By David N. Leff

Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.

After the Human Genome Project, what next?

That massive sequencing achievement identified the genetic parts list for the circuits of fundamental processes in health and disease, but not the connections that make life run.

Now scientists at Massachusetts Institute of Technology¿s Whitehead Institute for Biomedical Research in Cambridge, Mass., have mapped the complete circuit of the cell cycle, which tells cells when to divide. Their network diagram describes the genetic switches and connections that form the circuit ¿ common to a process found in all living organisms, from bacteria to humans.

The team¿s overall findings appear in the Sept. 21, 2001, issue of the journal Cell, under the title: ¿Serial regulation of transcriptional regulators in the yeast cell cycle.¿

¿This study is important,¿ observed MIT molecular geneticist Richard Young, the paper¿s senior author, ¿because it shows for the first time that we can use a technique called genome-wide location analysis to map the circuitry underlying many life processes. We now have a technique,¿ he added, ¿to connect the control switches that make up the network for any living process you can think of ¿ memory, digestion, aging. In turn, this will shed light on many diseases, which are basically breaks in the circuit. Understanding the fundamental cycle of when a cell knows when to divide is key to finding out what goes wrong in diseases such as cancer, where cells divide uncontrollably.

¿The pharmaceutical industry,¿ Young went on, ¿is based on therapeutics developed for correcting faulty protein products, which result from breakdowns in metabolic pathways. A new area of pharmaceutical industry,¿ he predicted, ¿will develop, based on drugs targeting breakdowns in genome regulatory networks.

¿During cell division,¿ Young explained, ¿several events have to occur in an orderly sequence. For instance, the chromosomes of the cell duplicate, the two sets of chromosomes segregate, and the cell splits into two daughter cells. Though scientists knew about the separate stages of the cell cycle,¿ he continued, ¿they didn¿t fully understand how the switches for each step were connected to the next one, or what controlled them. Our lab focused on nine master switches that are involved in the baker¿s yeast cell cycle.¿

The Cell paper¿s first author, postdoctoral fellow Itamar Simon, mapped how the cell cycle in yeast is controlled by the nine proteins, called transcriptional activators. He found that the activator from one stage of the cycle also turns on activators in the next stage ¿ creating a series of switches connected in a circular network. ¿That makes elegant sense,¿ Simon observed, ¿but it wasn¿t anticipated. We now see that the network controlling the cell cycle is itself a cycle of regulators regulating regulators.¿

Mixing Two Harmless Types Of Toxoplasma gondii Parasites Yields Highly Virulent Strain

Felines, from pet tabbies (Felis domesticus) to Bengal tigers (Panthera tigris) are the designated carriers of an infectious parasite called Toxoplasma gondii. It¿s one of the commonest protozoan parasites on Earth among warm-blooded vertebrates. As a rule, T. gondii¿s infection doesn¿t bother kittens, cats or people very much. In fact, it chronically infects about a quarter of the human population, most of them unaware that they¿re harboring the parasite. But the odds are 1-in-3 that they¿ll find out.

T. gondii comes in three genetic persuasions ¿ types I, II and III. The latter two strains are avirulent ¿ virtually non-symptomatic ¿ but type I is highly virulent in outbred mice, and perhaps in folks. Researchers sequenced two gene loci from six representatives of each of the three major types, as well as 13 loci from one representative for each type. These 18 strains came from seven host species on three continents ¿ mainly of pan-American origin.

T. gondii infection strikes pregnant women, organ transplant recipients and people with advanced AIDS, causing clinical effects from transient flu-like symptoms to lethality. But matters are not that simple. While types II and III are relatively harmless, when their genes are mixed, the upshot is a second form of virulence ¿ at least in mice. How come? That¿s what microbiologists and immunologists are trying to find out. Their research so far appears in Science, dated Oct. 5, 2001, under the title: ¿Success and virulence in Toxoplasma as the result of sexual recombination between two distinct ancestries.¿

Results of this ongoing research indicate that through random genetic reassortment, the two avirulent strains, II and III, can give rise to highly virulent progeny, possessing significantly altered biological properties. Their paper concludes: ¿Note that a mixed infection with different strains of Toxoplasma can produce in excess of 10⁸ [100 million] recombinant F₁ progeny from a single cat, and so occasionally, such infections can have a dramatic effect on the population biology of the species.¿

New Apolipoprotein Gene In Cluster Affecting Blood Lipids Could Lower Heart Disease Risks

Cholesterol levels in the blood are not the only gauge of cardiovascular disease susceptibility. An even more telling datum in the blood-lipid picture is the readout of plasma triglyceride. Members of the apolipoprotein gene family play a key role in determining an organism¿s lipid profile.

Genomicists at the Lawrence Berkeley National Laboratory have identified a new gene, APOAV, in this cluster that helps determine lipid levels in the plasma. They showed that mice expressing a human APOAV transgene had a threefold drop in plasma triglyceride levels. Contrariwise, knockout animals lacking the transgene had a fourfold increase.

Turning from mice to humans, the authors found that individual variations in the genes were significantly associated with plasma triglyceride levels. They propose ¿the possible use of APOAV polymorphisms as prognostic indicators for hypertriglyceridemia susceptibility and the focus on modulation as a potential strategy to reduce this known cardiovascular disease risk factor.¿ Their paper in Science, dated Oct. 5, 2001, is titled: ¿An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.¿