Ask a group of blind men to touch an elephant and one might declare its tail a snake, while another might call its tusk a spear. Every cell in your body is a bit like that elephant. If you ask a bunch of scientists about a celland specifically, how it gained a nucleusyou'll get a variety of answers, depending on which part of it they point to.

Image: Courtesy of BILL MARTIN

MERESCHKOWSKY'S VISION is depicted in this chart, which shows where he thought symbiotic unions had enriched the evolutionary history of eukaryotic life. Click here to enlarge.

One idea that has gained popularity over the past two decades originated with the Russian botanist Constantin Mereschkowsky. He first tentatively suggested in 1905 that the nuclei of today's complex cells once roamed free but were absorbed by larger cells because each had something to offer the other. Eventually they became dependent on each other, and their fates intertwined. In biological lingo, he proposed that the nucleus began its career as an endosymbiont.

But those who study the dawn of life still strongly disagree over the details of this scenario, and so the question of how the nucleus arose seems far from being answered. "It's one of the big, big unsolved mysteries: where does the nucleus come from?" says Bill Martin, chair of botany at Heinrich-Heine University in Dsseldorf.

Finding the answer would fill a major gap in the history of eukaryotes (literally, cells with a "true nucleus"), which in the space of two billion years have populated the world with everything from singled-celled amoeba and plankton to pine trees, scientists and, of course, elephants.

The Nuclear Divide

Though eukaryotes get their name from the nucleus, where the genome resides, they differ from nucleus-free prokaryotesrun-of-the-mill bacteria and the more exotic archaea, which tend to live in extreme habitatsin other ways. First, they have a sophisticated set of internal fibers, arrayed like pick-up sticks, that gives them shape and allows them to engulf food. Prokaryotes have versions of the proteins that make up this cytoskeleton but form nothing so elaborate.

Second, eukaryotes contain various organelles, internal compartments partitioned off from the rest of the cell by membranes. Such organelles as mitochondria, for instance, generate fuel; in plant cells, chloroplasts manufacture sugars to break down into that fuel. They were also endosymbionts in the past, as it turns out. Though a controversial idea when first proposed, molecular comparisons made the argument stick: both organelles have genomes that retain similarities to two distinct types of bacteria that persist today.

The nucleus also has some superficial similarities to these organelles: a two-layered membrane surrounds them all; they each have their own genome; and they are capable of reproducing. "It's easy to get [these features] when you're essentially swallowing a symbiont," says Hyman Hartman, a research scientist at the Massachusetts Institute of Technology who studies the origin of life. "It doesn't take a rocket scientist to [suggest] the nucleus had an endosymbiotic origin."


TWO CONTENDERS for the birth of the nucleus appear above. The sequence on top could have occurred if an early mitochondrion (not pictured) gave its host a gene for producing membrane building blocks. The endosymbiotic model diagrammed in the lower sequence shows a bacterium surrounding an archaeal cell called an eocyte.

Subsequent molecular data only fanned these speculative flames by revealing that the eukaryotic genome is a mixed breed. Genetic sequences indicate that eukaryotic genes for building and manipulating DNA, RNA and proteins seem to come from archaea, whereas genes for metabolism and other cellular functions likely hail from bacteria. "The heart of the problem is that the logic of the eukaryote is very different from the logic of the prokaryotic cell, yet there has been a huge input from the prokaryote to the eukaryote," Hartman says.

A Choice of Models

Hartman suggested in 1984 that the nucleus arose when a hypothetical cell that stored its genetic information as RNA instead of DNA and possessed a simple cytoskeleton became the host for an archaeal organism. He says this theory would explain why RNAs perform such a rich assortment of tasks in eukaryotesamong them, building proteins, snipping out unwanted pieces of other RNAs that are on their way to becoming proteins and turning genes on and off. "When you go into RNA, there's no comparison between the bacterial and the eukaryotic cell," Hartman says.

The mix of nuclear genes would come from the archaeal guest and later from the mitochondrion, which forfeited parts of its genome to the nucleus over time. Hartman is in the process of publishing the results of a study that found more than 300 eukaryotic genes bearing little similarity to anything in prokaryotes. He interprets these genes as remnants of the chronocyte, as he calls the early RNA-based life-form.

Others take a different stab at what sort of combination could have spawned the nucleus. Biochemist Radhey Gupta of McMaster University in Canada proposes that a bacterium and an archaean fused to form the first eukaryote, based on his analysis of a pair of slow-changing genes found in what may be one of the oldest cells with a nucleus, Giardia lamblia. Both genes produce the same basic proteinone of which ends up associated with the nucleus, the other outside of it. The former is more similar to its archaeal counterpart, the latter to the bacterial version.

Gupta therefore suggests that a bacterium might have slowly engulfed an archaean by evolving deep folds in its outer membrane, which eventually closed off and replaced the guest's membrane. The two genomes then would have fused into one, completing the transformation. The desire of the host to acquire antibiotic resistance genes from its guest could have driven this chain of events, he says. Jim Lake, a molecular biologist at the University of California at Los Angeles interprets Gupta's finding as support for a more traditional endosymbiosis between the two organisms.

The newest comer into this wild and speculative debate is Philip Bell, who studies yeast molecular biology at Macquarie University in Australia. He proposes that the nucleus might have come from a virus that once infected archaeal cells but eventually began sticking around. As do others in the field, Lake acknowledges that these models are mostly conjecture, but he is optimistic about the chances of endosymbiosis proving to be correct in the long run. "My hunch is the nucleus is an endosymbiont," he says, "and I think that's what we're going to find."

Hard to Swallow

Image: K. Leutwyler after Rivera et al.

GENETIC CONTRIBUTIONS from methane-producing archaea were mostly genes for building DNA, RNA and proteins (informational genes). Those for metabolism and other functions (operational genes) came from the bacteria that formed mitochondria and chloroplasts.

Martin, however, points out a number of sticking points for any endosymbiotic model. First, although the membrane surrounding the nucleus appears similar to those of mitochondria and chloroplasts, all of which have two layers, the nuclear membrane is unique. It is a single layer folded on itself, its pores are much different from those in bacteria, and it disintegrates when the cell divides. Second, even though the enzymes that build DNA and RNA do their work in the nucleus, that doesn't mean their genes necessarily started out there. "The argument that the nucleus is an endosymbiont (given by a number of authors) is just not borne out by our knowledge of the structure and function of the nucleus," concludes Anthony Poole of Massey University in New Zealand.

Martin's own thoughts on the birth of the nucleus stem from a further considerationnamely, that all eukaryotes appear to have had mitochondria at some point in their past. In 1998 he and colleague Mikls Mller of Rockefeller University proposed that eukaryotes emerged from a symbiotic relationship between methane-producing archaea and the bacterial ancestors to mitochondria based on their mutual metabolisms. They call this idea the hydrogen hypothesis because the bacterium fed the archaean the hydrogen and carbon dioxide it used as fuel and converted them to methane. Over time, the bacterium became a symbiont and transferred many of its metabolic genes to the host.

At some point, Martin speculates, the bacterium gave the archaean a gene for membrane synthesis, leading to a bubbling up of membrane within the host cell, something like what happens when modern eukaryotes divide and then reform their nucleus from membrane pieces grown inside them. As supporting evidence, he cites the finding by others that methane-producing archaea and eukaryotes share similar histones, proteins that bind to DNA in the nucleus. "Remember the histones!" he says. "That's a protein that links eukaryotes to methanogens, and I love it."

Others believe that a symbiosis based on hydrogen could directly account for the nucleus. Two French biologists published a model that described how the same driving force could have turned an archaeal methanogen and two kinds of bacteria into a nucleus surrounded by a cell with mitochondria. Lake is also preparing to publish a report suggesting that the hydrogen hypothesis could have more general explanatory power. "It may well be that you can apply it to generate the nucleus, too," he says.

None of these models accounts for all the differences between eukaryotes and prokaryotes, says biochemist Ford Doolittle of Dalhousie University in Nova Scotia. "We really probably don't have any idea what happened. It does seem like, whatever happened, it was probably very complicated and not very sensible." So what good are these competing models? As Doolittle sees it, they have caused researchers to experiment and gather a lot of information they wouldn't have had otherwise. "We have to recognize that we will always possibly be wrong about these things," he says. "It's still worthwhile to try to find out."