I was particularly struck by a recent paper from the Kozmin group on the mechanism of action of bistramide A. This very interesting natural product demonstrates promising anticancer activity, but is also highly toxic when delivered to mice. Interestingly, two other members of this family of compounds known as bistramides D and K, which both lack an enone moiety that is present in bistramide A, have been shown to be much less toxic while maintaining promising levels of anticancer activity in a mouse xenograft model.

The mechanism of action of this family of natural products has been hotly debated, but a few years ago the Kozmin group identified actin as the potentially therapeutically-relevant cellular target. This hypothesis was strongly supported by this group’s recent discovery and high resolution X-ray characterization of a bistramide A/actin complex. However, the mechanistic role, if any, of the conspicuous enone moiety of bistramide A could not be determined from this structure because this portion of the crystal was highly disordered.

In their recent PNAS paper, Kozmin and coworkers harnessed the remarkable efficiency and flexibility of their previously reported total synthesis of this complex natural product to prepare a series of elegantly designed analogs that collectively revealed the criticality of this enone moiety for potent cell-based growth inhibition. Moreover, consistent with the X-ray structure, these studies demonstrated unambiguously that both the spiroketal and amide subunits of bistramide A are required for high-affinity non-covalent interactions with actin that can lead to the severing of actin filaments. Follow-up studies with mass spectroscopy and a synthesized fluorescent analog collectively demonstrated that the enhanced cell-based activity attributed to the enone is due to covalent modification of the target protein, likely via conjugate addition of a cysteine residue. Collectively, these results support a dual mode of action of bistramide A involving the severing of filamentous actin as well as covalent modification of this protein target.

Interestingly, these results reveal a potential explanation for the increased in vivo toxicity of bistramide A relative to its enone-lacking counterparts. The severing of actin filaments (which does not rely on covalent modifications) may be sufficient to inhibit the proliferation of rapidly dividing tumor cells, whereas the dose-limiting toxicity may be caused by enone-mediated covalent modifications of this ubiquitous protein target. This compelling hypothesis remains to be tested, but this paper clearly demonstrates the critical importance of fundamental understanding of small molecule function to guide the search for more effective and less toxic therapeutics. It also represents a striking demonstration of the tremendous power of an efficient and flexible total synthesis of a complex natural product to enable the execution of illuminating experiments that are otherwise simply not possible.

Marty Burke is an assistant professor in the Department of Chemistry at the University of Illinois in Urbana-Champaign. His research focuses on the synthesis and study of small molecules with the capacity to perform higher-order, protein-like functions.

Newcastle University says researchers led by Lyle Armstrong have made hybrid embryos containing material from cows and humans. The announcement comes just as the government gears up on whether or not the creation of such embryos should be legal. Newcastle University, which already had approval for the research from UK regulatory authorities, decided to push forward so the research would not risk being stalled by an upcoming vote in the House of Commons, reports the BBC.

The embryos lived for three days, and were not used to make embryonic stem cells, according to that report. They were made by putting human DNA into cow eggs after the cow chromosomes had been removed. Scientists argue that such procedures are valuable both to understand how embryos develop, to develop better techniques for making embryonic stem cell lines, and to develop more useful embryonic stem cells. The hybrid embryos cannot, by law, be allowed to develop for more than two weeks, when some precursors of nerve tissue develops. The first reported human-animal chimeras combined human nuclei with rabbit eggs; other chimeric animals have been made as well. Here’s an old summary. Here’s a newer one.

See Nature Reports Stem Cells commentary on a scientific argument for chimeras by Ian Wilmut , a theological argument for chimeras by Ted Peters, and an argument against creating and destroying embryos for research by Markus Grompe. We also summarized the UK Academy of Medical Sciences’ report on this issue.

The UK press has been roiling with accusations by the Catholic Church that the work is monstrous. Scientists have responded that the Church is misrepresenting the science and have offered to meet with religious officials. For a recent example, see the New Stateman.

Newcastle has a history of dramatically announcing accomplishments before work appears in the peer-reviewed literature. In February, they announced the creation of embryos using material from three people. See Erika Check Hayden’s article in Nature News.

The Science Media Centre has already released statements of scientists’ responding to the news, all saying that they lack data to assess research. Here are those statements:

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