Cloning in Nature

In nature, clones exist among plants or animals that are able to reproduce asexually.  Special traits allow earthworms to regenerate lost body parts and certain plants (like the spider/airplane plant) to propogate through runners.  These worms and plants are technically clones, because as broken-off parts of the original, they share the same genetic material as the original.  The oldest methods of cloning involve a similar principle -- a cell is broken off from a very early embryo, and begins to divide as if it were a fertilized egg.  However, it is very difficult to clone adult cells because they are not "in gear" to divide and grow into a new organism.  Techniques needed to be developed that could allow the DNA from an adult cell to be removed and placed in a cell that could grow as an embryo.

Nuclear Transfer

Scientists' understanding of what makes an embryo cell different from a liver cell is not complete because the objects of study are so small.  However, they do know that a coating of proteins on the cell wall inhibits the DNA that is not neccesary for that cell's particular function.  When this coating is present, the cell is said to be differentiated.  Although differentiated cells contain all the necessary DNA to produce a new organism, the fact that they have differentiated keeps them from creating an entire new organism.  Egg cells, on the other hand, are unique in that they are the only cells capable of forming a new and complete organism.
       
The secret to cloning lies in removing an egg cell's nucleus and replacing it with the nucleus of a donor cell.  The egg cell, which has a "clean slate", and is primed to use the information in the DNA to create a new organism, now has the DNA of the donor organism.  However, this transfer is a very difficult process, more difficult in some cases than others.

Obstacles to Cloning
 

Link to Cloning Method graphic

The first animals cloned using the modern method of nuclear transfer were frog embryos, cloned in 1951.  The reason frog embryos were cloned long before anything mammalian is twofold.  First, the cells of an 8-celled frog embryo are huge compared to the cells of a mammal embryo; they can, in fact, be seen with the naked eye, and are therefore much easier to work with.  Secondly, frog embryo cells grow in lab conditions much better than mammal embryo cells.  This is because frog embryos are supposed to grow in water, without any added nutrition or outside assistance.  Mammals, however, take a long time to mature, and require the shelter and nourishment of a mother both before and after birth.  Because the clone has to grow from a single cell to an entire organism in the lab, it was easier to do initial experiments on amphibians.  Frogs were chosen because, as frequent subjects in lab tests, they are very well known to scientists.

Although happy about the cloned frogs, scientists wanted to see a cloned mammal; humans are mammals, so almost anything learned about other mammals can be applied to humans.  Unfortunately, because of the difficulties associated with mammal cloning, this was a difficult task.  Techniques to make this task possible were developed at the labs of Neal First and Steen Willadsen, who worked independently to produce the first mammals cloned from embryos.  Once the nucleus is transferred from the donor cell to the egg cell, the egg cell is put in a nutrient solution until it divides into an eight-celled embryo.  When the cell passes this point, the individual cells begin to differentiate; one cell may eventually form the head, and another the torso.  As this point is reached, the scientists move quickly to put the embryo into the removed and artificially sustained oviduct of a sheep or other animal.  The oviduct functions as an incubator to nurture the embryo thruough this critical period.  Once the embryo is large enough to be able to withstand the procedure, it is placed in a living surrogate mother where it will be carried to term, nourished by an umbilical cord.
       
With all these steps, it is no wonder that the success rate for cloning is so low; embryos die at each step along the way until only a few are carried to term and born.

Variations on a Theme
        
Of course, there are different approaches to all steps in the process.  Ian Wilmut, instead of transferring the nucleus from one cell to another, fused an enucleated (nucleusless) egg cell with an adult cell to form the first cell in the embryo.  The Honolulu method centers around the cells chosen to be DNA donors.  However, the principle behind cloning is always the same - give an egg cell, which is ready to divide and grow into a new organism, the nucleus of an old cell.  With the new set of instructions, the egg cell begins its journey to become an adult clone.

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