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What if we could edit our genes to cure diseases? We’re closer than ever!

By Jennifer Dennis, PhD, Kansas City University of Medicine and Biosciences–Joplin

I am an embryologist, which means I study how embryos—the cluster of cells that ultimately become a fetus and then a developing baby—develop and grow. In the mid-2000’s during my training, there was a longstanding drive across the scientific community to revolutionize the treatment of human disease. The goal? To not only cure these conditions, but to prevent them in future generations as well. During that time, scientific advances were happening with regular frequency in laboratories across the globe. In particular, scientists discovered they could repair the genetic causes of certain diseases in mice or other laboratory animal species, but it was a major leap to testing these approaches in humans.

Generally speaking, there are a number of obstacles to overcome for these approaches to be utilized in curing human disease: 1) anatomy—it is practically impossible to ‘get to’ a human fetus in the mother’s uterus without major risks; 2) physiology—there are notable differences in how cells, tissues, and organs work in laboratory species compared to humans; and finally, 3) ethical issues—which diseases should we fix, and which ones should (or can) we not fix? The sad reality is that not all human conditions are as easily treated as others. So, who decides which problems to address first? And who pays for these types of treatments? What if the individual cannot afford to pay for treatments or insurance? And as any American who has been paying attention to Capitol Hill can attest, insurance—and an individual’s right to coverage, if it is a right—requires its own lengthy conversation.

Despite the desire to improve the health of the human population, it was always a distant goal—someday, somehow, and sometime further in the future, perhaps even 30-40 years from now. However, that moment has officially arrived. In 2015, CRISPR technology was introduced as a remarkable tool for developmental biology research. CRISPR, which is an acronym for clustered regularly interspaced short palindromic repeats (now you see why it is an acronym!), is a technique that can identify regions of DNA with mutations that lead to diseases, clip them out, and insert a repaired version (Pulido-Quetglas et al. 2017). CRISPR has been used successfully in multiple laboratory species, including zebrafish, frogs, and mice (Wang et al., 2013; Blitz et al., 2013, Jao et al., 2013), revolutionizing science in the process. It easy to use (relatively speaking) and readily available. It was no surprise that CRISPR was awarded the ‘Breakthrough of the Year in 2015’ by the American Association for the Advancement of Science.

So yeah, DNA can be repaired. But why all the hype? Well, we know that mutations in DNA are responsible for numerous diseases. And now, researchers can use CRISPR to repair human DNA mutations, which has the potential to improve human health (Ma et al. 2017). Consider a human disease like Duchenne muscular dystrophy, which is caused by a mutation in the DNA for a particular muscle protein called dystrophin. When dystrophin is damaged (mutated), it causes muscle cells to be fragile and easily broken. Can scientists use CRISPR to fix this mutation in a human? Theoretically, the answer is yes.

CRISPR has been used in mice to repair DNA mutations (Wang et al., 2013; Long et al., 2014), but many of these studies have fixed mutations in body cells, not reproductive (germline) cells (sperm and eggs). This distinction is critical: body cells are found throughout the body, but are not involved in the production of a new individual. By using CRISPR in body cells, disease-causing mutations in DNA can be repaired: the affected individual could have his/her condition alleviated, but it would not impact the individual’s future children. In this case, using CRISPR is ideal because it has treats the disease in the one patient only. Any future individuals contain DNA that remains unaltered by CRISPR.

In contrast, germline cells are utilized in reproduction. When they meet and combine, a new human is formed. In this example, a mutation in a sperm or egg could be repaired using CRISPR and then the cells would be combined to form an embryo, which is then placed in a human via in vitro fertilization (IVF). After a successful pregnancy, the embryo would give rise to an individual without the disease. But there’s a catch: if this individual were to have a child, he/she would also not inherit the original mutation. In fact, CRISPR would remove the mutation from the family’s pedigree altogether, thereby altering the DNA of all future generations. The repair done by CRISPR would be ‘in the germline’ (in the reproductive cells) and would be inherited by all future family members. Great, a cure for everyone! But it would be altering a person’s DNA without their consent. Consider if you would want someone changing your DNA without your permission? The answer is likely no.

Without a doubt, CRISPR can repair DNA mutations in body and germline cells. Does that mean we can start healing people tomorrow? Absolutely not! CRISPR works well, but it is far from perfect. Depending on which laboratory animal is tested, the ability of CRISPR to repair a mutation varies. Furthermore, it can introduce something called “mosaicism”. Mosaicism means that some cells are repaired with CRISPR, while other cells are not. This is the same manner in which calico cats get all their different colored fur. In humans, repairing some (but not all) cells can cause a range of outcomes, good and bad. And, we do not know if CRISPR might cause new mutations to appear. If a new mutation happens, could it lead to the development of a different disease at a later time?

To have a better understanding of how CRISPR works in embryos, we need additional research on the early embryonic development—the time immediately after a new embryo is formed. Right now, we don’t completely know how this process works in humans because most of our understanding comes from other species like mice and zebrafish. We must determine these mechanisms to know how changing someone’s DNA could impact this early timeline. We can always compare back to these processes in the mouse or other laboratory animal, which is what is typically done. But, we already know that the early steps in a mouse embryo are slightly different than what happens in humans (Niakan and Eggan, 2013). These differences support the need for more studies in human embryos before we can use CRISPR to repair specific conditions—but that is not easy to accomplish…

The newest studies using CRISPR are a major scientific accomplishment, but due to the use of human embryos, they have been met with extreme concern. Because of this, it is important to thoroughly address the multiple ethical considerations surrounding CRISPR for use repairing DNA in the germline. Indeed, many scientific experts have expressed significant reservations for using the tool in human embryos (Doudna 2015). At present, in the United States the National Institutes of Health does not provide funding for using CRISPR in human embryo research. Further, the Food and Drug Administration is banned from considering studies that involve genetic altering of human eggs, sperm, or embryos. Any type of CRISPR research involving germline editing is occurring outside of the United States, or through privately funded projects.

Ultimately, the “30- to 40-years into the future” is now. CRISPR is here and scientists are using it in an attempt to repair the DNA mutations responsible for multiple diseases. With the power to edit human DNA, comes the great responsibility to do so in an ethical manner. Many people can probably justify using CRISPR to repair mutations that cause death during prenatal development and/or childhood. However, CRISPR is not limited to repairing lethal mutations in DNA. It can change any desired sequence of DNA, including those that influence intelligence or physical attributes, or those influencing biological sex and/or gender. Because of this, the scientific community, and the public, need to address ethical issues of using CRISPR in embryos. More importantly, there must be a strict adherence to any decision determining the use of CRISPR in the editing of human embryos.

As for myself, I never expected to see even the possibility of eradicating human disease, and I know it will take time before we see any true outcomes. While, it is a very exciting time for science, this is not the time for remaining uninformed. Scientists all over the world need to discuss CRISPR, and note the difference in repairing body cells versus germline cells. We need to educate our government officials and the general public about these issues. It is so critical to continue to communicate and discuss how we want to impact our own population for future generations to come.

 

Dr. Jennifer Dennis is assistant professor of anatomy at Kansas City University of Medicine and Biosciences – Joplin (KCUMB). She earned her MS and PhD in neuroscience in 2004 and 2009, respectively. Her doctoral work focused on the genetic regulation of neural crest cells and how various genes control craniofacial development. She currently teaches courses in embryology, histology, and anatomy at KCUMB. Follow Jennifer on Twitter.

 

 

 

REFERENCES

Blitz IL, Biesinger J, Xie X, Cho KW. Biallelic genome modification in F(0) Xenopus tropicalis embryos using the CRISPR/Cas system. Genesis. 2013 Dec;51(12):827-34.

Doudna J. Perspective: Embryo editing needs scrutiny. Nature. 2015 Dec 3;528(7580).

Jao LE, Wente SR, Chen W. Efficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system. Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13904-9

Lichun, T, Yanting Z, Hongzi D, Mengmeng G, Jin P, Buxi Z, Ming L, Fang Z, Weihua W, Xiaowei L, Jianqiao L. CRISPR/Cas9-mediated gene editing in human zygotes using Cas9 protein. Mol Genet Genomics 2017 292: 525-533.

Long, C, McAnally, JR, Shelton JM, Mireault AA, Bassel-duby, R; Olson EN. Prevention of Muscular dystrophy in mice by CRISPR/CAS9-mediated editing of germline DNA. Science. 2014. Sept 5 345(6201).

Ma H. et al. Correction of a pathogenic gene mutation in human embryos. Nature 2017 advance online publication: http://dx.doi.org/10.1038/nature23305.

Niakan K.K. and Eggan K. Analysis of human embryos from zygote to blastocyst reveals distinct gene expression patterns relative to the mouse. Dev. Biol. 2013 375, 54-64.

Pulido-Quetglas C, Aparicio-Prat E, Arnan C, Polidori T, Hermoso T, Palumbo E, et al. (2017) Scalable Design of Paired CRISPR Guide RNAs for Genomic Deletion. PLoS Comput Biol 13(3): e1005341. https://doi.org/10.1371/journal.pcbi.1005341

Wang H, Yang H, Shivalila CS, Dawlaty MM, Cheng AW, Zhang F, Jaenisch R. One-Step Generation of Mice Carrying Mutations in Multiple Genes by CRISPR/Cas-Mediated Genome Engineering. Cell 2013 May 9; 153(4): 910–918.

 


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Discussion
  1. Very interesting and most of the science is well beyond what I understand, but certain diseases just existing really scare me. Like Prion diseases. Rabies is another. Having had to be vaccinated twice thanks to infected wild animals, it’d be really nice if someone found a cure for that. Chagas disease is another scary one. Influenza would seem to be the biggest threat. It’d be nice if there were a cure for that. And, maybe the common cold? It’s amazing for some of us to think we can duplicate life, we can put men into outer space, we can unleash the power of the atom, but a cold, that one still eludes us.

  2. Is there a concern among geneticists that by altering a significant number of genes in order to ‘repair’ an embryo that we may open the door to future pandemics, because perhaps the human genome evolved in the way it has in order to fend off significant disease. Is this really a Pandora’s box that could in the end in the destruction of the human race?

    In computer software we have testing regimens that we apply to make sure we aren’t going to have catastrophic disasters. Would it be reasonable to require that when we inject CRISP modifications to any species(let alone humans) that we have a testing process that verifies that we aren’t opening that species up to an extinction event? Imagine if you will that Elon Musk’s Tesla made changes to Full-Self-Driving that would kill every person in every Tesla vehicle after it was propagated.

    I find this an interesting expression of the rigor of the Genetic sciences. Not too different from the Manhattan project as a question for nuclear physics.

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