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Making proteins by genetic engineering

Proteins are produced by living cells and have a huge number of different functions. They act as transporters and messengers around the body, control growth, help keep us healthy, and are the building blocks for body parts like muscles.

If we could make these proteins in large amounts in a lab, they could be used for a huge variety of different purposes.

Producing proteins in a lab

All living organisms contain DNA in their cells. This DNA is the code (or instructions) that cells use to make proteins.

The structure of DNA has been known for over fifty years, but it has taken time to work out what it does – and how it can be used in industrial applications. A breakthrough came in 1972, when Paul Berg explained how to cut and paste DNA from a bacterium into a virus. This had wide applications. If you could transplant DNA, you could make proteins to order!

This process of transferring DNA from one cell to another is called genetic engineering. The cell containing the foreign DNA is called a recombinant cell.

Making insulin

One of the first breakthrough uses of this technology was to produce large quantities of insulin, a protein that is needed to treat diabetes. Before then, the insulin came from pigs, cattle and human cadavers. Insulin is made in the pancreas of humans, but pancreas cells are difficult to grow outside the human body. In contrast, Escherichia coli, which is a rod-shaped bacterium found in intestines, is very easy to grow in large quantities in a lab. Scientists were able to transfer the gene needed to make insulin into the bacteria. In 1982, insulin produced by genetically engineered E. coli was approved for use with patients.

Solving the problems

It sounds easy. Find the protein that interests you. Find the gene (in the DNA) that is needed to produce it. Take the DNA and paste it into a helpful bacterium, and then produce any amount of the protein you like. Although this is a good idea it has many practical difficulties.

One of the difficulties is that bacterial cells and mammalian cells produce different types of proteins. In mammalian cells, many of the proteins get carbohydrates added to them. This doesn’t tend to happen in bacterial cells.

To produce many mammalian proteins properly, you really need mammalian cells – but mammalian cells will divide only so many times before they die. You can get around this fusing a tumour cell with the cell that produces the protein that is wanted to create a specific 'cell line'. This fused cell is called a hybridoma. It will go on living and dividing (and producing the protein you want) long after an ordinary mammalian cell would have died. This is all done in vitro. Special growth solutions are needed to provide the cells with all the nutrients they require.

A second problem is that cells make a huge range of different proteins. Harvesting the protein that you want requires many separation steps, so that the protein you want can eventually be isolated in pure form.

Growing the cells

The cells that are going to produce the protein you want need to be able to be grown in large amounts. Bioreactors are used to grow cells under conditions where they will make proteins. A bioreactor provides cells with all the substances they need to grow and reproduce.

Creating the perfect environment

One of the important jobs for the biotechnologist is to create the perfect environment for the cells to grow and thrive. Nutrients and oxygen must be delivered in exact quantities, the optimum temperature and pH must be maintained, and waste products must be removed. The cells are very picky about their living conditions.

Current New Zealand examples

Massey University and AgResearch are working together to produce several different types of proteins in their labs. Professor Yusuf Chisti is a world expert in this area.

Vaccines to control disease

In one bioreactor that technicians look after, bacteria are dividing and growing in a milky, nutrient-rich broth. These bacteria are being used to make a specific antigen. An antigen is any substance that causes the immune system to produce antibodies. When an animal is injected with the antigen, antibodies are made that can ‘fight off’ or protect the animal from infection. This is what happens when you are vaccinated. In this particular case, sheep that are injected with the protein made by cells in the bioreactor will develop immunity to hydatidosis. This is a disease that is caused by a worm parasite that can also infect and kill humans.

Hormones to affect fertility

In another bioreactor, genetically engineered yeast is producing follicle-stimulating hormone (FSH). This hormone can be used to cause ‘superovulation’, or the development of more than the usual number of eggs in female mammals. This can be used to help females who have trouble getting pregnant.

Source: Wood, Malcolm. How to be the perfect host. Massey Research, 2004, November, 33-37.

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