Background

My research background is based on a combination of medicinal chemistry and the chemical biology of lipids and proteins.  The approach behind the term chemical biology is using knowledge and techniques developed in physical science, applied to biological systems.  As I typically work at a molecular level, this approach is combined with the reductionist approach used in biochemistry.  The latter is defined as an analysis in which systems are broken down to their component parts and the interactions between those components are investigated in order to understand the system itself.

Chemical biology allows us entry into an understanding of the physical role of lipids in biological system.  However, it is also important to understand the molecular profile of the biological systems under study.  This makes metabolomics studies like lipidomics and proteomics important to this area of research.

Fig. 1, HeLAS cells dividing, showing the cervix. Image courtesy of Harold C. Smith, University of Rochester, Rochester, NY, USA.

The Wider Plan

It is not controversial to state that in order for a cell to reproduce mitotically three major processes are required.  First, the cell must replicate its nucleic acid structures and so form two nuclei.  The discovery of the structure of DNA in the 1950s precipitated the wider investigation of the chemistry of this process [1].

Second, protein synthesis must occur in order that the two new cells have the biological machinery required for survival [2], and so the cell cycle may be controlled [3,4].  The latter was the focus of the Nobel-prize winning work of Sir Paul Nurse, Sir Tim Hunt and others.

Third, the membrane needs to expand in surface area, bend, and be divided in order that two daughter cells are formed (Fig. 1.).  These physical membrane-division processes must occur in a tightly controlled manner in order that the biological dis‑equilibrium across the membrane is maintained in the daughter cells.

Fig. 2. An ordinary lipid bilayer, shown here with membrane proteins [2]. The latter are in grey, the red spheroids represent polar lipid head groups, where the green section represents fatty acid residues.

 

The current understanding of how membranes and other aggregations of lipids behave, has been formulated over the last five decades by independent advances in areas in life and physical science.  A well-known theory is the fluid mosaic model [5] (Fig. 2.).  Despite evidence that supports aspects of this theory, it fails to account for a number of the more recent observations concerning the behaviour of minor lipids [6-9], and proteins [10,11], in membranes.  Further, it cannot be extended to encompass the activity surrounding a membrane’s division, or movement of membrane surfaces [12].

Fig. 3. A graphical representation of tie Ia3d phase in which a lipid bilayer is draped over a [static] surface that curves in opposite directions simultaneously.

 

As many of the processes in cellular membrane division are intrinsically chemical or physical, biological techniques and data alone have not been able to answer this question.  Despite this, thorough investigation into the biophysical behaviour of the few lipid types that comprise the larger part of the membrane has established the physical behaviour of many of these biologically-relevant lipids [6,9,13,14].  Recent work on inositides in particular suggests that although they represent <10% of the lipid composition [15-22], they display behaviour consistent with a pronounced effect on the phase behaviour of lipid systems [23-25], with evidence for phases with surface topology consistent with the cervix of a dividing cell (Fig. 3.).  Although this in itself is not proof that lipids are entirely responsible for driving this change, it seems evident that their role is more than simply a complicit one [11,12], suggesting that the physical properties of lipids has a direct role in this process. However, this falls a long way short of explaining the physical lipid-driven part of the process of cell division.

Recent and Current work

As the work on the bulk lipid types does not explain all of the lipid behaviour observed in cellular transformations, and the physical structure of proteins is unable to overcome all thermodynamic barriers, the focus falls on the remaining factor. In this case, the minor components of the membrane, especially those that have a closely controlled turnover, become a focus. This led to an exploration of the physical behaviour of  inositides.  Previous work at Imperial College by Mulet et al. [23] found that hydrated phosphtidylinositol-dioleoylphosphatidylcholine systems produced mesophases with very high inverse curvature.  My work shows that a phosphatidylinositol phosphate also produces systems with strong curvature [24,25].

The behaviour of lipid and protein systems in plants, particularly inositides, has been investigated since their discovery [26-28], though a variety of questions remain, including many of the ones about the physical role of lipids that also pertain to mammalian systems. Some of my recent work at the University of Nottingham has shown that an amphiphilic protein from plants, called oleosin, may have the crucial role in maintaining certain organelles during seed desiccation [29].

Applications of This Research

Studies into cell division, especially with a focus on the role of lipids in the process has a potentially unending number of applications in cellular biological systems.  For example:

(a)   Cancer research
(b)   Foetal growth study
(c)   Growth of single-celled organisms in infectious diseases
(d)   Neuro-transmitter re-uptake systems with respect to anti-depressants etc.
(e)   Endocytosis, e.g. immune response to infectious disease

 

References

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[24] S. Furse, Ph.D., Imperial College London, 2011.
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[29] S. Furse, S. Liddell, C. A. Ortori, H. Williams, D. C. Neylon, D. J. Scott, D. A. Barrett, D. A. Gray. Journal of Chemical Biology (accepted for publication, 2012-12-28, available from January 2013 at http://dx.doi.org/10.1007/s12154-012-0090-1