Cell Death Sells: No Slowdown in Apoptosis "Hysteria"

Cell Death Sells:
No Slowdown in Apoptosis "Hysteria"

by Jeremy Cherfas

WHAT'S HOT IN BIOLOGY...

Rank	Paper	Citations This Period Sep-Oct 98	Rank Last Period Jul-Aug 98
1	S. F. Altschul, et al., "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs," Nucleic Acids Res., 25(17):3389-3402, 1 September 1997. [NIH, Bethesda, MD; Pennsylvania St. U., University Park] *XU793	75	1
2	R.M. Kluck, et al., "The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis," Science, 275(5303):1132-6, 21 February 1997. [La Jolla Inst. Allergy and Immunol., San Diego, CA] *WJ503	67	5
3	J. Yang, et al., "Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked," Science, 275(5303):1129-32, 21 February 1997. [Emory U., Sch. Med., Atlanta, GA:] *WJ503	63	4
4	F.R. Blattner, et al., *"The complete genome sequence of Escherichia coli* K-12,"** Science, 277(5331):1453-74, 5 September 1997. [U. Wisconsin, Madison; U. Michigan Sch. Med., Ann Arbor; FMC Bioproducts, Rockland, ME; U. Natl. Autonoma Mexico, Moreles] *XV429	59	2
5	V.V. Ogryzko, et al., "The transcriptional coactivators p300 and CBP are histone acetyltransferases," Cell, 87(5):953-9, 29 November 1996. [NIH, Bethesda, MD] *VV774	43	3
6	P. Li, et al., "Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade, " Cell, 91(4):479-89, 14 November 1997. [Howard Hughes Med. Inst., U. Texas Southwest. Med. Ctr Dallas; Thomas Jefferson U., Philadelphia, PA] YG492	41	†
7	Z.-G. Liu, et al., "Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kB activation prevents cell death," Cell, 87(3):656-76, 1 November 1996. [U. Calif., San Diego; Tularik Inc., S. San Francisco, CA] *VQ466	39	†
8	J.-F.Tomb, et al., *"The complete genome sequence of the gastric pathogen Helicobacter pylori,"* Nature, 388(6642):539-47, 7 August 1997. [6 U.S. and Swedish institutions] *XP722	38	†
9	J. Zou, et al., "Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3," Cell,90(3):405-13, 8 August 1997. [U. Texas Southwestern Med. Ctr. Dallas; Genentech, South San Francisco, CA] *XQ063	38	†
10	A.A. Beg, D. Baltimore, "An essential role for NF-kB in preventing TNF-alpha-induced cell death," Science, 275(5288):782-4, 1 November 1996. [MIT, Cambridge] *VQ145	37	7

SOURCE: ISI's Hot Papers Database. Read the full legend.

No apologies for returning yet again to apoptosis (programmed cell death), surely the hot topic of the year, possibly of the decade, and definitely the only source of novelty (of a sort) this time around, with the only two newcomers to the What's Hot list. Both are from Xiaodong Wang's lab at University of Texas Southwestern Medical Center at Dallas, and they weld shut the final missing link in the chain of command that controls cell suicide.

The story so far is that cell suicide has at its core a set of proteins called caspases. These are proteolytic enzymes that are responsible not only for some of the characteristic pattern of destruction that marks apoptosis, but also for activating themselves and other caspases. The caspases are present in all cells all the time, but as inactive precursors. When activated, they set off a torrent of protein destruction that ends in apoptosis. The presence of inactive caspases, along with their auto-catalytic ability, is what enables apoptosis to proceed so swiftly, sometimes no more than minutes from trigger to termination.

The two hot papers, at #6 and #9, identify the first mammalian homolog of the nematode gene CED-4, which many people had spent much time searching for. "Apaf-1 is still the only published CED-4 homolog,"Wang tells Science Watch. Oddly, several plant disease resistance genes also share the homology between Apaf-1 and CED-4. Says Wang, "We don't understand the meaning of it. But it could be potentially very interesting."

So it is only right and proper that Wang's work should be highly cited by other researchers active in the field. But you will search in vain for any mention of it in the ordinary press, which adds to the peculiar sense of dislocation felt by this writer and many readers. Here's the problem: if you are at the cutting edge of apoptosis research, you don't need Science Watch to tell you what was hot a year or more ago; if you're not, and especially if you are a news editor, you maybe don't see why a couple of papers stir up such a fuss. In which case run—don't walk—to take a look at a "Special Report" from Science and a "News and Views" Feature from Nature.

Science's offering (281:1305-26, 1998) consists of five cracking review papers that take you from the death receptors (see Science Watch, 8(6[6 ]: 8, November/December 1997) to Bcl-2, the subject of an earlier paper by Wang that was the most-cited paper of 1997 and is currently at #3. In Nature, Martin Raff boils all that down to just four readable pages that bring both the complexity and the importance of cell death to life (see M. Raff, "Cell suicide for beginners," Nature, 396:119-122, 1998).

As Raff points out, because apoptosis is deliberately such a clean process, leaving little in the way of debris, it is remarkably hard to observe in life. For years it was a quiet backwater, coming to some prominence with the genetic dissection of the nematode worm Caenorhabditis elegans. Then, with the discovery of mammalian (and especially human) counterparts of the C. elegans cell death genes, apoptosis moved "from neglect to hysteria in one or two years," says Raff.

The hysteria, however, is richly deserved, because the death in apoptosis is, as researchers have become fond of pointing out, the key to life. Too much cell death results in degenerative diseases, too little in cancer. And the right amount is crucial during growth and development. The search for therapeutics is obviously a major driver of the field, but simple scientific curiosity has a place, too. Wang's group is now trying to re-create the whole caspase activation system using pure recombinant proteins so they can study the biochemical mechanisms in detail.

Despite the record-breaking pace of research, Wang says he is "just scratching the surface" of apoptosis. And while he admits that therapeutics are one motive, he also tells Science Watch that "the fascination to understand death even at the cellular level may also be a reason." An actual drug may eventually push apoptosis into the public limelight. In the meantime, researchers must make do with the praise of their peers—and three Hot Papers.