Operation on the Open Genome

Heino Boekhout via Twitter (Licence) DNA

What can genetic modification do for our health? Michaela Mrschtik examines how a novel DNA cutting tool paves the way for futuristic treatments of currently incurable diseases.

New ‘DNA scissors’, called CRISPR/Cas or simply CRISPR, have taken the academic world by storm in the past two years. A growing number of studies demonstrate the huge potential of this tool to one day cure a wide array of human diseases, ranging from genetic disorders such as Huntington’s disease to persistent infections like HIV or Leishmania. A recent study on Cystic Fibrosis neatly shows what CRISPR technology is capable of.

Using CRISPR, scientists from the University of Utrecht recently managed what would have been unthinkable a few years ago: they cured a genetic disease in patient cells. The team grew ‘miniguts’ out of cells that had been extracted from Cystic Fibrosis patients and then treated these miniorgans with CRISPR and a piece of DNA. The DNA gave the diseased cells a template enabling them to repair the faulty CFTR gene that causes Cystic Fibrosis. After the treatment, the researchers were able to isolate miniguts that carried a corrected version of CFTR and that no longer showed symptoms of Cystic Fibrosis – these miniorgans were healed from the disease 1 by CRISPR-aided gene therapy.

The CRISPR revolution

Other DNA scissors have been studied for a while, but none of them got the attention that CRISPR receives right now. One of these DNA snippers, zinc-finger-nucleases, are already being tested to treat diseases: A recently completed clinical trial using them showed promising results in fighting off HIV infections 2 (see recent GIST snippet 3). In this study, these DNA scissors were used to cut and in this way damage the CCR5 gene; this gene usually produces a ‘tag’ on the surface of cells, which the HI virus needs in order to enter them. No tag, no entry for HIV – so it’s game over for the virus.

What makes CRISPR so special then? There is a simple reason why researchers are flooding us with CRISPR studies right now: this system is much easier to use than previously available methods. Also, in addition to cutting and damaging genes, it can induce a ‘cut and insert’ mechanism in the cells’ DNA. This means that you can send a therapeutic DNA sequence together with CRISPR to a cell in order to repair the gene that CRISPR cuts – just like the researchers did with the CFTR gene in the Cystic Fibrosis study. In contrast with classical gene therapy approaches that can deliver a therapeutic gene to a cell, CRISPR treatment can actually repair disease-causing genes to truly cure a cell from genetic defects.

Using CRISPR, both damaging and repairing genes is much easier than previously assumed – and if we manage to exploit this potential to cure human diseases, we could help millions of people worldwide.

Application, application, application

In the Cystic Fibrosis study, CRISPR was shown to work in cells that were grown in a lab – outside the body where they belong. But could we use this technique directly, in living animals?

The answer is yes: two new studies reported that CRISPR+DNA treatment could repair genetic diseases in mice.

In one study, some babies of blind mice could be spared the fate of their parents by injecting CRISPR and a correct version of the disease-causing gene into the fertilised egg 4.

This only helped the offspring; however, another team of scientists actually cured a disease in fully grown mice: researchers from the MIT corrected a genetic liver disease in adult mice using the CRISPR technology. The mice were given a CRISPR+DNA injection into their tail vein, and this treatment repaired some of their sick liver cells. These cells then regenerated parts of the liver 5 and enabled the mice to survive without additional medication.

Nature, modified

CRISPR is a system that scientists copied from nature; to be more precise: from bacteria. In 2007, scientists from the food company Danisco found that these tiny one-cell organisms use it as a defence mechanism against repeated viral infections 6 – and yes, even bacteria have to battle viral infections, but their way of dealing with these intruders is very different from our immune system.

Dr Graham Beards via WikiCommons (Licence)

Electron micrograph of Bacteriophages [note: viruses that infect bacteria] .
Image Credit: Dr Graham Beards ( License )

It works roughly like this: when a bacterium fights off a viral infection, it keeps a trophy of its victory – a piece of the virus’ DNA. It integrates this piece into its own DNA, in an area called the CRISPR locus – you can think of this as the bacterium’s trophy shelf.

Now, a similar virus comes along and infects this bacterium, but this time the bacterium has an advantage: It can use the DNA in its trophy shelf to fight the viral intruder. The bacterium’s attack is executed by the enzyme Cas – the DNA scissors of this system – which uses the CRISPR DNA to recognise and cut the virus’ DNA. This can destroy the virus and stop the infection.

Only less than two years ago, scientists isolated and adapted this system to work in non-bacterial cells and in any area of DNA they choose 7. Leading CRISPR researchers soon realised the great potential of the technique in treating diseases, and five of them pulled together to open the start-up company Editas Medicine in Cambridge, MA 8. Their aim is to develop CRISPR gene therapy for humans – an idea that investors seem to be rather keen on. The initial venture capital for the launch of the company was $43 million.

The catch

Well, no method is perfect, and CRISPR is no exception. Despite promising results, there are some important things we need to tackle in order to make this treatment effective and safe.

One major concern is how we can bring CRISPR to where the treatment is needed. Conventional gene therapy is often delivered by engineered viruses, which is not risk-free. An alternative to this might be the use of nanocarriers – tiny capsules that are currently being tested for delivering chemotherapeutic drugs into cancer patients’ tumours (for a fantastic discussion of the recent advances in this field, you can read the recent GIST article about nanocarriers 9).

Even when we get CRISPR where we want it, it currently only cuts its DNA target in a fraction of the cells it reaches. Additionally, CRISPR might cut DNA that is not its target, so-called ‘off-targets’. By breaking genes that we do not want to be defective, new illnesses like cancers could arise; therefore limiting these off-target cuts while improving the target cuts is a crucial point if we want to use this technique in humans.

Editas Medicine is working on resolving these issues, but it might take a while until we see the first CRISPR treatments for humans.

Brave new world?

Dystopian thinkers among you might already be considering one possible misuse of the technology: the creation of designer humans.


With the possibility of modifying anything in our DNA, some people might pay considerable sums of money to change things that are not life-threatening: “Would you like to have blue eyes? Or a faster metabolism, that allows you to eat more while not putting on weight? CRISPR can help you!”

Hence CRISPR technology could open many doors – including those that do not aim for the greater good. Looking at our world today, we might predict to see a multitude of unnecessary CRISPR applications if we get it to work effectively in humans.


Operation on the Open Genome by Michaela Mrschtik was specialist edited by Sarah Neidler and copy edited by Nia Linkov and Tina Goldie.



  1. Schwank, G. et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell stem cell 13, 653-658, doi:10.1016/j.stem.2013.11.002 (2013).
  2. Tebas, P. et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 370, 901-910, doi:10.1056/NEJMoa1300662 (2014).
  3. Here it is.
  4. Wu, Y. et al. Correction of a genetic disease in mouse via use of CRISPR-Cas9. Cell stem cell 13, 659-662, doi:10.1016/j.stem.2013.10.016 (2013).
  5. Yin, H. et al. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nature biotechnology, doi:10.1038/nbt.2884 (2014).
  6. Barrangou, R. et al. CRISPR provides acquired resistance against viruses in prokaryotes. Science 315, 1709-1712, doi:10.1126/science.1138140 (2007).
  7. Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819-823, doi:10.1126/science.1231143 (2013).
  8. Nature paper.
  9. See theGIST article here.

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