Humans, in common with most other animals and even bacteria, live and grow best at a moderate temperature with little change either up or down. On examining the physical behaviour of the lipids involved, we find a set of biomolecules exquisitely organised for our continued existence. There are lots of different sorts, and many organisms can adapt their lipid profile when conditions change a bit. For example, yeast can change the length of the carbon chains in its fatty acid residues to make its membranes less fluid. It can also introduce more unsaturated bonds into its lipids to make its membranes more fluid. However, the scope for this adaptation is limited both by what it can achieve (fluidity only goes so far) and that the genetic hardware for the different types of adaptation is not present all species. This raises the question of how we acquired the lipid profile we now have.

We could develop two hypotheses about the evolution of lipids in cells from the observations above. First, that the lipids we rely upon are difficult molecules that only really work well under quite particular conditions and our cells have exploited flexibility where it exists, but essentially, have obediently evolved around it. Second, that we have acquired a set of lipids that fits our purpose. That they have evolved alongside us, and the compromise that applies to all other aspects of evolution applies equally to lipids.

An observational comparison of the lipids in, say E. coli and Homo sapiens, might lean rather towards the first hypothesis. E. coli is made up principally of phosphatidyl ethanolamine (PE), with lesser amounts of phosphatidyl glycerol (PG), and cardiolipin (CL). Homo sapiens have all three of these lipids in plentiful supply in their cells. There are other lipid species too, but not in a way that makes one think that the two or three billions of years of evolution that separate humans and bacteria have reshaped the lipid fraction all that much.

The comparison between the lipids of E. coli and Homo sapiens is not really inconsistent with the second hypothesis, however—one might simply argue that humans and bacteria have similar requirements, such as a body temperature of 37 °C, and that is what shapes the lipids they have.

What we really need to conclude whether hypothesis one or two is correct is the existence of one or more lipid systems that demonstrably do not conform to the rules of ~37 °C, 0·9% salt and pH 7·4. We would have to see basically the same cells that we are familiar with but under considerably and obviously different conditions, and with different lipids.

This may be regarded as a good justification for searching for life on other planets. However, that approach has a fundamental flaw: there are terrestrial life forms that allow us to choose one of the hypotheses over the other. That is the domain of life known as Archaea. These are sometimes known by the slightly twee name of ‘extremophiles’ because they live in conditions that are different to our own preferred ones. The optimum conditions for growing Haloferax volcanii are 45 °C, 2·5 M NaCl and ~0·17 M Mg++ [1,2]. For comparison, this means it grows in conditions that are about 20°C warmer than we can comfortably live at, with 13× as much salt and very nearly 250× as much magnesium. There are others that seem less plausible still. Sulfolobus acidocaldarius have optimum growth conditions of 70-80 °C at a pH of about 2 [3].

Such conditions would hydrolyse the lipids that make up our cells. The ester groups that bond the fatty acid residues to the glycerol moiety* in would be hydrolysed, as would the phosphate moiety from its alkyl groups. Our cells would survive only for a few seconds.  This raises the question of which lipids these extraordinary organisms have and what protection they offer to archaea that our own lipids do not confer on us.

First, the carbon chains are attached by ether, rather than ester, functional groups. These are much more resistant to acid- and heat-mediated hydrolysis. Furthermore, most of the lipids found in archaea are really ‘double’ lipids called bolamphiphiles. This means they have a head group at either end of a longer pair of chains. There are few or no unsaturated bonds. These features give a more rigid structure and may be the reason for other, counter-intuitive properties.

The higher temperatures that archaea grow at mean that deliberate efforts to confer fluidity on membranes do not seem to be as important. This means that the appearance of larger carbon rings than those observed in prokaryotic life forms: 5- and 6-membered instead of 3-membered, are remarkable. Furthermore, the hydrocarbon fraction of the lipids contains far more methyl groups than are typically observed in prokaryotes or eukaryotes. These also confer fluidity on the hydrocarbon fraction of the lipids.

There are several features that are very similar, however. The lipids in Haloferax volcanii also comprise analogues of PA, PG, PG phosphate and CL [4]. This is rather surprising because archaea are almost as distant a life from Homo sapiens as are E. coli. The evidence that these lipids appear in all three domains suggests that these lipids may be the oldest phospholipids. This is a tantalising clue as to what the common ancestor to all life on earth might have been like.

Despite this insight, there are still a number of questions that remain. Does the evidence that archaea have genomic strategies consistent with the ancestral life forms that gave rise to all current terrestrial life [5] extend to lipids, i.e. does it give us clues as to what the very first lipids were? Do archaeal cells shift their lipid profile through the cell cycle in the way that E. coli [6] and cells from Homo sapiens [7,8] do? At present, even the phase behaviour of archaeal lipids is not particularly clear. The third domain really has opened up a new line of research questions for both lipids and their role in vivo.


References and Notes

[1] T. Allers, S. Barak, S. Liddell, K. Wardell, M. Mevarech, Applied and Environmental Microbiology, 2010, 76, 1759–1769. DOI: 10.1128/AEM.02670-09.

[2] T. Allers, H. P. Ngo, M. Mevarech, R. G. Lloyd, Applied and Environmental Microbiology, 2004, 70, 943–953. DOI: 10.1128/AEM.70.2.943–953.2004

[3] L. Chen, K. Brügger, M. Skovgaard, P. Redder, Q. She, E. Torarinsson, B. Greve, M. Awayez, A. Zibat, H. P. Klenk, R. A. Garrett, Journal of Bacteriology, 2005, 187, 4992-4999. DOI: 10.1128/JB.187.14.4992–4999.2005

[4] G. D. Sprott, S. Larocque, N. Cadotte, C. J. Dicaire, M. McGee, J. R. Brisson, Biochimica et Biophysica Acta, 2003, 1633, 179–188. DOI: 10.1016/j.bbalip.2003.08.001

[5] M. Wang, L. S. Yafremava, D. Caetano-Anollés, J. E. Mittenthal, G. Caetano-Anollés, Genome Research, 2007, 17, 1572–1585. DOI: 10.1101/gr.6454307

[5] S. Furse, H. Wienk, R. Boelens, A. I. P. M. de Kroon, J. A. Killian, FEBS Letters, 2015, 589, 2726-2730. DOI: 10.1016/j.febslet.2015.07.043

[6] G. E. Atilla-Gokcumen, E. Muro, J. Relat-Goberna, S. Sasse, A. Bedigian, M. L. Coughlin, S. Garcia-Manyes, U. S. Eggert, Cell, 2014156, 428-439. DOI: 10.1016/j.cell.2013.12.015.

[7] C. V. Hague, A. D. Postle, G. S. Attard, M. K. Dymond, Faraday Discussions 2013 161, 481-497. DOI: 10.1039/c2fd20078c

*This is often called a ‘glyceride backbone’. I don’t know why because it’s more like the pelvis than anything. I think saying ‘glyceride backbone’ is an effort by science communicators to make this sort of molecule sound cool/accessible. I have no interest in being cool so I am opting for blind adherence to factual accuracy. I think that’s more daring.