by Lauretta Hannon
Sifting through genetic junk, Dr. Susan R. Wessler is uncovering scientific gems that lay hidden for millions of years.
The treasures she's found in the trash heap of genetics have led to startling discoveries in her field of molecular biology. The findings could lay the foundation for groundbreaking work in agriculture and medicine and even shed new light on the process of evolution itself.
Wessler studies genes and gene fragments that can "jump" from one place to another, the so-called "transposable elements," or TEs. Some TEs are stationary; others move in and out of the genes. Together, they make up as much as half the genetic content in human beings and even more in many plants and animals. Although some TEs are stationary, others move in and out of genes.
Some geneticists consider TEs "junk," saying that they don't perform any function. Although no one understands why these elements exist, they are known to create and alter traits.
"What we're finding out is that TEs really may have some purpose," said Wessler, a molecular biologist at the University of Georgia.
Transposable elements appear in every living thing, from the tiniest bacteria to the giant blue whale. It wasn't until 1978, however, that scientists even discovered them. Because it had been a fundamental tenet that genes simply did not jump about, the discovery of TEs changed the understanding of genetics.
Now, following a decade of work by researchers like Wessler, scientists are finding that TEs may play a part in helping living things adapt to their surroundings.
"All organisms have TEs, and TEs are the cause of mutations in many organisms," Wessler said. "If you have a good system to understand mutations, you'll learn something that will benefit both plants and animals."
And that's why these jumping genes have researchers from many disciplines hopping. For instance, AIDS researchers are interested in the fact that one class of TEs resembles the HIV virus in structure.
Likewise, research into the role TEs play in causing cells to mutate could lead to a better understanding of another kind of mutation -- cancer. Here's why:
We all start life as one cell. The genetic information or DNA in each of our cells is essentially the same. It is how that information is "expressed" by the genes that determines whether a particular cell becomes blood, bone or kidney tissue.
Genetically speaking, expression means the production of a protein based on the genetic code. Since TEs affect the area that determines expression, they can have an influence on the protein produced and, consequently, may change the cell. Wessler's research has shown that genetic alterations frequently result from the insertion of TEs into certain genes.
Wessler also is examining the genes that make the decisions about expression. What she learns may apply to the study of cancer cells, which divide wildly and profusely.
Such research has yielded other potential benefits, too, such as using TEs to "tag" other genes so scientists can trace their function in DNA.
And with a better understanding of how TEs operate, scientists are now asking new questions about the ongoing process of life itself: evolution.
Wessler studies the TEs in maize, a plant that is well-suited to genetic research.
As a postdoctoral fellow in the early 1980s, she received a fellowship from the American Cancer Society to pursue her maize research. "They funded my work using the rationale that mutations are what cause cancer. And to understand them in corn may in some way help somebody doing cancer research because of the underlying similarities," she said.
"Corn is a terrific experimental system," Wessler said. "It has been a major organism for genetic studies for 70 years, so there is a large base of knowledge to work from. Also, it's easy to make mutations and the seeds are stable, allowing researchers to store them for decades."
Another benefit of studying maize mutations is that they're eye-catchingly obvious. For example, the speckled reds and blues of Indian corn reveal evidence of TEs at work.
"Corn seeds have lots and lots of visible traits," Wessler said. "You can look at a kernel and determine when a TE jumped out of one gene and into another. The size of the color spots is related to when the TE left. The bigger the sector, the earlier in development it happened. Corn is almost designed for genetics."
The other advantage of corn is that, unlike many other plants, it doesn't have "perfect" flowers; the male and female components are not together in one flower. The tassel on the top makes the pollen, and the ears on the side make the ovules.
"If you have the male and female parts in one flower, it's not very easy to do a cross. It can self-pollinate," Wessler said.
Not so with corn.
In the greenhouse or in the field, Wessler and her group cover the corn tassels and silks with paper bags. When the silks start to emerge, she decides which male to use in pollinating an ear. "When we do a cross and dump the pollen onto one ear, we don't just make one seed, we make hundreds of seeds," Wessler said. "To do genetics you need lots of progeny because mutations are rare."
The sheer number of genes in corn, from 50,000 to 100,000, makes for a complex organism.
"One way to find a particular gene is to get a transposable element to insert into a gene and knock it out," Wessler said. "You can then use the transposable element as a fishing hook to pull out the element plus the gene that it inserted into. It's called a tag. It is a way to identify the gene."
Mutations Contribute to Diversity
While a run-of-the-mill mutation knocks out expression of the gene it enters, a TE does not always destroy the gene. This is surprising considering that the TE is often larger than the gene it invades. Instead, TEs can alter the gene, allowing partial expression. And when the TE exits, the gene is different, not restored, and usually a little damaged.
"It's to the advantage of both the transposable element and the organism to work together. Your best parasites are those that don't harm the host, because then they will be propagated and tolerated," Wessler said. "People describe TEs as parasites -- if they are, they're remarkably adaptable and adapted."
The jumping of a TE into a gene is a one-in-a-million event; if TEs moved around too much, the plant would not survive. Fortunately, they jump at a very low rate and are somewhat choosy about where they go.
Each time a mutated cell divides, the mutation is copied as well. Without the capacity to reproduce changes, organisms could not evolve or adapt through time. Mutations caused by TEs may help ensure a plant's survival by increasing genetic diversity. A species is much more likely to survive if it is rich in genetic variation, whether inherited from its ancestors or caused by mutations.
The major research focus in Wessler's laboratory has been to understand the molecular basis for mutations in maize. She has several breakthroughs in TE research to her credit. As the first person to isolate a transposable element in maize, she determined its location in the gene.
Wessler showed that the elusive elements disguised themselves as introns, the part of the gene that does not code for anything. "By acting like introns, the elements can enter the gene and make subtle changes that are not reflected in the final product -- without destroying the gene," Wessler said. "It seems that TEs have worked with their hosts, suggesting a mutually beneficial relationship."
Wessler's research also contributes to the basic understanding of TEs at the molecular level. Using a technique called electrphoresis, she has determined for the first time the molecular structure and size of some TEs in maize.
In addition to her work with transposable elements, another research target is to understand what controls gene expression for certain traits, in this case red pigment in maize. To do this she must introduce certain DNA sequences into cells, and that's one of the hardest steps in the process.
Using a "gene" gun, she injected a certain gene sequence into maize cells and demonstrated that the gene sequence itself is the switch that turns on red pigment.
A .22-caliber shell is fired into a blocking plate, which suspends a drop of liquid. The impact of the shell forces the liquid, which contains DNA-coated gold or tungsten particles, to penetrate their targets -- tough cell walls and membranes of the maize kernels. Cells shot with DNA rapidly produce the red pigment.
TEs and Evolution
"The more we learn about TEs, the more questions we have, especially about the role they play on the evolutionary stage," Wessler said. "Although I can in no way be considered an evolutionary biologist, I'm getting very interested in evolution because my work is leading up to that area."
Evolution has been compared to a car factory. The organization of the factory and the ability to make small but important changes have been essential to the success of the automobile through the years. Sleek, aerodynamic cars have evolved as a result of problems with earlier models like hulky, gas-guzzling Studebakers. Though driven by natural selection rather than by market demand, the same factors determine the success of living organisms.
Some scientists say that the way genes are organized, and the way transposable elements act on them, facilitates evolution. As organisms have encountered evolutionary problems time and time again, they have developed ways of solving such problems. Wessler stresses that there are many different opinions in the scientific community about how the elements may fit into the evolutionary picture.
"Organisms are very opportunistic," Wessler said. "One theory states that transposable elements were able to `evolve' a way to disguise themselves as introns and then take advantange of the gene's internal machinery. Such machinery might enable them to exist in the genome but be removed from the RNA, having much less of an effect on gene expression."
As a result of the building-block process of evolution, organisms sometimes appear messy and clumsy. Wessler likens their appearance to a house. "Imagine that you keep having more kids or more people moving into your house, so you have to keep adding rooms. When you look at the thing, it looks horrible, but it functions," she said. "If you had planned on housing more people, it would not have looked like that. But you had to start with a basic unit and expand it.
"It's the same way with organisms. For them to be complex, yet gain in complexity, they can't scrap everything they have. They have to make do with what they have and modify it -- jimmy rig it." Although organisms may seem messy to human perception, they work with brilliant efficiencies that machines can't match.
Organisms have a history of increasing expertise. "It has been said that organisms not only evolve, but they evolve ways to evolve," Wessler said. There are many examples of organisms that have confronted environmental changes. Fortunately, drastic environmental alterations happen very rarely, and some species have become so expert at evolving that they can surmount such alterations, even though they may become seriously changed in the process.
Two theories of evolution coexist: One that it happens continually and gradually; the other that organisms live undisturbed for long periods until a cataclysmic change occurs. Under the second view, new organisms and species may evolve as a result of a dramatic event such as a severe change in climate.
Just as theories of evolution are disputed by different camps, the question of the TE's role in evolution is an unsettled one. According to one theory, transposable elements are quiet until there is a shock to the system. The shock activates systems in the organism; like shrapnel, TEs disperse and damage the genes. The elements are represssed until the organism faces the shock, such as ultraviolet light or intense heat, that stimulates the TEs to move around -- jumping in and out of the genes.
When an element leaves a gene, it doesn't come out cleanly; it leaves a little bit behind. And that little bit frequently can add a few amino acids to the protein -- possibly creating a "better" protein. "Making a better protein could mitigate the jumping gene's negative effects," said Wessler. "By becoming less harmful, a transposable element may be potentially useful."
But Wessler cautions that this idea of a "better" protein is just one theory of the role TEs play. "What we're talking about is highly theoretical and speculative," she said. "But what we're learning about TEs is exciting. It has been only in the last few decades that we've had the tools to learn more about them. But keep in mind that TEs are the products of four billion years of evolution."
And scientists need time to unravel a mystery that old.