a carbon atom thought not to undergo reactions. The team discovered, using accelerated serendipity, a way to cause this carbon to react, resulting in addition of functional groups, and potentially leading to new drugs or other important industrial chemicals. (Source: Science)

This new chemical reaction has wide applications, MacMillan said. “This is a fundamental reaction which any chemist can start using.”

For example, a chemist who is building a drug to treat Alzheimer’s disease might desire to add a chemical group to the reluctant carbon atom. Normally that would require the chemist to conduct several different chemical reactions over several weeks, but with the new reaction the chemist could build the drug in two days and be testing drug candidates much more quickly.

Similarly a chemist at a fragrance company could use the new reaction to experiment with the creation of new perfume formulations.

MacMillan’s original paper on accelerated serendipity, published in 2011 in Science, successfully discovered a reaction now used in the drug industry. Yet it was controversial because other scientists interpreted the robotic searches as random searches, when in fact they were not random. “We chose chemicals that had never been shown to react with each other – those are the ones we believe might lead to as-yet undiscovered reactions.” MacMillan said that these reactions may have been created in the past by chemists who didn’t recognize what they were.

Read the abstract.

Michael T. Pirnot, Danica A. Rankic, David B. C. Martin, David W. C. MacMillan. Photoredox Activation for the Direct β-Arylation of Ketones and Aldehydes. Science 29 March 2013. Vol. 339 no. 6127 pp. 1593-1596.

This research was supported by the National Institute of General Medical Sciences grant R01 GM103558-01 and gifts from Merck, Amgen, Abbott, and Bristol-Myers Squibb.