Drew Endy

Posted on 05 Sep 2007 by Corie Lok

Massachusetts Institute of Technology, Cambridge, USA

A biological engineer searches for simplicity.

Several years ago, a good colleague suggested that I read about a discussion held in 1864 on nuts and bolts (J. Franklin Inst. 77, 344–351; 1864). The focus was a paper by one William Sellers that argued for the adoption of a uniform system of screw threads — 60° angles, squared off along the edges.

Machinists across the United States eventually started producing nuts and bolts according to Sellers’ scheme. As a result, hardware stores now offer a wide selection of standardized parts that can be used in combination and behave as expected.

Inspired by this example and others, I have been studying how synthetic biological parts might be made as regular and easy to use as Sellers’ nuts and bolts.

The starting complexity of nature has led some distinguished researchers to doubt such work is practical. But given that there has been little research on manufactured bio-simplicity, this seems premature.

And there are examples: a team at the California Institute of Technology in Pasadena recently developed a uniform system for engineering simple biological switches made from ribonucleic acids (M. N. Win and C. D. Smolke Proc. Natl Acad. Sci. USA doi:10.1073/pnas.0703961104; 2007).

The ‘nuts and bolts’ of the switches are RNA sensor and actuator domains. The method for combining any sensor domain to an actuator domain through a third communication domain provides the ‘uniform screw threads’. Because such switches are produced by a standard process, many switches could be quickly programmed to control diverse cellular functions in response to myriad molecular inputs, from small molecules, to peptides, to nucleic acids.

I suspect that further efforts to engineer biological simplicity will have similarly powerful results.

Michael A. Marletta

Posted on 11 Jul 2007 by Corie Lok

University of California, Berkeley, USA

A biochemist marvels at a molecule that shares his love of playing with fire.

I like to capture my students’ attention by recounting how my early fascination with fire inspired my interest in the stability of sugars.

Glucose will ‘burn’ to carbon dioxide and water, liberating lots of energy. But it is stable enough that you can stamp on it without triggering the reaction — the energy barrier to the reaction is too high.

In my research, I am interested in how biology harnesses and controls oxygen reactivity. Most reactions, such as burning glucose, are held back by an energy barrier to getting things started. Enzymes can bypass this, finding a lower energy route through some reaction intermediate, to carry out a ‘controlled burn’. Their control is not perfect, sometimes causing damage to both themselves and surrounding molecules, but by and large it works.

Typically, these enzymes have metal or organic components, which drive the oxidation. I often tell students that enzymes need their metal and organic cofactors because the 20 naturally occurring amino acids cannot carry out all the chemistry. Two recent papers shake that belief.

The surprise comes from the enzyme DpgC, which is involved in the biosynthesis of the antibiotic vancomycin. The first paper (C. C. Tseng et al. Chem. Biol. 11, 1195–1203; 2004) reports that DpgC uses oxygen in a complex dioxygenase reaction with no bound metal or organic cofactor.

More recently, researchers reported the structure of DpgC and confirmed that it has no cofactor (P. F. Widboom et al. Nature 447, 342–345; 2007). They find that the enzyme has a structure known as an oxyanion hole, which helps to stabilize the reaction intermediate.

I am still amazed that DpgC does oxygen chemistry with no help — and my students should be too.

Allan Balmain

Posted on 04 Jul 2007 by Corie Lok

University of California, San Francisco, USA

A cancer geneticist delves into family matters.

A mystery lies at the heart of a small family of growth signalling enzymes (K-Ras, H-Ras and N-Ras), which are widely mutated in human cancers. In culture, all three enzymes have similar functions, but different ras genes are associated with cancers in different tissues.

My laboratory, for instance, noted more than 25 years ago that skin cancers show activation of H-ras. Others have demonstrated that lung, colon and pancreatic cancers show activation of K-ras, whereas N-ras is the oncogene of choice in melanomas and some leukaemias.

What determines this intriguing specificity? Are the enzymes’ functions somehow modified in certain tissues in vivo? Or is it regulation of the genes, affecting where and when they are expressed, that matters?

We may get some answers by following the lead of an elegant study (N. Potenza et al. EMBO Rep. 6, 432–437; 2005). In this work, the authors knocked out K-ras in mice, but simultaneously replaced the gene with its close relative H-ras, doctored to have the regulatory elements of K-ras. Mice can survive without the H-ras or N-ras genes (or even both of them) but usually die if K-ras is deleted. These mice, despite lacking K-ras, were viable and lived to a ripe old age.

This important observation provides novel opportunities to probe the mechanisms of cancer initiation. Are the mice lacking K-ras now resistant to the lung and pancreatic cancers that are normally linked to K-ras? If yes, this would indicate a true requirement for the K-Ras protein in lung-cancer development; if not, the focus would switch to regulation.

A straw poll of Ras cognoscenti suggests that opinion is for now divided, but my group and others are working on this mouse model, and hope to have answers soon.

Jeffery W. Kelly

Posted on 07 Mar 2007 by Corie Lok

The Scripps Research Institute, La Jolla, California, USA

A biochemist considers whether protein misfolding plays a part in type II diabetes.

Much of my research is on cellular protein folding, and in particular on how protein misfolding or protein aggregation causes disease. My group has developed therapies for a spectrum of misfolding diseases, most of which are associated with neurodegeneration, such as Alzheimer’s.

But we are beginning to appreciate that therapies that affect protein folding could have a role in treating a much wider spectrum of diseases than is currently realized.

A compelling article from Gokhan Hotamisligil and his colleagues at Harvard University (U. Özcan et al. Science 313, 1137–1140; 2006) presents one example. They found that mice that are both obese and diabetic benefit from treatment with drugs that enhance protein folding.

Their experiment was motivated by observations that linked obesity and diabetic insulin resistance to stress in the endoplasmic reticulum (ER), a compartment in cells where a third of all proteins are folded.

The researchers gave their fat, diabetic mice chemicals that enhance protein folding in the ER. The effect was notable: the mice’s blood-sugar levels fell, they showed increased glucose tolerance and reduced lipid accumulation in the liver.

This suggests to me that protein misfolding may be at the heart of type II diabetes, the age-related disease for which these mice are a model.

Folding of the insulin receptor is inefficient. So it seems reasonable to speculate that cells could become insulin-resistant because of compromised insulin-receptor folding in the ER.

We may find, as we develop more selective small molecules to enhance ER folding, that we discover other disorders that can be treated in this way.

David R. Liu

Posted on 21 Dec 2006 by Corie Lok

Harvard University, Cambridge, Massachusetts, USA

Thanks to the discovery of a new catalytic RNA, a chemical biologist can satisfy his student’s curiosity.

An first-year undergraduate recently asked me a remarkable question: are all natural ribozymes, RNA molecules with catalytic activity, simply leftovers from the ‘RNA world’? The RNA-world hypothesis supposes that RNA molecules were precursors to the first primitive forms of life, before the evolution of DNA and proteins.

Unanswered, my student’s question preoccupied me until I encountered a recent paper by Jack Szostak of Massachusetts General Hospital, Boston, and his co-workers (K. Salehi-Ashtiani et al. Science 313, 1788–1792; 2006).

Prior to this work, only two of the known natural ribozymes were associated with mammals. The rarity of catalytic RNAs in more recently evolved, higher-order cells could reflect their attrition on the evolutionary battlefield during the rise of more highly functional protein enzymes.

This paper, however, supports a different conclusion. Szostak’s group designed an ingenious system to isolate self-cleaving RNA molecules from RNA encoded in the human genome. Using this system, they discovered several new ribozymes.

One of these ribozymes, associated with a gene known as CPEB3, is highly conserved among placental mammals and marsupials, but is absent from non-mammalian vertebrates. This observation suggests that it arose relatively recently, around 200 million years ago.

We can therefore infer that some ribozymes have evolved in modern organisms, long after the era of the RNA world. The work elegantly demonstrates a new approach to the study of ancient molecules — and also reminds me that our youngest students can ask some of the best questions.

Lewis E. Kay

Posted on 06 Dec 2006 by Corie Lok

University of Toronto, Canada

The molecular dance of a protein allows a chemist’s secret wish to come true.

One fascinating aspect of molecular function is the way information propagates between parts of a molecule that can be many tens of angstroms apart.

Our understanding of how proteins do this, a process termed allostery, emerged from Max Perutz’s pioneering studies of oxygen-carrying haemoglobin. Three-dimensional images show that when a ligand binds to part of the molecule, a discrete set of structural changes take place at distinct sites. This, in turn, influences the ease with which subsequent ligands bind.

Nature has chosen this model in designing many allosteric proteins. However, as a practising nuclear magnetic resonance (NMR) spectroscopist with a strong interest in protein dynamics, I was secretly hoping she might design proteins in which information is communicated through changes in the dynamics between distal sites, with little or no change in overall structure. Moreover, I was rooting for NMR to play a major role in characterizing such a system.

How exciting it was, therefore, to read that Charalampos Kalodimos and his co-workers recently found such a case by studying the motional properties of a protein in different ligated states (N. Popovych et al. Nature Struct. Mol. Biol. 13, 831; 2006). Using NMR spectroscopy, the team quantified protein dynamics for a wide range of timescales. Remarkably, ligand binding at one site is linked to changes in motion far removed, over the complete set of timescales, while a corresponding propagation of structural changes does not occur.

The work of Popovych et al. provides a striking example of the importance of protein dynamics to information transfer. I eagerly await the discovery of more molecular dances and of how they, too, will relate to biological function.

Frances Ashcroft

Posted on 08 Nov 2006 by Corie Lok

University of Oxford, UK

A physiologist discusses matters close to the heart.

This time last year my father was suffering from congestive heart failure. He became increasingly frail, slowing down like an unwound clockspring until, in February, his heart simply stopped.

As a physiologist, I had some idea of his condition, but I did not then realize how close it was to my own research area.

In 1983, ATP-sensitive potassium (K-ATP) channels were found in the heart. These channels are gated pores that control potassium fluxes across the cell membrane. However, their precise role in the heart was unclear.

One year later, I discovered that these channels are central to the mechanism by which glucose stimulates insulin secretion from the pancreas. Unravelling the role of K-ATP channels in diabetes, and the way in which channel structure influences function, has been an all-consuming passion for me ever since.

To my surprise, it now turns out that these channels also play a role in heart failure. Heart failure is usually caused by narrowing of the arteries, which increases the pressure against which the heart has to pump, making it work harder. Eventually, it fails.

Recently, Andre Terzic of the Mayo Clinic in Rochester, Minnesota, and his group showed that K-ATP channels confer protection against heart failure (S. Yamada et al. J. Physiol. Lond. published online doi:10.1113/jphysiol.2006.119511; 2006). In normal mice, cardiac K-ATP channels open in response to an increased pressure load, reducing stress on the heart. Mice lacking K-ATP channels rapidly develop heart failure and die.

In the pancreas, K-ATP-channel activity is finely balanced: too much causes diabetes and too little hyperinsulinism. But in the heart, as this paper shows, opening is almost always beneficial.

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