Warburg redux

Eighty-five years ago, the German biochemist Otto Warburg had a theory about cancer. In an age when electron microscopes were little more than a theoretical dream, Warburg, who won the Nobel Prize in 1931 for his work on cell biology, hypothesized that cancer resulted from a dysfunction of the mitochondria, often considered the power plants of cells because of their ability to generate energy.

In healthy cells, the mitochondria use oxygen to break energy free from a power-packed acid called pyruvate in a process known as respiration. Cancerous cells generate their energy without oxygen, a trait that has come to be known as the “Warburg effect.” Warburg hypothesized that defects in cellular structure associated with the process of respiration were a prime cause of cancer.

Since Warburg’s time—he died in 1970 at the age of 86—theories of cancer have gone in another direction, and it has been accepted that tumors result from mutations in the oncogenes, strands of DNA that activate cell growth. The Warburg effect was seen as a response to the oxygen-deprived conditions brought on by tumorous growth. However, Warburg’s overlooked theory can still inform today’s cancer research, according to Thomas Seyfried, a biology professor at Boston College.

Looking at spontaneous and induced brain tumors in mice, Seyfried found the cancerous cells had abnormalities in their mitochondria. Specifically, they had defects in their cardiolipins, a relative of fat found in the inner mitochondrial wall. These abnormalities were enough to compromise the respiration of the cancer cells, triggering a change in how the cells’ energy was produced, Seyfried wrote in a report published in the Journal of Lipid Research last year.

Such abnormalities can have many causes. It is possible the mutations that caused the cancerous tumors are to blame. It is also possible they are inherited. “Environmental insults”—including oxygen deprivation, premature cell death (called necrosis), and dietary imbalances—could produce the failed cardiolipins, as well.

While Warburg thought irreversible injury to respiration initiated cancer, Seyfried says it is unclear whether the cardiolipin abnormalities he found in the mice “arose as a cause or as an effect . . . of tumor progression.” He notes that other diseases, diabetes among them, exhibit similar abnormalities. Still, he writes, the findings “provide new evidence” of links between dysfunction of cardiolipins and Warburg’s neglected theory.

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Change agents

A new catalyst designed by researchers at Boston College in collaboration with scientists at MIT has proven effective at solving one of the thornier challenges of catalysis: producing organic (carbon-based) compounds that are uniform in shape. The work, reported in the December 18, 2008, issue of Nature by Amir Hoveyda, the University’s Vanderslice Millennium Professor of Chemistry, and others has potential applications in the development of medicines, fuels, and polymers.

While simple molecules are two-dimensional, most complex compounds generated by catalysts (the substances that encourage and cause chemical reactions) are three-dimensional. They also tend to emerge in two forms at once—as mirror-image creations that each behave differently. Think of your two hands, which are copies but cannot be superimposed; this condition is known as chirality. Hoveyda’s goal was to design catalysts to yield complex molecules sans their twin compounds, through a specific kind of reaction.

The new catalyst causes olefin metathesis reactions, a process pioneered in part by MIT’s Richard Schrock, a 2005 Nobel Prize winner and Hoveyda’s collaborator since 1997. Olefin metathesis is frequently compared to a country square dance where partners are swapped mid-song. In this catalytic dance, the partners are tightly bonded carbon atoms. You can find carbon-carbon double bonds in the simple feedstock chemicals that are used to create a wide range of plastics as well as in many medicines.

Olefin metathesis is frequently triggered using one of two catalysts, each with a transition metal at its center. A popular class of catalysts contains ruthenium, but it has trouble producing molecules with high efficiency and without also generating their mirror-image partners. The other catalyst, which uses molybdenum, is capable of producing pure chiral compounds—only left hands, no right hands. Unfortunately, it does not always react well with other molecules.

Hoveyda and his colleagues developed a molybdenum-based catalyst that generates olefin metathesis reactions with a wide range of chemicals, and does so efficiently and economically. This is largely due to the catalyst’s ligands, four swappable molecules that stem off the central molybdenum in appendage-like fashion.

These ligands are fastened to the molybdenum core by single atoms, and despite this weak bond, they do not wobble or rotate. (If they did, the catalyst would fail to produce consistent molecules at predictable rates.) Also, thanks to their single bonds, the ligands, which help to shape molecules during the reaction, accommodate larger structural changes than previous catalysts. That allows the new catalyst to cause faster reactions than earlier generations, which used two atoms to stabilize their ligand arms.

In a detailed analysis of the Nature paper, Steven Diver, a chemist at the University of Buffalo, wrote in Nature that Hoveyda, Schrock, and associates have “discovered a bold new design . . . that will inspire the development of future generations of catalysts, not only for olefin metathesis but also for many other catalytic reactions.”

Paul Voosen ’03 is a writer based in Washington, D.C.

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