BSS - Postgraduate Admissions

General Information

We are seeking applicants for the following projects, starting in 2012. For informal enquiries please contact a member of staff or email the sector administrator at admin @ bss.phy.cam.ac.uk; see the Graduate Studies Prospectus for details of the application and admissions process for postgraduate study.

Projects marked with * are also suitable for an MPhil. Projects marked with ** are only suitable for an MPhil.

Dr K Chalut

There is an important but unfilled niche at the intersection of embryonic stem (ES) cell biology and physics: forces and motion, as well as intrinsic structural properties of ES cells, modulate the placement of cells within the embryo; this positioning augurs their eventual fate. Although much is known about the biochemical signatures of events in the developing embryo – how the gene expression of specific developmental markers changes at particular times in the life cycle of an embryo – much remains to be elucidated about the role of physics. Little is known about individual physical characteristics, or phenotypes, of these cells, less how and why they matter, and how they coalesce in embryonal dynamics. The proposed research is driven to fill this niche. We strive to understand how physical parameters drive ES cell state, or the present condition of ES cells, regarding their fate decisions. Do nuclear mechanics play a role? What about the structure and organisation about the genome? The genome is after all a physical formation with dynamics. We are developing biotechnology to observe the physical world of embryos and embryonic stem cells, with the aim of understanding how physics drives biological development.

Biotechnology

We will strive to use existing techniques in the Physics of Medicine facility such as optical stretching, atomic force microscopy, compliant gel substrates and digital holographic microscopy for studying physical phenotypes of ES cells. We are pushing digital holographic microscopy forward to enable meausurement of 3-D refractive index maps of single cells to give unprecedented views of subcellular structure. We will also be developing new techniques such as microfluidic cell rheology, which is a microfluidic-based technique for high-throughput measurements of mechanical phenotypes of single cells. Another technique we will develop in our laboratory is nanoparticle tracking techniques to measure nuclear mechanics within embryos. In this area of research, we are seeking researchers interested in optics, bioimaging, and nanobiotechnology.

Physical phenotyping

We will use our developed biotechnology to establish physical phenotypes of stem cell pluripotency and differentiation. The physical phenotypes we will primarily explore are nuclear mechanics and structure, and how they correlate with the state of embryonic stem cells. We are particularly interested in the role the remodelling of chromatin &endash; the machinery in the nucleus of which chromosomes are built &endash; plays in ES cell function. Chromatin is highly dynamic: in order to control accessibility to the genome, it condenses or decondenses, and moves throughout the nucleus as a cell fulfils its function. The physical phenotypes we will study focus on more big-picture views of cell behaviour to generate a broader understanding of changes in cell function, and will emphasize marker-free and non-perturbative techniques of biological observation.

Biophysics of development

In this aspect of our research, we will be testing the hypothesis that the decisions of embryonic development are driven by biophysics, such as cell/nuclear mechanics and chromatin structure. A particularly enticing aspect of this is to consider that ES cells are controlling their development – i.e. what somatic cells they are to become – by physically regulating access to the genome. We have evidence that this is the case, and we will continue by using particle tracking rheology and refractive index imaging to assess how the physical phenotypes of ES cells change as they sort in the embryo, and at what point in the sorting process these physical phenotypes change. In this area of research, we welcome those interested in bioimaging and biophysics, and also molecular biologists or embryologists interested in the role of biophysics in development.

Dr P Cicuta

Processes at the biological cell membrane (3.5 years)

Biological membranes are ubiquitous in living organisms. They separate a cell from its surroundings, and create compartments within cells. They serve to regulate diffusion of chemical components between compartments, and also as scaffolds. Optical tweezers allow to exert and measure forces of the order of pico-Newtons, by holding and moving micrometer sized beads. The possibility of interrogating live biological matter on a sub-cellular level, in real time, is opening a new field of experimental cell biology. While many biological problems involve very detailed biochemistry and specific interactions, there are a number of processes that are more general, and a consequence of soft matter physics. As far as the membrane is concerned, these include phase transitions in the membrane, mechanics of the composite membrane-cytoskeleton structure, correlation and interaction of objects (proteins) included in the membrane. Preliminary experiments are being carried out to explore the membrane deformation and the forces active during phagocytosis, one of the mechanisms by which cells can incorporate objects from the outside.

Research in this area will take advantage of expertise and new techniques (including the tweezers and a state of the art confocal microscope) for working with live matter, existing both within BSS and in other university departments. If you are interested in this area please contact Pietro for more details.

Microscopic Swimmers and Pumps (3.5 years)

Life at the cellular level takes place at low Reynolds number (Re), i.e. biological flows are dominated by viscous forces. In order to generate flows or to propel themselves, cells and bacteria have adapted techniques which are very different from the way that pumping and swimming occur at macroscopic scales (everyday flows are high Re). Optical tweezers allow us to exert and measure forces of the order of pico-Newtons, by holding and moving micrometer sized beads. We have recently shown how the possibility of actively moving colloidal particles can be used fruitfully to model the action of cilia and flagella, opening up a new area of research in exploring how the coordinated motion of these elements arises out of hydrodynamic interaction.

Professor AM Donald

Self Assembly in Protein Mixtures

Proteins show apparently universal behaviour, both around their isoelectric points (when the overall protein has no net charge) when particulates form, and away from this point, when amyloid fibrils form. What happens when more than one species is present? This project will look at mixtures of proteins, starting with the commercially important but model case of whey protein mixtures, to test whether at high and low pH, away from the isoelectric points of the constituents, gross phase separation, mixed fibrils, or some alternative form of aggregate occurs for different thermal histories, and the impact of the structure on subsequent properties (e.g. mechanical). The hypothesis to be tested is that mixed amyloid fibrils form away from the isoelectric point, but as charge effects becomes less important in the vicinity of the isoelectric point, phase separation will dominate as entropic effects dominate over enthalpic. A range of techniques will be used including various microscopies, scattering (including the use of national and international facilities such as the new Diamond beamlines) and mechanical testing.

Physical Processes involved in Cell Adhesion and Mobility

In order for cells to adhere, proliferate and move they need to be able to interact with the substrate through the formation of specific contacts (e.g focal adhesions). By using modified surfaces, such as those with chemical or physical patterning, together with novel live cell dyes, it is becoming possible to unravel the nature of the interactions and their impact on processes such as motility and division. We will work with a variety of cell lines (and in close collaboration with biomedical scientists), using light (confocal/fluorescence) and electron microscopy to explore these questions at a physical level to help build up a fuller picture of the processes involved.

Dr E Eiser

Colloidal crystals

The fascination of researchers with colloids started with Perrin and Einstein in the early 20th century, when the existence of atoms was confirmed. It was Perrin and Einstein who realized that one-micrometer large particles (colloids) that are observable by a microscope in time can be used as model system to describe equilibrium properties of atomic or molecular systems. Since then researchers, in particular theoreticians and simulators computed the phase diagrams of colloidal systems for different interaction potentials that would reflect atomic interaction potentials. Very soon it was discovered that for a binary system where the ratio between large to small colloids is about 20 or larger, a distinct solid-to-solid transition must exist. Although we know from condensed metals, that structural polymorphism exist, experimentalists were until now not able to observe such transitions in binary colloidal systems. The main reason is that while atoms of one type are perfectly monodisperse in size, it turned out to be very difficult to make sufficiently monodisperse colloids.

In this project the student will explore colloidal crystallization with a new type of colloid produced here in Cambridge. To study the crystalline structure of the colloids and analyze them the student will have to build a static and dynamic light scattering setup. This demands very good experimental, optics and electronics/computational skills.

DNA-based nanomachines: building molecular sensors

The fact that DNA is made of two specific polymers that are held together by hydrogen bonds alone makes it a very versatile system that can be used to build new nano-machines. Hence by choosing the appropriate sequence of bases in the single-stranded DNA chains one can build arbitrarily many structures ranging from nanometer seized tetraheder to "smilies" and other exotic structures. However, a more practical application of short DNA strands is their potential for biosensors. One example is the detection of single base-pair mismatches. In this case one makes use of collective interactions induced by the presence of gold-nanoclusters. pH-sensitive DNA-switches provide a second example. Here specific folding properties of DNA (forming a so-called I-motive) are used. Such switches can be introduced into confined areas such as cells or nuclei detecting the pH locally.

In this project we use Holliday-junctions (4-way junctions made of four different single strands) to develop logical switches such as AND or NOR switches that could be used both as building blocks to make photonic crystals and/or molecular motors. Although this project is mainly experimental, extensions to theory and simulation studies are possible.

Aggregation and phase behaviour of proteins

While proteins are the motors that make our body function they can also cause severe diseases ranging from cataract formation in the eye lens to Parkinsons or Altzheimers disease. Their generic characteristic is the aggregation of a specific protein. In Altzheimers disease it is the tau-protein that leads to filamentous amyloid-formation while the turbidity (cataract) in eye lenses is due to the aggregation of crystallin-proteins. Although each disease is related to the aggregation of a specific protein, they all suffer from the fact that these aggregates seem to form irreversibly, which makes it hard to treat.

Recently we have discovered that the aggregation of ovalbumin in egg white observed when boiling an egg can be not necessarily reversed into a solution of well folded functional protein but transformed into a different type of gel with optical and mechanical behaviour very different to that of a hard boiled egg or the raw viscoelastic egg white. Further experiments also indicate that the change in aggregation can be explained on the grounds of colloidal physics. Colloids are small entities with sizes ranging between a few nanometres up to microns. Consequently, their behaviour is determined by thermal motion and therefore need to be described with statistical mechanics. Examples of colloids are polymers, viruses, hard spheres, or red blood cells amongst many others. Thus, the biological or chemical nature is not primarily important for the understanding of the phase diagram of colloidal systems. It is rather the interactions between colloids (typically due to Coulomb, van der Waals, steric and depletion forces) that determine their phase behaviour. These interactions can be fine tuned by varying parameters like the ionic strength (in charged systems), temperature or the addition of other molecules. A great example of such fine tuning is milk. Adding bacteria that change the pH of the solution makes the protein (casein) micelles in milk aggregate into a soft gel. While rennet, an enzyme that cuts of the stabilizing part of casein micelles, transforms milk into a tougher gel that we know as cheese.

In this project we want to understand the aggregation observed in globular proteins such as ovalbumin or serum bovine albumin that form at high pH, by building a model colloidal system that can elucidate the general aggregation paths and the relevant interactions involved. We use fluorescently labelled colloids to track aggregation in real time and space using microscopic techniques. Furthermore we want to investigate possible routes to reversibility.

Dr Yan Yan Shery Huang

Spectroscopy of biopolymer/carbon nanotube complexes*

Single-walled carbon nanotubes (SWNTs) demonstrate rich optical response which varies with their surrounding environments. With their small and needle-like physical size (1nm in diameter, and micron in length), they are able to gain access into different narrow channels or cellular compartments with ease. The above two attributes of SWNTs make them ideal probes for chemical substances in microfluidics devices such as lab-on-chip, or in biological cells (typically 10s of micron in size). The aim of this project is to investigate the optical response of SWNTs when they are integrated with various biological polymers, such as DNA, RNA, to sugar molecules in vivo. Spectroscopy techniques such as fluorescence and Raman scattering will be used in conjunction. The ultimate goal is to develop tiny probes based on suitable biopolymer-SWNT complexes, which can report the health of the biological cells using non-intrusive optical techniques.

This project is carried out in conjunction with Dr Ulrich Keyser, Prof Eugene Terentjev (both at Biological Soft Systems, Physics), and Prof Lisa Hall (Analytical Biotechnology, Institute of Biotechnology).

Tailoring soft composites for tissue regeneration*

Mechanical stiffness of the interfacing substrate plays a critical role in the process of cell differentiation/ growth and tissue regeneration. An emerging focus is to develop material interfaces which have mechanical compliance akin to the soft biological surroundings where the bioelectronics are embedded. Combining long thin -F¡flexible¢ conductors (carbon nanotubes) inside a soft polymer-A matrix forms a composite system ideal for stretchable, soft electrodes. These compliant electrodes will see a wide range of applications where electrical stimuli are required to deliver to the cellular system, a good example being the brain electrode. A new process of centrifuge film forming technique has been developed to tailor the electrical conductivity and mechanical compliance of the composite. The project is hoped to bring further understanding in how the change in different physical environments (such as stiffness, electrical stimuli, surface roughness and anisotropy) will affect the differentiation/ growth of different cell lines. The results also hold the key to optimise the material microstructure for bioelectronic applications.

This project is carried out in conjunction with Prof Eugene Terentjev (Biological Soft Systems, Physics).

Dr UF Keyser

DNA Tug of War – Controlling and understanding DNA translocation and relaxation

Single DNA molecules can be inserted and controlled in a single solid-state nanopore. The DNA is driven into the pore by an electrical field in the nanopore. We are able to stall and control the translocation by grabbing the end of the DNA strand using optical tweezers. With this novel technique we study the influence of hydrodynamic interactions on the transport of DNA though these nanopores. We are investigating if it is possible to detect proteins bound to the DNA to determine the primary sequence. In addition, we work on extending the technique to single proteins and nucleic acids in biological nanopores.

Probing the force on DNA-protein complexes in a nanocapillary

Recently, we demonstrated for the first time the detection of the folding state of double-stranded DNA in nanocapillaries with the resistive pulse technique. We show that glass capillaries can be pulled into nanocapillaries with diameters down to 20 nm. We study translocation of DNA which is driven by an electrophoretic force through the nanocapillary. We would like to push the limits of the technique by detecting a single protein molecule on a DNA strand in a nanocapillary by combined measurements with optical tweezers and nanocapillary-based resistive-pulse sensing..

Mimicking protein channels in a chip

Transport of ions, metabolite molecules and macromolecular solutes across biological membranes is an ubiquitous process in nature. Specifically membrane proteins form metabolite-specific channels with large aqueous pores exhibiting affinities to their metabolites. Recently we have introduced a novel approach for the control, detection and manipulation of single nanoparticles by combining microfluidics with laser scattering and holographic optical tweezers. The aim of this project is to study the particle translocations through micro/nano-fluidic channels driven by concentration gradients or electro-osmotic/phoretic forces.

Membrane transport through E. coli and pure lipid membranes

Passive membrane transport is ubiquitous in living organism. One class of special interest are small organic compounds like indole. Our understanding of the roles of indole in bacterial signalling has grown rapidly in recent years. The list of processes in which indole participates is long and diverse. In many respects indole behaves like the signalling component of a quorum sensing system. Indole synthesised within the producer bacterium is exported into the surroundings where its accumulation is detected by sensitive cells. By direct observation of indole import into individual liposomes we have shown that indole can cross a lipid membrane without the aid of a proteinaceous transporter. These observations enhance our understanding of indole signalling in bacteria and, perhaps more importantly, provide a simple explanation for the ability of indole to signal between biological kingdoms.

Dr Sumeet Mahajan

We work in the area of nano-spectroscopy and bio-imaging. Primarily our aim is to develop ultra-sensitive chemical/ bio-sensors via nanotechnology and novel label-free molecular imaging methods for in vitro and in vivo studies. We use surface-enhanced Raman spectroscopy (SERS), which utilizes the electric field enhancement produced from nanostructures, non-linear spectroscopic techniques (such as coherent anti-Stokes Raman scattering, CARS) and continue to innovatively use other conventional optical microscopic methods. We also utilize combinations of spectroscopic and electrochemical techniques to interrogate biosystems and their interactions for developing diagnostic tools for use by medical practitioners. The research in the group is highly inter-disciplinary with many avenues to develop imaginative projects at the interface of physical sciences with biology. So you are advised to get in touch to discuss feasibility of new ideas.

Interactions of drugs with cellular cancer targets*

Techniques such as surface-enhanced Raman (SERS) and coherent anti-Stokes Raman spectroscopy (SERS and CARS) are very sensitive, chemically selective label-free techniques ideal for studying small weakly-fluorescent molecules such as therapeutic drugs in trace quantities. On the other hand kinetics of drug uptake, their mechanism of action and interaction with various cellular components are poorly understood in general. In this project specific cancer therapeutic drugs would be studied by using a combination of Raman spectroscopy based techniques and fluorescence. The techniques could also be applied to study novel molecules being investigated at the Cancer Research Institute at Cambridge. In particular the aim would be to understand the uptake and interaction mechanism with sub-cellular structures such as microtubules (cancer drug targets).The initial in vitro and in cellulo studies would be extended to study perfusion in tissues. The expertise and understanding developed during the project could have wide implications. Besides increased understanding it could lead to design of better drugs (with lesser side-effects) and improved methods for screening drugs aiding their development. The project could also be modified to look at drug delivery.

Raman spectroscopic techniques for characterization and identification of stem cells*

Therapies based on embryonic stem cells (ESCs) for treating neurodegenerative and cardiac diseases are being developed. However, one of the major challenges in this development is to identify and characterize these cells non-invasively, non-destructively without modifying their behaviour. Raman spectroscopy based techniques offer label-free, non-invasive and non-destructive molecular level identification. Unlike fluorescence it doesn't rely on staining or labeling for detection. Surface-enhanced Raman scattering (SERS) and coherent anti-Stokes Raman spectroscopy (CARS) are Raman based techniques which possess high sensitivities along with chemical selectivity to permit cellular imaging. In this project the aim will be to apply various Raman imaging methods to characterize ESCs, ESC-derived and differentiated cells. By suitable component analysis and/or identification of Raman markers the aim will also be to track the level of maturation as these cells differentiate into different lineages. The work would involve collaboration with the Stem Cell Institute at Cambridge.

Ultra-sensitive Sensors for Chemotherapeutics*

Monitoring drug levels in serum or plasma is extremely crucial in chemotherapy and a lot of other disease management regimes. This is necessary due to variability in drug performance due genetic differences between individuals, metabolic conditions and combination medicines usually given to patients. Therefore a fast, highly sensitive and specific method that quantitatively detects drugs is clinically needed. Over the past several years we have developed SERS as a technique, improved its reproducibility and have applied it to DNA mutation detection & chemical sensing. Although SERS is the technique of choice other nano-enhanced techniques which increase sensitivity could also be explored in this project. Nevertheless, the overall aim will be develop a scalable and reproducible method utilizing nanostructures for highly sensitive detection at the physiological level in biofluids. The student will be expected to work collaboratively with scientists at Cancer Research Institute.

Professor U Steiner

Block co-polymer based metamaterials

A metamaterial uses sub-wavelength building blocks that have resonant optical characteristics, mimicking atoms or molecules, but fabricated from metals into shapes such as rings, slots, voids, or plates. The resulting optical characteristics can then be described by a uniform complex dielectric constant but can exhibit negative refraction, super-refraction, electromagnetic cloaking, enhanced absorption/emission, and host of other phenomena. One of the greatest difficulties in constructing nanostructures in which the fundamental building blocks are much smaller than the wavelength of visible light, is the restricted technology available for their fabrication. The aim of this project is to synthesise materials with well controlled sub-wavelength structures which are formed by molecular self-assembly processes. These organic materials are used as scaffolds for the synthesis of optical metamaterials. The project is an interplay of material synthesis strategies and the optical characterisation of the resulting nano-structured specimen. This project is a collaboration with Prof. Jeremy Baumberg.

Non-equilibrium polymer morphologies in confinement

Polymers in thin films are technologically important in coatings but also in high-tech applications such as semiconductor lithography. As smaller and smaller structures become technologically relevant, the relatively large size of macomolecular molecules starts to paly a role. This project aims to develop a quantitative understanding how the physical properties of polymers changes upon confinement and how they depend on film preparation.

Structure-function relationship in organic photovoltaics

The performance of all-organic solar cells has substantially improved over the past 10 years, caused by advances in the synthesis of new materials and their assembly into photovoltaic devices. While the performance of the these devices depend on the detailed assembly of several component on the 10-nm length scale, only very little is know about how the 10-nm morphology of these materials influences the solar cell performance, and how these morphologies arise from the preparation of these devices. From a fundamental view, this is a very complex problem. It involves the interplay of polymer-polymer demixing with the crystallisation of the individual components. The purpose of this project is to make use of the current know-how in polymer science to gain a quantitative understanding in structure formation in photovoltaic blends, and the resulting photovoltaic performance. This project is collaboration with Prof. Richard Friend.

Butterfly photonics

The colour of butterfly wing scales arises mainly from the photonic structure in these scales. In contrast to pigment colour, these structural colours are particularly brilliant, and have interesting directional reflection and polarisation properties. As such, butterfly colours are interesting in the field of optical security labels (e.g. bank notes, passports), because they cannot be easily copied. This project entails the development of a manufacture strategy to generate a replica of the Morpho butterflies, which are among the optically most striking butterflies.

Professor E M Terentjev

The specific nature and details of proposed research are changing and evolving, so it is best to contact me directly about the current state of affairs. Some themes may continue from the work done in the past years:

Organic synthesis of new polymers and liquid crystalline systems

There is certainly a scope for a full PhD project in synthetic chemistry and material characterisation, based in our chemistry lab and supervised jointly with an experienced organic chemist. The aim here is to obtain new molecules with mechanical or photo-functionality, such as a new surfactant for the dispersion of carbon nanotubes in a given polymer, which would impart photo-mechanical or photo-electric response to the matrix.

Thermal, photo and electric actuators

Embedding orientationally ordered and aligned units into a rubbery matrix, and making them change their state on a given external stimulus, results in a spontaneous equilibrium mechanical actuation of the composite. Our group has over 10 years of history in this field, ranging from carbon nanotube composites to nematic liquid crystal elastomers. This project has a strong engineering and/or chemistry element because new materials need to be frequently produced. Present and near-future targets are in developing actuating fibres, micron-size shape-changing particles and large-area tactile displays.

Molecular and phase chirality by optical rotation

As with all other projects, this is a generic group of problems which combine theoretical and experimental issues related to the spontaneous formation of coherent (macro- or mesoscopic) structures with chiral nature. Familiar examples of these include d-helix of DNA and a-helix motif of protein folding, but there are many other structures in non-biological as well as living soft matter. One of the experimental methods to investigate the phase transformations that lead to such structures is the optical rotation, which is a developing instrument in the group.

Theoretical modelling of soft-matter and biological systems

The range of possible problems under this heading is large and constantly evolving: for instance, recently we were active in studying properties of semiflexible filaments and their network &emdash; both from the point of views of their growth kinetics (related, for instance, to the amyloid fibrils or actin cytoskeleton) and the resulting dynamic-mechanical properties. Another problem with good prospects for the future is modelling cell adhesion and mobility by combining the stochastic dynamics of Kramers-like systems with our understanding of gel viscoelasticity, leading to the modelling mechanosensitivity of cells (the response to external forces or mechanical constraints).