Do captured viral genes make human pregnancies possible?
The bond between a mom and her newborn is strong, but it doesn't compare to the connection formed during pregnancy. Soon after conception, the fetus literally invades the woman's uterine uterine /uter·ine/ (u´ter-in) pertaining to the uterus.
Of, relating to, or in the region of the uterus. wall, acting like a parasite that steals nutrients and oxygen from its host.
The placenta placenta (pləsĕn`tə) or afterbirth, organ that develops in the uterus during pregnancy. It is a unique characteristic of the higher (or placental) mammals. In humans it is a thick mass, about 7 in. , a tissue created by the developing embryo while it's still a ball of cells, mediates this intrusion. As the physical interface between mother and child, a placenta helps prevent the maternal immune system immune system
Cells, cell products, organs, and structures of the body involved in the detection and destruction of foreign invaders, such as bacteria, viruses, and cancer cells. Immunity is based on the system's ability to launch a defense against such invaders. from rejecting the baby as foreign tissue. Early in pregnancy, it also secretes hormones that prepare the uterine lining to receive the fetus. Then, placental placental
pertaining to or emanating from placenta.
the placental separation of maternal and fetal blood which varies in its structure and permeability between the species. cells burrow into the uterus, where they burst maternal blood vessels Blood vessels
Tubular channels for blood transport, of which there are three principal types: arteries, capillaries, and veins. Only the larger arteries and veins in the body bear distinct names. to create pools of blood from which a fetus draws sustenance and into which it deposits wastes. Later, placental hormones ready the fetus for delivery.
"In many ways, the placenta is the SCUBA system for the fetus, while at the same time being the Houston Control Center guiding the mother through pregnancy," reproductive biologist Harvey J. Kliman of Yale University Yale University, at New Haven, Conn.; coeducational. Chartered as a collegiate school for men in 1701 largely as a result of the efforts of James Pierpont, it opened at Killingworth (now Clinton) in 1702, moved (1707) to Saybrook (now Old Saybrook), and in 1716 was School of Medicine in New Haven New Haven, city (1990 pop. 130,474), New Haven co., S Conn., a port of entry where the Quinnipiac and other small rivers enter Long Island Sound; inc. 1784. Firearms and ammunition, clocks and watches, tools, rubber and paper products, and textiles are among the many , Conn., notes.
Despite the tissue's sophistication so·phis·ti·cate
v. so·phis·ti·cat·ed, so·phis·ti·cat·ing, so·phis·ti·cates
1. To cause to become less natural, especially to make less naive and more worldly.
2. , evolution created the placenta only within the past 100 million years. Earlier, all animals laid eggs, which forced offspring to develop quickly and independently of their mothers. Biologists view placental pregnancy as a major advance because it allows a mother to nourish and protect an embryo longer.
"We know that the longer the gestation, the greater potential there is for fetal neurological development," notes placental biologist James C. Keith of the biotech firm Genetics Institute in Cambridge, Mass.
As with many evolutionary adaptations, the origins of the placenta remain shrouded in mystery. That hasn't kept biologists from speculating, however. One remarkable conjecture concerns viral genes that became embedded in the genomes of the forerunners of mammals. These captive genes, the theory holds, may have facilitated the placenta's evolution.
This provocative scenario recently got its first solid dose of supporting data. At least two viral genes captured by the human genome millions of years ago encode proteins that, according to new experiments, may guide the development of the human placenta. The data on one of the proteins remain controversial, but work with the other protein strongly suggests that it fuses placental cells. This finding may explain the creation of the unusual but crucial barrier linking the blood supplies of mother and fetus.
Beyond shedding light on placental evolution, these viral genes could provide insight into pregnancies that go awry. Investigators are already examining whether the genes are defective in women who have had problem pregnancies.
The story of the placenta and its viruses begins with some suspicious black-and-white photos. In the 1970s, investigators focused powerful electron microscopes on placental tissue from mice, cats, baboons, and people. The resulting images unexpectedly revealed viruslike particles budding from apparently healthy cells.
The particles turned out to be retroviruses, a viral family that includes the AIDS virus AIDS virus
See HIV. . Like other viruses, retroviruses must sneak their genetic material into cells and command a cell's internal machinery to replicate themselves. Unlike their viral relatives, retroviruses have adopted a strategy for permanently inserting a copy of their genes into the genomes of the cells they invade.
Throughout the 1970s and 1980s, notes Erik Larsson of the Uppsala University in Sweden, investigators continued to gather evidence that the placenta is a hot spot for retroviral activity. They also began to theorize the·o·rize
v. the·o·rized, the·o·riz·ing, the·o·riz·es
To formulate theories or a theory; speculate.
To propose a theory about. about why. Larsson and other biologists saw a few obvious possibilities.
As the AIDS virus so tragically confirms, most retroviruses have a knack for suppressing a host's immune system. Consequently, the fetus may use retroviral proteins to help prevent the mother from rejecting it as foreign. After all, half the fetus' genes come from the father.
"You just need to express [the retroviral genes] for a rather short time because the placenta produces several strong immunosuppressive Immunosuppressive
Any agent that suppresses the immune response of an individual.
Mentioned in: Antirheumatic Drugs, Graft-vs.-Host Disease, Immunosuppressant Drugs
1. pertaining to or inducing immunosuppression.
2. proteins that are not related to retroviruses," says Larsson.
Another theory drew upon the unusual anatomy of the placenta. As it invades the uterine wall, this tissue develops fingerlike projections that penetrate pools of maternal blood. These fingers extend from a single thin cell, called the syncytiotrophoblast or the placental syncytium syncytium /syn·cy·ti·um/ (sin-sish´e-um) a multinucleate mass of protoplasm produced by the merging of cells.
n. pl. , which contains multiple nuclei.
Such merged cells are rare in the human body, and scientists have wondered whether proteins from retroviruses create this cell layer. Viral surface molecules known as envelope proteins fuse certain viruses to a cell as the first step in infecting it. The AIDS virus, HIV HIV (Human Immunodeficiency Virus), either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. , even appears to use its envelope proteins to fuse immune cells to each other (SN: 12/19&26/98, p. 391).
It's hard to imagine that women get infected with a retrovirus retrovirus, type of RNA virus that, unlike other RNA viruses, reproduces by transcribing itself into DNA. An enzyme called reverse transcriptase allows a retrovirus's RNA to act as the template for this RNA-to-DNA transcription. every time they become pregnant. Where else could the placental retroviral components come from? From within. Surprisingly large portions of mammalian genomes, perhaps as much as 1 percent in people, consist of so-called endogenous retroviruses.
These remnants of ancient infections result from instances in which a retrovirus happened to slip inside a host's sperm or egg cell. Any embryo then conceived would have the genes of the virus embedded within the DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. of all its cells. Descendants of that organism would also contain those viral genes.
The human genome has more than a thousand sites where a retrovirus has inserted its genes. Because of the ravages rav·age
v. rav·aged, rav·ag·ing, rav·ages
1. To bring heavy destruction on; devastate: A tornado ravaged the town.
2. of evolutionary time, most of these genes consist of quiescent, tattered DNA.
Investigators have found that a few of the endogenous retroviruses remain relatively intact. In some cases, the viral genes still produce retroviruses. In other cases, a single gene, often the one encoding the protein that makes up the viral envelope viral envelope
The outer structure that encloses the nucleocapsids of some viruses. , persists in a functioning state. One explanation for the enduring integrity of such genes, investigators speculate, is that the host cell has co-opted the viral proteins for some vital function.
Unfortunately, admits Larsson, investigators who suggest a placental role for endogenous retroviral proteins have failed to amass much evidence. "We've never been able to prove it," he says.
Biologists have shown, for example, that the envelope proteins of most retroviruses share a common fragment that curbs immune cell activity in test-tube experiments. Yet they haven't shown that any envelope protein produced by an endogenous retrovirus plays that role in the placenta.
Over the past decade, an endogenous retrovirus named ERV-3 has drawn most of the attention of researchers trying to establish a role for viral proteins within the placenta. ERV-3 doesn't produce complete retroviral particles because most of its genes harbor debilitating de·bil·i·tat·ing
Causing a loss of strength or energy.
Weakening, or reducing the strength of.
Mentioned in: Stress Reduction mutations. Its envelope gene, however, remains well preserved and active in a few human tissues, including the placental syncytium. Indeed, ERV-3's envelope protein makes up as much as 0.1 percent of all the protein in this microscopic sheet of fused cells (SN: 9/2/95, p.151).
Since ERV-3's envelope protein harbors the characteristic immunosuppressive domain, scientists were quick to suggest that it was part of the fetal defense against a mother's immune cells. Last year, Neal S. Rote of Wright State University in Dayton, Ohio, and his colleagues reported that the ERV-3 protein may play other roles as well.
In their experiments, described in the January 1999 PLACENTA, they added the gene for the ERV-3 envelope protein to laboratory cultures of trophoblasts, cellular precursors of several placental layers, including the syncytium. The inserted gene drove the trophoblasts, called BeWo cells, to slow their growth, alter their shape, and begin producing human chorionic chorionic
pertaining to the chorion.
a circular band of cells of placental origin that invade the endometrium and form the endometrial cups in the mare. gonadotropin--the hormone that home kits detect in urine to indicate pregnancy.
All those changes reflect what happens when trophoblasts start to form the placenta. In Rote's view, these findings represent the first strong evidence that an endogenous retroviral protein has an essential role in the placenta.
The ERV-3 story remains murky, however. In 1998, before Rote's paper came out, Nathalie de Parseval and Thierry Heidmann of the Institute Gustave Roussy in Villejuif, France, had delivered an apparent knockout blow to speculation about ERV-3. They documented that about 1 percent of the people they examined have a mutation in both their copies of the ERV-3 envelope gene. The defect would severely shorten the resulting protein. Indeed, the protein that these people make doesn't include the immunosuppressive domain or the part thought to mediate cell fusion cell fusion
The nondestructive merging of the contents of two cells by artificial means, resulting in a heterokaryon that will reproduce genetically alike, multinucleated progeny for a few generations. in the syncytium.
While many researchers interpreted de Parseval and Heidmann's data as a clear dismissal of ERV-3's importance to the human placenta, Rote holds fast. He speculates that the short form of the ERV-3 envelope protein retains some of its active elements and still has the effects on placental cells that his group observed. Although the people with the ERV-3 envelope mutations are healthy today, it's not certain that they resulted from problemfree pregnancies, he adds.
Finally, Rote argues that the body often builds in redundancies for important functions. Even if a person has a defective ERV-3 envelope gene, he says, "there might be a backup system. There might be multiple endogenous retroviruses performing the same functions."
Although ERV-3's possible placental roles continue to draw debate, another human endogenous retrovirus has popped up to steal the spotlight. Several years ago, hoping to identify molecules that have commercial potential as drugs, Genetics Institute launched an intensive search for genes encoding novel proteins secreted by human cells.
As part of that effort, the company identified a fragment of a gene active in human testes testes
Male reproductive organs (see reproductive system). Humans have two oval-shaped testes 1.5–2 in. (4–5 cm) long that produce sperm and androgens (mainly testosterone), contained in a sac (scrotum) behind the penis. . The firm's scientists would ultimately find that the gene encoded a protein that sits on the surface of testes cells rather than being secreted. Before that, however, they determined the full DNA sequence DNA sequence Genetics The precise order of bases–A,T,G,C–in a segment of DNA, gene, chromosome, or an entire genome. See Base pair, Base sequence analysis, Chromosome, Gene, Genome. of the gene and deduced the amino acid amino acid (əmē`nō), any one of a class of simple organic compounds containing carbon, hydrogen, oxygen, nitrogen, and in certain cases sulfur. These compounds are the building blocks of proteins. sequence of the protein it encoded. They then scanned a database of previously discovered proteins for similar molecules. Their search found an unexpected match: An envelope protein from a baboon baboon, any of the large, powerful, ground-living monkeys of the genus Papio, also called dog-faced monkeys. Five subspecies live in Africa, with one species extending into the Arabian peninsula. endogenous retrovirus bore a significant, though far from complete, resemblance to their protein.
"That's what originally peaked our curiosity," recalls John M. McCoy, who recently moved from Genetics Institute to its Cambridge neighbor Biogen.
Curious about why human testes would make a retroviral-envelope protein, McCoy, Keith, Sha Mi, and their other Genetics Institute colleagues took a closer look at where else in the human body the protein's gene is turned on, or expressed. The gene was much more active in the human placenta than in the testes. "It wasn't expressed anywhere else as far as we could see," says McCoy.
The scientists next documented that the envelope gene functions primarily in the trophoblast trophoblast /tro·pho·blast/ (tro´fo-blast) the peripheral cells of the blastocyst, which attach the blastocyst to the uterine wall and become the placenta and the membranes that nourish and protect the developing organism. cells that fuse into the placental syncytium. Because they knew that other viral-envelope proteins fuse cells, the group set out to explore whether their protein performs such a function.
It does. In a series of experiments, the scientists showed that adding their gene to nonplacental cells causes them to fuse as if they were forming a syncytium. Many n Cells engineered this way would nurtures even join to liposomes Liposomes
Aqueous compartments enclosed by lipid bilayer membranes; liposomes are also known as lipid vesicles. Phospholipid molecules consist of an elongated nonpolar (hydrophobic) structure with a polar (hydrophilic) structure at one end. , sacs composed only of the fatty molecules that make up a cell's membrane.
The investigators also determined that when they treated BeWo cells with a chemical that triggers trophoblasts to fuse, the envelope gene dramatically increased its expression. Moreover, chemically treated BeWo cells that were exposed to antibodies to neutralize the gene's protein fused much less often than cells not subjected to the antibodies. To reflect the retroviral protein's putative role in forming the placental syncytium, the company named it syncytin.
In an independent search for new human endogenous retroviruses, Francois Mallet mallet,
n a hammering instrument.
n a small hammer with a leather-, rubber-, fiber-, or metal-faced head; used to supply force or to supplement hand force for the compaction of foil or amalgam and to seat cast and his colleagues at the Ecole Normale Superieure (body) Ecole Normale Superieure - (ENS) A higher education and research institution in Paris, France. in Lyon, France, also identified the gene for syncytin. In the April JOURNAL OF VIROLOGY The Journal of Virology is an academic journal that covers research concerning viruses, using cross-disciplinary approaches including biochemistry, biophysics, cell and molecular biology, genetics, immunology, morphology, physiology and pathogenesis. , they confirm that placental cells make the protein and that it can fuse cells in the test tube.
The investigators at Genetics Institute and in France caution that their research hasn't proved that mammals use syncytin in their placentas. Indeed, there's a wrinkle in that notion. While people and certain primates possess the gene for syncytin, scientists haven't found the retroviral gene in mice or other mammals that also have placentas.
That's not discouraging to McCoy, who suggests that other mammals may have co-opted the envelope proteins of different endogenous retroviruses. "It's not out of the realm of possibility that this happened more than once" during mammalian evolution, he says.
Still, verifying syncytin's role in mammalian placentas poses a challenge. If mice had a similar gene, biologists could simply deactivate de·ac·ti·vate
tr.v. de·ac·ti·vat·ed, de·ac·ti·vat·ing, de·ac·ti·vates
1. To render inactive or ineffective.
2. To inhibit, block, or disrupt the action of (an enzyme or other biological agent).
3. it in fertilized fer·til·ize
v. fer·til·ized, fer·til·iz·ing, fer·til·iz·es
1. To cause the fertilization of (an ovum, for example).
2. mouse eggs and observe whether placentas develop and support healthy offspring. Researchers obviously can't perform such experiments on people. Rather, to disprove disprove,
v to refute or to prove false by affirmative evidence to the contrary. that the protein has an essential role in the placenta, investigators are trying to find people who were born healthy despite mutations in the gene for syncytin.
Meanwhile, Genetics Institute has started to compare the production of syncytin in healthy and abnormal placental tissue. Some of the latter comes from women who during pregnancy developed preeclampsia--dangerously high blood pressure thought to be caused by defective placental development.
Academic scientists will no doubt continue to investigate the role of the endogenous retroviral protein, but Genetics Institute may stay interested in syncytin only if the researchers there find that it's altered or missing in infertility or problem pregnancies.
"If it isn't involved in a pathology, it's an interesting footnote, as far as a biotech company is concerned. If it is, then things get a little bit more exciting," says McCoy.
At the very least, the company has already offered the most compelling evidence to date for the seemingly outrageous idea that human and some primate embryos depend on ancient viral genes to form their life-endowing link with their mothers.
"There are multiple endogenous retroviruses turned on in the placenta. It wouldn't surprise me if there were more that actually contribute to placental function," says Rote. "This might be the tip of the iceberg tip of the iceberg
n. pl. tips of the iceberg
A small evident part or aspect of something largely hidden: afraid that these few reported cases of the disease might only be the tip of the iceberg. ."