Jan/Feb 2006 Nonfiction

DNA, RNA, and Alphabet Soup

First of a series on science

by Anju Kanumalla

Biology is a science intimately tied to hope. There is rarely a "so what" biological discovery. Advancements like the sequencing of the human genome and the manipulation of stem cells are often heralded as the first steps to a new era of medicine. Even when that era may be decades away, we still look forward to it eagerly. Now, discoveries about a molecule called ribonucleic acid, or RNA, are contributing to our vision of that era.

Scientists and drug companies are particularly interested in a type of RNA called small interfering RNA, or siRNA for short. They hope that siRNA will help lead to treatments for all sorts of diseases: macular degeneration, a lung disease called respiratory syncytial virus infection, Huntington's disease, Alzheimer's disease, asthma, hepatitis C infection, diabetes, and cancer. One company is even looking to apply siRNA to hair removal.

siRNA is one of several types of RNA. Some of the other important types of RNA include messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA). In order to understand RNA, we need to start by looking at DNA.

The DNA Library

The organs in your body are all made of tissues. These tissues are in turn made up of cells. You can think of cells as little towns. Most of the cell is made up of proteins, which act like the bricks and mortar of the town. In order to keep the cell-town working, there are also other proteins called enzymes. These enzymes build things up and break them down the way that cranes and bulldozers would.

Each of the towns has a central area that is separated from the rest of the cell. This is the nucleus, where the DNA is kept. The nucleus is like the town's library, and the DNA is the library's reference section. It contains a lot of useful information on all sorts of subjects. The DNA library is the same in each cell, and it contains information on how to build every piece of every cell of every organ in the body. As with any reference section, you can't take the books out of the library. You can, however, make photocopies of the pages you need. In the cell, these photocopies are made of mRNA.

Just like a reference book in the library, you can think of DNA as having words and letters. There are four letters in the DNA alphabet: A, C, G, and T, which stand for adenine, cytosine, guanine, and thymine. These are the names of special molecules called nitrogenous bases, which are often just called bases. Each word is made up of some combination of three letters, for a total of 64 possible words. The instructions for every protein in every cell of the body are made up of combinations of these 64 words.

Understanding the DNA alphabet has been the key to understanding how DNA and many types of RNA work. The letters in the DNA alphabet tend to pair up because of their chemical structure. The pairing is precise: A pairs with T, C pairs with G. This pairing is sometimes called Watson and Crick pairing, in honor of the two scientists who first described it.

The pairing of these letters is important when DNA gets copied. While a regular photocopier can do a whole page at once, a DNA molecule gets copied one letter at time. Copying DNA requires enzymes, proteins that change molecules. The enzymes separate the two halves of the double helix and copy one of the halves. These copying enzymes add letters to a growing chain. The letter that gets added is the partner of what is in the DNA original. If it sees a C, it adds a G. If it sees a G, it adds a C. If it sees a T, it adds an A.

Some copying enzymes make DNA and some make RNA. If the copying enzyme makes DNA, it puts a T in where it sees an A. If the enzyme makes RNA, however, it adds a U instead. It does this because RNA has an alphabet similar to that of DNA, but not exactly the same. The RNA alphabet is missing a T, but instead has a U, some other letters, and fewer rules. For one thing, bases don't have to pair so strictly.

Control Issues

The reason for making mRNA from DNA is to produce protein. DNA is the reference library of blueprints, and mRNA molecules are photocopies of a small subset of those blueprints. Protein is what you make if you follow those instructions. Proteins form most of the structure of the cell—its bricks and mortar—as well as all its enzyme machinery. Making mRNA from DNA is the first of two steps in the protein-making process.

siRNAs are a way of controlling the second step in the protein-making process. They work because they use the same alphabet as other types of RNA. Scientists can design an siRNA so that it targets a specific set of mRNA photocopies. Knowing that in RNA, As pair with Us and Cs pair with Gs, scientists can look at the words and letters in the target, and spell out the siRNA. The siRNA attaches to the mRNA photocopy, cutting it into two pieces. This acts as a signal to the cell, which sends out its cleaning crew to destroy the mRNA pieces. Once the photocopied instructions are destroyed, the cell can't make protein until more photocopies are made.

That's the "interfering" part of small interfering RNAs. They are considered small because they only contain 20-25 bases. That's much smaller than the mRNA targets, which can have hundreds or even thousands of bases.

Putting siRNAs to work

There are two siRNA products in clinical trials now for the treatment of an eye disorder called age-related macular degeneration. In this disease, loss of vision is caused by blood vessels that grow too much. Both siRNA products target a specific protein involved in blood vessel growth. Other siRNAs in clinical trials target hair growth and a lung disease called respiratory syncytial virus infection. All of these products will have to prove they are safe and that they work in people.

Even if siRNAs don't produce the next batch of wonder drugs, they are already valuable research tools. siRNAs have also shown us that what we know about RNA is only the beginning. Understanding RNA will help scientists understand why stem cells are able to become so many different types of tissues, how genes are controlled, why some cells become cancerous, and why there seems to be so much DNA in the library that looks more like a four-year-old's scribbles than real information.


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