NEWS AND THE INSIGHT FROM THE STOWERS INSTITUTE FOR MEDICAL Stowers RESEARCH REPORT FALL 2 0 0 Stowers Institute for Medical Research principal investigators who have received recent noteworthy awards and honors gather at the west end 3 of the Stowers Institute® campus. Front row, from left: Paul Trainor, Robb Krumlauf, Chunying Du. Second row, from left: Olivier Pourquié, Peter Baumann, Jennifer Gerton, Ting Xie. Ultimate solutions take time. Inside this issue . That’s particularly true with complex • Dr. Scott Hawley makes some surprising discoveries about how mistakes human diseases and birth defects during meiosis can lead to miscarriages and birth defects (Page 2). since there is still much we don’t • Dr. Olivier Pourquié sheds light on how the segments of the body begin to understand about the fundamentals grow at the right time and place in the embryo (Page 4). of life. At the Stowers Institute for • How do cells know when and where to differentiate and when their useful Medical Research, investigators healthy life is over? Dr. Chunying Du discovers a curious double negative seek to increase the understanding feedback loop in the apoptosis process that goes awry in cancer (Page 6); of the basic processes in living cells – Dr. Ting Xie investigates the importance of an environmental niche for VOLUME 6 stem cells (Page 7); and Dr. Peter Baumann studies the role of telomeres in a crucial step in the search for new aging and cancer (Page 8). medical treatments. • Scientific Director Dr. Robb Krumlauf and fellow Stowers Institute investigators inspire and are inspired by scientists and students in embryology at the Marine Biological Laboratory in Woods Hole, Massachusetts (Page 10). SCOTT HAWLEY: The Bonds of Matrimony in Meiosis “Organisms are very, very careful about meiosis. The glaring exception is humans. No other organism is as fundamentally sloppy as we are about this most fundamental biological process.” -Scott Hawley, Ph.D. It has been 120 years since scientists As described in the October 2003 During the matching step, the first described meiosis, the process of issue of Genetics, Dr. Hawley’s lab at the homologous (similar) chromosomes forming reproductive cells such as the Stowers Institute has discovered a key somehow recognize each other and form egg and sperm. But how the process works protein involved in meiosis, and its name pairs. The chromosome 21 you received at the molecular level is still shrouded is Matrimony. “Matrimony holds paired from dad picks the chromosome 21 you in mystery. Solving that mystery has been things together for a while,” Dr. Hawley said. received from mom out of the crowded Stowers Institute for Medical Research tangle of DNA in your cell’s nucleus. Investigator Scott Hawley’s holy grail Match, Lock, and Move Biologists still don’t understand how this for 20 years. pairing occurs, so according to Dr. Hawley Meiosis is at the heart of how In meiosis, the chromosomes in they use textile analogies like button, zipper, Mendelian genetics works in sexually diploid cells (containing two copies of or Velcro to describe the combination. reproducing organisms, he explained. It is each chromosome) segregate and form Then, the chromosomes segregate and also at the heart of human joy – and misery. haploid reproductive cells (the sperm and move to opposite poles of the cell, which “You mess meiosis up; you lose off- the egg, which carry just one copy of divides and forms two daughter cells. The spring,” Dr. Hawley said. “We humans are each chromosome). Dr. Hawley nicknames chromosomes are pulled apart by thread- lousy at meiosis. We lose 25 to 50 percent of the three fundamental steps in meiosis like spindles that attach them to the poles. our conceptions because we make mistakes “match them; lock them; move them.” in the process of sorting our chromosomes. In a review article in the August 8, 2003 Drifting Apart It is a testament to other drives (best dis- issue of Science, he and his Stowers cussed by psychologists) that our popu- colleague Dr. Scott Page described these The locking step is where things lation continues to increase.” steps in more detail as a pas de deux ballet. can really go wrong. For humans and many other organisms, the main locking system is the exchange of DNA (also called recombination, crossover, or chiasma formation), in which chromosomes inter- lock long portions of their arms. If the exchange fails, the homologous chromo- somes may drift apart and lose track of each other, inviting disaster. For example, one daughter cell may have two copies of chromosome 21 and the other may have no copies at all. If a normal sperm fertilizes these eggs, the resulting embryo will have either three copies of chromosome 21 (trisomy), which results in Down Syndrome, or just one copy (aneuploidy), which is usually not viable. For humans, a locking failure is most relevant to chromosome 21. It is one of the few cases in which errors in chromosome segregation can produce Scott Hawley, Investigator, joined the Stowers Institute in 2001 from the University of California-Davis viable embryos, probably because it has and continues to research the molecular mechanisms of meiosis. the fewest genes. 2 The Stowers Report – Fall 2003 To learn more about the backup Stowers Institute, showed Dr. Hawley system, Dr. Hawley studies a very simple stunning photographs of membranes meiotic system: the backup mechanism encasing the meiotic spindles. They used by female fruit flies of the species determined that Axs helps build those Drosophila melanogaster. These studies spindle membranes. Without them, the uncovered the locking protein his lab chromosomes cannot stay in position, termed Matrimony, which binds to the resulting in faulty meiosis. heterochromatin and holds the chromo- The discovery of this whole new some pairs together. Mutations in biological structure and the importance Matrimony appear to destroy the of the Matrimony protein may help explain heterochromatin’s bonds. how meiosis functions – or, as is too often Dr. Hawley continues to investigate the case in humans – malfunctions. Photo of membrane around spindles. A homolog exactly where Matrimony binds on the (close relative) of the meiotic Axs protein defines a membrane that encases the spindles during chromosomes, whether it is part of a larger Discovering Matrimony was not protein complex, and if so, how that mitosis. In this photo of a Drosophila cell a planned event. Two researchers in undergoing mitosis, the chromosomes (blue) are complex is assembled and then disassembled attached to microtubular spindles (red). They when it is time for the chromosomes to Hawley’s lab made a chance observation are encased in a membrane (green) produced by separate. He is exploring what dose of about the failure of meiosis in a control an Axs homolog, a close relative in the family of Axs proteins. (Deconvolution microscopy Matrimony is sufficient for meiosis, and for an unrelated experiment. Later, photo by Dr. Cathy Lake, Research Specialist I how the backup system stands in relation David Harris, a research technician, at the Stowers Institute) to the exchange mechanism. However, who is now in graduate school at the that is proving to be quite challenging. Massachusetts Institute of Technology, Backup Matrimony “We are just now creating the genetic tools we need to do it,” Dr. Hawley said. investigated the problem on his own. “Eventually, though, this research will He identified a DNA binding protein Because locking is so important, tell us exactly how this conjunction in most organisms have a backup system, (and the gene that produced it). Then meiosis works. We will be able to describe known as homologous achiasmate he demonstrated that mutations in that at a molecular level how homologous segregation or the distributive system. chromosomes hang on to one another gene, which he named Matrimony, disrupt Using this backup, the chromosomes are and then separate.” the locking step in Drosophila’s meiosis. linked together not by exchange but by the persistent pairing of a specific region A Surprising Spindle Membrane of DNA, known as heterochromatin. Recent Papers from the Hawley Lab Heterochromatin is made of highly Earlier this year, Dr. Hawley’s lab Harris, D., Orme, C., Kramer, J., repetitive DNA sequences, also called reported another important finding in Namba, R., Champion, M.D., Palladino, M.J., Natzle, J.E., & Hawley, R.S. (2003) satellite DNA, and it is normally found the February/March 2003 journal Nature A deficiency screen of the major autosomes around the centromere, near the middle Cell Biology. On Christmas Eve in 1983, identifies a single gene (matrimony) that is of the chromosome. Dr. Hawley had discovered a mutant haplo-insufficient for achiasmate segregation Humans, who are unusually “sloppy” known as Axs (for Aberrant X chromosome in Drosophila oocytes. Genetics (in press). at meiosis, appear to have a backup Segregation) that causes defective segre- Page, S.L. & Hawley, R. S. (2003) system that works well while women are gation of chromosomes during meiosis. Chromosome Choreography: The meiotic young, but fails as they approach A few years ago, much to everyone’s ballet. Science, 301(5634), 785-789. menopause. Thus, a 20-year-old woman’s surprise, his lab realized that the product Hawley, R.S. (2003) The human Y chromosomes can segregate properly of this gene, the Axs protein, is a trans- chromosome: Rumors of its death have been even when the main exchange program membrane protein. greatly exaggerated. Cell, 113(7), 825-828. fails during meiosis, but that is frequently “That was weird,” Dr. Hawley said. not the case for a woman in her forties. “What was a membrane protein doing Kramer, J. & Hawley, R.S. (2003) The spindle-associated transmembrane That failure may account for the increasing inside the cell? It sounded messy.” protein, Axs, identifies a membranous difficulty of pregnancy and risk of birth Then postdoctoral student Joseph structure ensheathing the meiotic spindle.