Have you ever wondered why some people can not taste bitter? Why are some people more resistant to malaria? Why are some persons at a higher risk of getting Alzheimer? Having in mind that all humans carry the same genetic information, it is quiet remarkable that we are so incredible different!
More than 10 years ago, the human genome project was completed and since then has provided a reference that represents a hypothetical genome of mankind. Why hypothetical? As accurately pointed out by Eric Green, the director of the National Human Genome Research Institute, the published genome was built from bits and pieces of different people’s genomes. This reference genome gave scientists a roadmap through the genomic jungle, however as it always is with science, it generated a whole lot of new questions! In fact, no two genomes are the same. Every person has the same order of roughly 3 billion bases but every now and then small parts of the genetic code differ.
These DNA sequence variations can have no effect at all or alter the genetic recipe. In the later case this can lead to changes in physical appearance, disease susceptibility and in the worst case it can be the cause of a disease. For instance sickle cell anemia, a hereditary blood disorder, is caused by a change from the base A to T, that leads to a sticky form of the hemoglobin molecule making it inefficient in transporting oxygen.
Finding sequence variations
With the enormous drop in cost and being close to the 1000$ genome, scientists have turned again to genome sequencing, but this time they explore genomes of many individuals. Comparing many DNA sequences allows to associate genetic variants with a trait, disease susceptibility or disease progression.
The Cancer Genome Project and the Cancer Genome Atlas for example aim to find DNA variations that occur frequently in cancer and thus could be critical for the development of cancer and treatment success.
Just recently, the sequencing veteran Craig Venter revealed that his new company Human Longevity Inc. aims to sequence 40 000 healthy individuals to scan their DNA for variations that increase human lifespan. Once a connection between DNA variation X and a disease or trait is established, the chicken and egg dilemma has to be solved to distinguish between cause and consequence. For example does a certain DNA variant make us more susceptible to cancer or do cancer cells introduce this DNA change? Correcting the DNA might prevent cancer in the first case but unlikely does so in the latter.
Hitchhiking the bacterial immune defense
The classic concept to test causality in science is to disrupt a gene or to insert an extra copy of it in the genome of a model organism (mouse, fly, worm ect.) and observe the impact of this manipulation. The toolkit to edit the genome however has been limited and unprecise. Creating a mouse with one defective gene can easily take a year. Luckily, early 2013 a new genome-editing method came along. Joined forces from Dounda’s & Charpentier’s labs pioneered the use oft “Clustered Regularly Interspaced Short Palindromic Repeats”, short and more handy CRISPR. This technology is based on a naturally occuring bacterial defense. Short RNA molecules guide the protein Cas9 to the hostile DNA from e.g. a virus, which then acts as molecular scissors and chops up the DNA.
Watch the bacterial scissors Cas9 in action:
Using short RNA molecules complementary to a desired DNA region, scientist can precisely direct the Cas9 scissors to any base in genome and introduce a cut. This cut can be then used to introduce DNA at the cut site, changing the DNA sequence by providing a backup copy of the DNA sequence as a template to fix the cut DNA region or deleting a DNA stretch by letting the scissors cut twice.
“In little more than a year, CRISPR has begun reinventing genetic research.” MIT Technology Review.
In the short time since its introduction, the CRISPR technology has proven to be a versatile tool. For the first time genomes can be edited fast, efficient and with a high precision at nucleotide-resolution. Especially for complex diseases like psychiatric diseases, which are based on the interplay between small genetic changes, can now be tackled. In a proof-of-principle experiment, Zeng Zhang (listed as Innovators under 35) from MIT mastered to introduce several mutations at the same time in mice and stem cells using the bacterial weapon.
CRISPR may be used to edit our genomes.
CRISPR is not only advancing basic research but has an enormous impact on applied sciences. What if we could just edit the genome to repair a detrimental sequence in the DNA? Researcher at the Georgia Institute of Technology have already used the system to correct the single base involved in sickle cell anemia in human cells in a pedri-dish. Beginning this year the first primates were born with customized genome modifications in China, bringing up the possibility that it might be applicable for humans. CRISPR could be the revival of gene therapy, a field that encountered tragic drawbacks. Indeed, backed with 43 million $ five pioneers have already founded the first company (Editas Medicine) based on the technology of CRISPR. In a long perspective one could also use this new technique to not only repair but also to customize your genome the way you wish.
In the near future the use of genome editing approaches in humans has to be assessed very carefully and we have to start thinking about the ethical consequences as the feasibility is in reach. But it is clear that what can already be done with CRISPR opens up many possibilities to use it for the common good.
Header image credits: Royalty free