Visualizing the Unseen

• From life’s building blocks to cosmic forces, Northwestern research is transforming the world
• Northwestern is home to the IIN, Convergence Science and Medicine Institute, and other nano-focused centers and labs
• Vicky Kalogera is one of the Northwestern experts boldly leading discovery at the edges of the cosmos

It would take about 140,000 nanometers to eclipse the thickness of a single magazine page. Make no mistake, though, these tiny objects help support huge advances across a range of sciences.

“Whether studying nanoscience, business, or galaxies, researchers have to calibrate their approach to scale. Big and small can have very different meanings depending on who you are talking to,” says Chad Mirkin, founding director of Northwestern’s International Institute for Nanotechnology (IIN). “Much of our work focuses on biomedical challenges and the reason that is so interesting and important is that biology’s scale is the nanoscale.”

For instance, a red blood cell is about 5,000 nanometers (nm) in diameter; the flu virus about 100nm; and duplex DNA just 2nm. “The great thing about modern biology is that many pathways that control how we function and get sick are now understood,” says Mirkin, the George B. Rathmann Professor of Chemistry.

Diagnosing Cancers

Vadim Backman, the Walter Dill Scott Professor of Biomedical Engineering and an IIN member, is exploiting that fact using the power of light to examine cells from easily accessible areas of the body. His pioneering bio-optic technology could make diagnosing stage 1 lung cancer as simple as collecting a swab of cheek cells and sending it to a lab for analysis. The early detection test may be available in 2017 and could transform cancer treatment and outcomes.

“To advance to this point in our research, we first had to be able to see the previously unseen,” says Backman. “The way we addressed this issue was not simply by increasing the power of optical microscopy; we developed an entirely new methodology.”

The method is based on an optical technique called partial wave spectroscopic (PWS) microscopy. PWS allows the identification of cell features as small as 20 nm, revealing cell differences that would not be detected by standard microscopy techniques.

Backman collaborated with Allen Taflove, electrical engineering and computer science, to verify that his technique was measuring what he expected: minute changes in chromatin, the macromolecule within a cell’s nucleus that controls gene expression.

“One of the questions my lab asks is how the nanoscale structure of a biological object modulates molecular or physiological processes in the system,” says Backman.

“We’ve learned through a combination of novel imaging techniques and new biological discovery that, in cancer, chromatin is the mastermind and genes are the tools.”

Taflove is world-renowned for developing theoretical approaches that have helped solve some of the world’s most complex scientific and engineering problems.

His finite-difference time-domain method is a numerical analysis used for modeling the interaction of electromagnetic fields with objects.

“Without Al’s research, we would not have been able to verify we were seeing what we thought we were seeing,” says Backman. “We have since begun to develop assays for seven different types of cancer screening, and are likely to see our noninvasive lung cancer and colon cancer tests in use in the next two years.”

Lung cancer screening via cotton swab is possible because as precancerous changes occur in the lung, they also do so in upper respiratory system cells, like inside the mouth. Backman believes the screening could produce a revolution in diagnosing and treating lung cancer similar to the advent of the Pap smear, which went into wide use 60 years ago. Following its implementation, cervical cancer deaths fell 90 percent.

The lab’s identification of nanoscale changes in chromatin lie at the heart of potential progress.

'Life-saving Therapeutics'

“I’m convinced that nanoscience is where the big solutions will be found,” says Mirkin. “We’re poised to create new ways of making materials that can effectively carry therapeutic payloads to specific sites in the body. It means we’ll be able to enter these pathways and begin to manipulate them to either manage or cure disease.”

A researcher whose work integrates chemistry, materials science, molecular biology, and biomedicine, Mirkin’s 1996 discovery of spherical nucleic acids (SNAs) provided a major nanoscience breakthrough. “The ultimate goal is to take advantage of these materials that don’t occur in nature but that can be made in the lab at the right length scale and with the right set of properties.

That would allow a researcher to take all of the information that biologists have collected over the past 30 years and begin to create approaches to developing life-saving therapeutics,” he says.

SNAs are comprised of round nanoparticles densely covered with DNA or nucleic acids — the genetic code of living organisms. The 3D structures have chemical and physical properties that are radically different from DNA configured in other shapes, which allow them to cross the blood-brain barrier, penetrate cells, or circumvent or selectively stimulate the human immune system.

These are important characteristics because when a person is infected with a virus or bacteria, their immune system is trained to eradicate the problem.

“SNAs are some of the most potent immunotherapy agents out there. Because the nucleic signatures that diseases trigger are well known, we can reconstitute them in an SNA and create a structure to train the immune system to eradicate cancer cells without many of the horrible side effects of chemotherapy,” says Mirkin. His lab, in collaboration with Exicure LLC, a biotechnology firm he founded in 2011, has successfully eliminated lymphoma in a rodent model and is working with physicians at Northwestern Memorial Hospital and elsewhere to test a treatment for glioblastoma, a deadly brain cancer.

An ongoing clinical trial in Europe to treat psoriasis could substantiate the SNA-based platform and provide care options for most genetic based skin diseases.

“The drugs are attached to SNAs to knock down a gene and revert cells to a healthy state,” says Mirkin. “Once the platform is proven, the same architecture could be used with a different sequence to treat a different disease.”

By taking a gold-plated approach to nanoscience, another Northwestern expert is looking to solve one of medicine’s biggest challenges.

Teri Odom, the Charles E. and Emma H. Morrison Professor of Chemistry and IIN associate director, is using drug-loaded gold nanostars to destroy cancer cells. Using human cell lines, Odom has shown how the nanostar constructs can bind to a target protein on the cancer cell’s surface and then move toward the cell’s nucleus. When just outside the nucleus wall, the nanostars can drop off their therapeutic hitchhikers when triggered by light.

“These nanostar particles have tips that are several nanometers in diameter but with overall particle sizes tens of nanometers. The different length scales allow the tips to target proteins of similar sizes,” says Odom, executive editor of ACS Photonics and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern. “Their unique shape facilitates superior cellular uptake, imaging, and delivery of drugs.”

From Medicine to Materials Odom is an expert in designing structured nanoscale materials that exhibit extraordinary size and shape-dependent optical properties.  She has pioneered a suite of multi-scale nanofabrication tools that has resulted in novel nanoscale lasers.

“Our ability to manipulate materials into multi-scale structures — starting at the nanoscale — is key,” she says. “Because we can do this through different approaches, these new materials can be used for different applications.”

For example, the ability to produce light sources at the nanoscale will enable faster computing speeds, further miniaturization of chip-based electronics, increase resolution for photolithography, and enhance sensitivity to detect single pathogens and molecules.

Nano Epicenter

With IIN, the newly created Convergence Science and Medicine Institute, and other nano-focused centers, institutes, and labs, Northwestern is poised to continue its standing as a giant in the nanoscience field.

Since Mirkin’s SNA discovery, more than 1,800 commercial products have arisen from the technology. The world’s top-cited researcher in nanomedicine and one of the most cited chemists, Mirkin has founded numerous companies. Exicure has raised more than $42 million — including a large investment by philanthropist Bill Gates.

In 2015, Mirkin’s lab developed Sticky-flares, the first real-time method to track and observe the dynamics of RNA inside living cells. RNA is a fundamental ingredient in all known forms of life and RNA misregulation plays a critical role in the development of many disorders, like cancer. Sticky-flares may help scientists track rare cells by both the amount and location of RNA within them. No other technique provides such capabilities.

SmartFlares use a similar technology to measure the genetic content of live cells, allowing researchers to take a sample of cells, identify if a disease is present based on its DNA signature, and then create unique treatment options.

“This is going to blow open the field of personalized medicine,” says Mirkin. “By looking at the genetic roots of disease, we can not only attack disease in a unique way, but treat people on a patient-by-patient basis.”

DNA is usually thought of as the genetic blueprint of life, but Mirkin and others have used it to modify nanoparticles so that they can act as programmable atom equivalents.

“This creates a fundamentally new way to think about building matter,” says Mirkin. “Instead of taking what nature gives us, researchers can break the process down into elemental building blocks and then reassemble an object using DNA so that the elements have the desired properties for a given application.”

In essence, researchers are creating a new table of elements with a near-infinite number of entries.

“Properties and performance of materials are dictated by complex atomic and nanoscale features and their hierarchical arrangement in 3D (or space),” says Vinayak Dravid, the Abraham Harris Professor of materials science and engineering and director of NUANCE. “The world is made up of atoms and molecules, and we’re learning what happens when you arrange them in new ways.”

For instance, you could mix a bunch of carbon atoms together randomly and get dirt, or you might combine them differently in a special 3D symmetry arrangement to get a diamond.

Dravid’s lab explores just how atoms and molecules come together and behave when exposed to stimuli. The NUANCE Center provides state-of-the-art and core analytical characterization instrumentation and is one of six shared facilities at Northwestern that in-part comprise the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource, a National Science Foundation venture that provides academic, small business, and industry researchers access to cutting-edge nanotechnology facilities and expertise.

“Our lab creates new tools and refines techniques across a range of fields, meaning we have an opportunity to contribute as much to the future of energy as medicine,” says Dravid. “Just as astronomers take us further into outer space, NUANCE brings us ever deeper into the subatomic ‘inner’ world.”

The Outer Limits

Vicky Kalogera, the Erastus O. Haven Professor of physics and astronomy and director of Northwestern’s Center for Interdisciplinary Exploration and Research in Astrophysics, is one of the Northwestern experts boldly leading discovery at the edges of the cosmos.

Nearly everything known about the universe has been discovered with light of some kind, such as x-rays, infrared radiation, and radio waves. So when a global research team that included Kalogera discovered gravitational waves — actual ripples in the fabric of spacetime — last September, the breakthrough ushered in a new era for physics and astronomy.

“Gravitational waves carry completely new information about black holes and other cosmic objects, and they will unlock a new part of the universe,” says Kalogera. “We want to use the gravitational wave observations to learn about our universe for centuries to come.”

Researchers in the LIGO Scientific Collaboration concluded that the detected gravitational waves were produced during the final fraction of a second of the merger of two black holes, which produced a single, more massive spinning black hole, a cosmic event that occurred 1.3 billion years ago.

“That’s the beauty of basic science; humans have an innate, almost inexplicable curiosity about figuring out how nature works,” says Kalogera, one of the senior astrophysicists on the LIGO team. “What we see in technology today is rooted in the basic science discoveries of the past.”