Robert Austin

Princeton University | PU · Department of Physics

Time-reversal symmetry breaking and entropy production are universal features of nonequilibrium phenomena. Despite its importance in the physics of active and living systems, the entropy production of systems with many degrees of freedom has remained of little practical significance because the high dimensionality of their state space makes it diff...

Chemoresistance can be increased by cells in the polyaneuploid cancer cells (PACC) state, a major cause of treatment failure in various cancers. The life cycle of cells in the PACC state is understudied, and the mechanism of their drug resistance is unknown. In this study, we induced the development of doxorubicin (DOX)-resistant PACCs from triple...

Therapeutic resistance is one of the main reasons for treatment failure in cancer patients. The polyaneuploid cancer cell (PACC) state has been shown to promote resistance by providing a refuge for cancer cells from the effects of therapy and by helping them adapt to a variety of environmental stressors. This state is the result of aneuploid cancer...

Recent evidence suggests that a polyaneuploid cancer cell (PACC) state may play a key role in the adaptation of cancer cells to stressful environments and in promoting therapeutic resistance. The PACC state allows cancer cells to pause cell division and to avoid DNA damage and programmed cell death. Transition to the PACC state may also lead to an...

We present a theoretical modeling framework, called the G function, to understand cancer speciation, diversification, and environmental adaptation. The G function integrates both the ecology and evolution of cancer and has been used in evolutionary ecology. However, the G function has not yet been widely applied to problems in cancer. Here, we buil...

Metastatic cancer is incurable because tumors evolve resistance to all classes of therapy, resulting the in the deaths of 10 million people each year. Therapy resistance is typically attributed to the presence of a cancer stem cell or genetic tumor cell heterogeneity. However, therapeutic resistance can also emerge through a transient cell state: t...

Despite major advances in cancer research over the last several decades, advanced cancers largely remain incurable due to the evolution of resistance. Recent experimental evidence suggests that a poly-aneuploid cancer cell (PACC) state may contribute to the emergence of therapeutic resistance by allowing cancer cells to avoid the effects of and ada...

Significance We present a fully realized adaptive resource landscape with diploid three-gene robots presenting interacting roles of population dynamics, mutations, breeding, death, and birth. Although modeling and theory serves as a guide here, the inherent complexity of our robobiology world makes it an experiment in exploring rules of Darwinian n...

Landscapes play an important role in many areas of biology, in which biological lives are deeply entangled. Here we discuss a form of landscape in evolutionary biology which takes into account (1) initial growth rates, (2) mutation rates, (3) resource consumption by organisms, and (4) cyclic changes in the resources with time. The long-term equilib...

We reinvestigate a simple model used in the literature concerning the thermodynamic analysis of protein cold denaturation. We derive an exact thermodynamic expression for cold denaturation and give a better approximation than exists in the literature for predicting cold denaturation temperatures in the two-state model. We discuss the “dark-side” im...

Time-reversal symmetry breaking and entropy production are universal features of nonequilibrium phenomena. Despite its importance in the physics of active and living systems, the entropy production of systems with many degrees of freedom has remained of little practical significance because the high-dimensionality of their state space makes it diff...

We present an ecology-inspired form of active matter consisting of a robot swarm. Each robot moves over a planar dynamic resource environment represented by a large light-emitting diode array in search of maximum light intensity; the robots deplete (dim) locally by their presence the local light intensity and seek maximum light intensity. Their mov...

We theoretically show that isolated agents that locally and symmetrically consume resources and sense positive resource gradients can generate constant motion via bootstrapped resource gradients in the absence of any externally imposed gradients, and we show a realization of this motion using robots. This self-generated agent motion can be coupled...

We describe an evolutionary game theory model that has been used to predict the population dynamics of interacting cancer and stromal cells. We first consider the mean field case assuming homogeneous and nondiscrete populations. Interacting Particle Systems (IPS) are then presented as a discrete and spatial alternative to the mean field approach. F...

Bacteria which grow not on the featureless agar plates of the microbiology lab but in the real world must navigate topologies which are nontrivially complex, such as mazes or fractals. We show that chemosensitive motile E. coli can efficiently explore nontrivial mazes in times much shorter than a no-memory (Markovian) walk would predict, and can co...

The heterogenous, highly metabolic stressed, poorly irrigated, solid tumor microenvironment – the tumor swamp – is widely recognized to play an important role in cancer progression as well as the development of therapeutic resistance. It is thus important to create realistic in vitro models within the therapeutic pipeline that can recapitulate the...

Cancer led to the deaths of more than 9 million people worldwide in 2018, and most of these deaths were due to metastatic tumor burden. While in most cases, we still do not know why cancer is lethal, we know that a total tumor burden of 1 kg—equivalent to one trillion cells—is not compatible with life. While localized disease is curable through sur...

Polyploidy has been often associated with poor prognosis and has been described to some extent in histological samples for most types of solid tumors. In cancer biology, it has been proposed to induce the gain of a stem-like phenotype and drive tumor progression by increasing the potential for cellular transformation. Experiments with chemotherapy...

The ability of a population of PC3 prostate epithelial cancer cells to become resistant to docetaxel therapy and progress to a mesenchymal state remains a fundamental problem. The progression towards resistance is difficult to directly study in heterogeneous ecological environments such as tumors. In this work, we use a micro-fabricated “evolution...

Background The physics of cancer dormancy, the time between initial cancer treatment and re-emergence after a protracted period, is a puzzle. Cancer cells interact with host cells via complex, non-linear population dynamics, which can lead to very non-intuitive but perhaps deterministic and understandable progression dynamics of cancer and dormancy...

Significance We have discovered an emergent mechanism by which Escherichia coli can escape high-stress regions, such as near-lethal concentrations of antibiotics, by forming long motile helical filaments that are poized at the critical shear buckling point: 2 π twist rotations independent of the length of the filament. All filaments, independent of...

Metastatic prostate cancer remains a lethal disease. Taxane chemotherapy used to be restricted to the hormone-resistant metastatic setting in which most patients with castration-resistant prostate cancer (CRPC) develop therapeutic resistance to chemotherapy, achieving limited therapeutic benefit. Recently, two trials demonstrated adjuvant chemohorm...

Metastatic prostate cancer remains incurable. Taxane-based chemotherapy used to be restricted to the hormone-resistant metastatic setting. Unfortunately, most patients with castration-resistant prostate cancer (CRPC) rapidly develop resistance to chemotherapy. Recently, two trials demonstrated increased survival in men with high-risk metastatic hor...

We present a phosphorescence lifetime imaging (PLIM) based oxygen sensor to monitor the local O2 level in conventional petri dish-based or microfluidic in vitro cell culture. The sensor film is fabricated by dissolving Pt(II) meso-tetrakis(pentafluorophenyl) porphine (PtTFPP) into a thermal curable poly(perfluoroether) (PFPE). The lifetime response...

The systematic emergence of drug resistance remains a major problem in the treatment of infectious diseases (antibiotics) and cancer (chemotherapy), with possible common fundamental origins linking bacterial antibiotic resistance and emergence of chemotherapy resistance. The common link may be evolution in a complex fitness landscape with connected...

Flow cytometry analysis requires a large amount of isolated, labelled, and purified cells for accurate results. To address the demand for a large quantity of cells prepared in a timely manner, we describe a novel microfluidic trap structure array for on-chip cell labelling, such as intracellular and extracellular labelling, and subsequent washing a...

We have improved our microfluidic cell culture device that generates an in vitro landscape of stress heterogeneity. We now can do continuous observations of different cancer cell lines and carry out downstream analysis of cell phenotype as a function of position on the stress landscape. We use this technology to probe adaption and evolution dynamic...

We have constructed a microfabricated circular corral for bacteria made of rings of concentric funnels which channel motile bacteria outwards via non-hydrodynamic interactions with the funnel walls. Initially bacteria do move rapidly outwards to the periphery of the corral. At the edge, nano-slits allow for the transport of nutrients into the devic...

We provide a tool for data-driven modeling of motility, data being time-lapse recorded trajectories. Several mathematical properties of a model to be found can be gleaned from appropriate model-independent experimental statistics, if one understands how such statistics are distorted by the finite sampling frequency of time-lapse recording, by exper...

We previously developed a Deterministic Lateral Displacement (DLD) microfluidic method in silicon to separate cells of various sizes from blood (Davis et al., Proc Natl Acad Sci 2006;103:14779-14784; Huang et al., Science 2004;304:987-990). Here, we present the reduction-to-practice of this technology with a commercially produced, high precision pl...

Photodynamic therapy (PDT) is a noninvasive technique that selectively targets cancer cells. The photosensitizer absorbs light of a specific wavelength and generates highly reactive oxygen species (ROS) such as singlet oxygen, from molecular oxygen in the surrounding tissue. However, PDT is limited by the penetration depth and scattering of the vis...

We revisit mid-IR pump–probe experiments at the FELIX picosecond Free Electron Laser which probed the vibrational dynamics of the α-helix rich protein in search of long-lived anharmonic trapped vibrational states (solitons). We analyze and try to understand something puzzling that we observed in the context of unusual ‘hidden’ quantum phenomena in...

We describe a microfluidic device for on-chip chemical processing, such as staining, and subsequent washing of cells. The paper introduces "separator walls" to increase the on-chip incubation time and to improve the quality of washing. Cells of interest are concentrated into a treatment stream of chemical reagents at the first separator wall for ex...

Significance There are two broad components of information dynamics in cancer evolution. One involves permanent changes in which genes are subject to gain or loss-of-function substitutions. This is well established and the main focus of cancer research. The other component is the information in the human genome and preservation of that content. The...

We demonstrate that a microfabricated bump array can concentrate genomic-length DNA molecules efficiently at continuous, high flow velocities, up to 40 μm/s, if the single-molecule DNA globule has a sufficiently large shear modulus. Increase in the shear modulus is accomplished by compacting the DNA molecules to minimal coil size using polyethylene...

Microfluidic deterministic lateral displacement (DLD) arrays have been applied for fractionation and analysis of cells in quantities of ~100 µL of blood, with processing of larger quantities limited by clogging in the chip. In this paper, we (i) demonstrate that this clogging phenomenon is due to conventional platelet-driven clot formation, (ii) id...

In a top–down approach the interactions are still complex in vivo. They might include competition and cooperation among various phenotypes of the cells in the ecology, keeping in mind these interactions may well change during different stages of metastatic process. For example, cancer cells in the primary tumor may stop growing due to environmental...

Significance Understanding how bacteria rapidly evolve under antibiotic selective pressure is crucial to controlling the development of resistant organisms. We show that initial resistance emerges from successful segregation of mutant chromosomes at the tips of filaments followed by budding of resistant progeny. We propose that the first stages of...

The transport of objects in microfluidic arrays of obstacles is a surprisingly rich area of physics and statistical mechanics. Tom Duke's mastery of these areas had a major impact in the development of biotechnology which uses these ideas at an increasing scale. We first review how biological objects are transported in fluids at low Reynolds number...

Political correctness urges us to state how wonderful it is to work with biologists and how, just as the lion will someday lie down with the lamb, so will interdisciplinary work, where biologists and physicists are mixed together in light, airy buildings designed to force socialization, give rise to wonderful new science. But it has been said that...

The issue of resistance to targeted drug therapy is of pressing concern, as it constitutes a major barrier to progress in managing cancer. One important aspect is the role of stochasticity in determining the nature of the patient response. We examine two particular experiments. The first measured the maximal response of melanoma to targeted therapy...

Do genetically closely related organisms under identical, but strong selection pressure converge to a common resistant genotype or will they diverge to different genomic solutions? This question gets at the heart of how rough is the fitness landscape in the local vicinity of two closely related strains under stress. We chose a Growth Advantage in S...

Preventing relapse is the major challenge to effective therapy in cancer. Within the tumour, stromal (ST) cells play an important role in cancer progression and the emergence of drug resistance. During cancer treatment, the fitness of cancer cells can be enhanced by ST cells because their molecular signalling interaction delays the drug-induced apo...

One of the predictions of game theory is that cooperative behaviours are vulnerable to exploitation by selfish individuals, but this result seemingly contradicts the survival of cooperation observed in nature. In this review, we will introduce game theoretical concepts that lead to this conclusion and show how the spatial competition dynamics betwe...

One of the physiological responses of bacteria to external stress is to assemble into a biofilm. The formation of a biofilm greatly increases a bacterial population's resistance to a hostile environment by shielding cells, for example, from antibiotics. In this paper, we describe the conditions necessary for the emergence of biofilms in natural env...

Drug development faces its nemesis in the form of drug resistance. The rate of bacterial resistance to antibiotics, or tumor resistance to chemotherapy decisively depends on the surrounding heterogeneous tissue. However, in vitro drug testing is almost exclusively done in well stirred, homogeneous environments. Recent advancements in microfluidics...

Significance Ultimately, chemotherapy often fails because of the emergence of cancer cells resistant to the chemotherapy. We show that this emergence can be driven by the presence of chemotherapy drug gradients and motility of the cancer cells within the gradient.

To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the Physical Sciences–Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic MDA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Exper...

We show that MDA-MB-231 metastatic breast cancer cells collectively invade a three dimensional collagen matrix by following a glucose gradient. We observe that due to the 3D physical deformation of the matrix, as measured by the displacement of reporter beads within the matrix, there exists a long range deformation mechanical field inside the matri...

Deterministic lateral displacement arrays have been used to separate circulating tumor cells (CTCs) from diluted whole blood at flow rates up to 10 mL/min (K. Loutherback et al., AIP Advances, 2012). However, the throughput is limited to 2 mL equivalent volume of undiluted whole blood due to clogging of the array. Since the concentration of CTCs ca...

Drug resistance in cancer is usually caused by the spatial drug gradients in tumor environment. Here, we culture multiple myeloma in a gradient from 0 to 20 nM of doxorubicin (genotoxic drug) across 2 mm wide region for 12 days. The myeloma cells grew rapidly and formed 3D colonies in the regions with less drug concentration. However, we have seen...

Evolution of antibiotic resistance is a growing problem. One major reason why most antibiotics fail is because of mutations on drug targets (e.g. essential enzymes). Sequencing of clinically resistant isolates have shown that multiple mutational-hotspots exist in coding regions, which could potentially prohibit the binding of drugs. However, it is...

Escherichia coli (E. coli) cells when challenged with sublethal concentrations of the genotoxic antibiotic ciprofloxacin cease to divide and form long filaments which contain multiple bacterial chromosomes. These filaments are individual mesoscopic environmental niches which provide protection for a community of chromosomes (as opposed to cells) un...

We report an integrated nanochannel/nanoelectrode sensor for the detection of DNA using alternating currents. We find that DNA can be detected using platinum as the metal for the detecting electrodes, with a signal to noise ratio exceeding 10. We argue that the signal is at least in part electrochemical in nature, thus holds the promise to yield a...

Metastasis, the truly lethal aspect of cancer, occurs when metastatic cancer cells in a tumor break through the basement membrane and penetrate the extracellular matrix. We show that MDA-MB-231 metastatic breast cancer cells cooperatively invade a 3D collagen matrix while following a glucose gradient. The invasion front of the cells is a dynamic on...

Circulating tumor cells (CTCs) and circulating clusters of cancer and stromal cells have been identified in the blood of patients with malignant cancer and can be used as a diagnostic for disease severity, assess the efficacy of different treatment strategies and possibly determine the eventual location of metastatic invasions for possible treatmen...

Stem cell research can significantly benefit from recent advances of microfluidics technology. In a rationally designed microfluidics device, analyses of stem cells can be done in a much deeper and wider way than in a conventional tissue culture dish. Miniaturization makes analyses operated in a high-throughput fashion, while controls of fluids hel...

DNA is the central storage molecule of genetic information in the cell, and reading that information is a central problem in biology. While sequencing technology has made enormous advances over the past decade, there is growing interest in platforms that can readout genetic information directly from long single DNA molecules, with the ultimate goal...

This is a theoretical paper which examines at a game theoretical perspective the dynamics of cooperators and cheater cells under metabolic stress conditions and high spatial heterogeneity. Although the ultimate aim of this work is to understand the dynamics of cancer tumor evolution under stress, we use a simple bacterial model to gain fundamental...

It is a common mistake to view cancer as a single disease with a single possible cure which we have just not found yet. In reality cancer takes on many forms that share a common symptom: uncontrolled cell growth and successful invasion of cancer colonies to remote regions of the body. The key reason why we may never be able to defeat cancer may lie...

In order to study the evolution of drug resistance in cancer, it is important to mimic the tumor microenvironment, in which cells are exposed to not uniform concentrations but rather gradients of drugs, nutrients, and other factors Compared to traditional in-vitro methods, microfluidic structure enables better control of the temporal and spatial pr...

Most bacteria have a single circular chromosome that can range in size from 160,000 to 12,200,000 base pairs. Considering the typical gene density, i.e. 1 gene per 1,000 base pairs, both the number of genes and the ways to arrange are huge. Intuitively, the arrangement of genes on the circle is not important if all of them can be replicated. Howeve...

Replacing non-renewable energy sources is one of the biggest and most exciting challenges of our generation. Algae and bacteria are poised to become major renewable biofuels if strains can be developed that provide a high,consistent and robust yield of oil. One major stumbling block towards this goal is the lack of tolerance to high concentrations...

One well-known fact is that cancer cell genetics determines cell metastatic potentials. However, from a physics point of view, genetics as cell properties cannot directly act on metastasis. An agent is needed to unscramble the genetics first before generating dynamics for metastasis. Exactly this agent is cell behavioral phenotype, which is rarely...

The GASP phenotype in bacteria is due to a mutation which enables the bacteria to grow under high stress conditions where other bacteria stop growing. We probe using our Death Galaxy microenvironment how rapidly the GASP mutant can evolve resistance to mutagenic antibiotics compared to wild-type bacteria, and explore the genomic landscape changes d...

Transformation, the process by which bacteria uptake DNA directly from their environment and incorporate it as their own genetic material, is a form of Horizontal Gene Transfer that occurs throughout nature as an important mechanism for spurring on bacterial evolution. We examine the capacity of bacteria to undergo transformation and will discuss w...

Circulating tumor cells (CTCs) and circulating clusters of cancer and stromal cells have been identified in the blood of patients with malignant cancer and can be used as a diagnostic for disease severity, assess the efficacy of different treatment strategies and possibly determine the eventual location of metastatic invasions for possible treatmen...