Humans have been adjusting the characteristics of living things for thousands of years. We have our ancestors to thank for the breeding of juicier fruit, meatier cows and cuter dogs, amongst many others. Plants or animals with desirable features were interbred, to create new and improved varieties, in a process known as selective breeding. It was not clear how selective breeding worked, until scientists discovered the ‘instruction manual’ behind all living things.
The instruction manual they found was a long string of code, called DNA. Each living thing has a unique DNA code, a copy of which is stored in each cell (the tiny building blocks that make up animals and plants).
Figure 1: DNA is the instruction manual behind all living things, divided into shorter chapters called genes. These genes each provide the instructions a cell needs to produce a specific chemical tool called a tool box
(adapted from https://fragilex.org/fragile-x/genetics-and-inheritance/fmr1-gene/).
The long ‘instruction manual’ is broken up into ‘chapters’, each one tells the cell how to produce a specific protein (the chemical tools the cell uses to do its job). These chapters are called genes, and they can be turned on or off in each cell. For example, skin cells and brain cells use different chapters of the instruction manual to do their job, turning on genes they need and turning off those they don’t.
The discovery of this system can explain the phenomenon of selective breeding. When two animals or plants reproduce, half of each parent’s DNA is combined, mixing their characteristics together. Sometimes during this process, genes become damaged or lost. When an animal or plant develops without a copy of the correct gene, some of its cells can’t make the protien tools they need to do their job. This shows itself in humans as genetic disease- diseases that are caused by DNA changes and can be passed from generation to generation.
Hemophilia B is a genetic disease where the Factor IX (Factor 9) gene is damaged. Usually Factor IX is made and released into the blood by cells in the liver. When an injury causes bleeding, Factor IX and other protiens help blood to stick together into clots, which stop blood flow. Since people with Hemophilia B have a damaged version of the Factor IX gene, they produce little or no working Factor IX. This means their blood does not clot properly, so when they are injured, they can bleed for a dangerously long time.
To treat Hemophilia B, Factor IX needs to be restored to functional levels in the patients blood, to allow for normal clotting. This can be achieved by protein replacement therapy, where working Factor IX proteins are injected into the patient regularly.
As our understanding of DNA grows however, it is becoming possible to fix faulty genes, such as the Factor IX gene in Hemophilia B. For this, scientists took inspiration from viruses. Viruses are micro-organisms which enter human cells and infect them. They add their DNA to the DNA of the human cells, so that the human cell produces copies of the virus. Some viruses add their DNA in a separate loop, whilst others add it into the human DNA code.
Figure 2: Viruses are able to enter cells and add their DNA close to or within the human DNA, this means the cell is forced to produce copies of virus proteins, allowing more and more viruses to accumulate until the cell bursts and releases them.
(adapted from Encyclopedia Britannica 2006)
Researchers are able to harness the ability of viruses to enter and infect human cells. Adding a copy of a corrected human gene into a virus, allows it to be transported into and used by human cells. This equips the cell with the protein tool it was lacking, causing disease. For example, the Factor IX gene was added into a virus that infects liver cells. As a result, when the virus was allowed to infect a human, it added its DNA (containing the Factor IX gene) to liver cells.
Figure 3: Viruses can be used to transport a correct version of the Factor IX gene in to human liver cells, allowing them to start producing the protein at a higher level and reducing the severity of patients disease
(Adapted from http://www.innovationessence.com/gene-therapy/)
In clinical trials the edited virus was infused into the blood of severe heamophilia B patients. All 10 of the men in the trial showed an increase in Factor IX production after the treatment, indicating that the virus had successfully reintroduced the correct Factor IX gene into liver cells.
These results are promising for patients with genetic diseases like hemophilia B, as well as type I diabetes and cystic fibrosis which are some more common genetic diseases these techniques could be applied to. However, there are still some issues with the technology. When viruses do not combine their DNA with the human cell DNA, the replacement gene copy could get lost as the cells grow and divide, so the solution is not permanent. However when viruses do combine their DNA into the human cell DNA, they do so randomly, which may damage other genes. These changes could make the patient vulnerable to cancer and other side effects.
Therefore, the next step in this constantly developing area of science is the development techniques which can accurately add genes or cut genes from a specific place in DNA. This should allow for more efficient and targeted therapies for genetic diseases.
By Lauren Davis; Undergraduate Student, University of Exeter