Empowering Fertility - The New Pandora’s Box: Creating “GMO” Babies?
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The New Pandora’s Box: Creating “GMO” Babies?

By Paul Bergh, MD

 

The New Pandora’s Box: Creating “GMO” Babies?

Over the past two weeks, a leading group of biologists and bioethicists writing in the journals Nature and Science, have sounded the alarm  regarding the use of a new technology that allows scientists to change the genetic makeup of gametes (sperm and egg) and embryos. This is similar in principle to genetically modifying food referred to as genetically modified organisms (GMO).  The past several years have seen a flurry of research in genetic engineering in both animal models and human cell lines.  The concern is that this research has advanced much faster and farther than anyone anticipated.  Rumors abound in both China and the U.S. that human trials with this new genetic engineering technology are already underway.

The Technology

Zinc Finger Nucleases

In 2002, Dana Carroll of the University of Utah realized that a type of engineered proteins called zinc finger nucleases could be modified to target and modify specific genes.  While this was the first tool to enable scientists to make specific changes to a chromosome, every modification required a relatively arduous and time-consuming task to engineer a new protein.  Once developed, these zinc finger nucleases could be temperamental and didn’t always work.

TALENs

Another significant advance in methods for editing genes became available in 2011. TALENs (transcription activator-like effector nucleases) are  a type of artificial protein that can find and cut and edit specific DNA sequences.  They were a major improvement over zinc finger nucleases as they were much easier to develop and tailor to specific genes.  The problem with TALENs is that they are very large, and thus, are difficult to manipulate.  Thus delivering them into the cells requiring treatment, can be quite challenging.

CRISPR

The latest technology, CRISPR (clustered regularly interspaced short palindromic repeats), came on the scene in 2012 and has made the genetic engineering of organisms, including humans, a practical reality.  A component of CRISPR utilizes a short segment of RNA to target the DNA that is to be excised or modified.  A second part consists of an enzyme which can cut DNA (endonuclease)and then either remove a specific sequence of DNA or replace it with a new sequence, thus altering the gene.  A specific endonuclease known as Cas9 (CRISPR associated protein 9) has gained in popularity.   CRIPSR/Cas9 refers to the use of this particular endonuclease.  The RNA targeting component of CRISPR is much easier to manufacture than the complex proteins employed in the earlier methods described above.  Not only can these proteins be made quickly and easily, but given their small size, they are easy to handle and are easily inserted into cells.

Areas of Active Research

An area of interest is treating individuals suffering from serious, life-threatening infections.  An example is using the technology to modify  the white cells of persons infected with HIV.  If a person with AIDS had their cells genetically engineered so that HIV could not recognize them, it would cure them.  This line of treatment has eerie parallels to the genetic alteration of crops to make them resistant to disease.

Another area of interest is elucidating the function of specific genes by altering them in animal models.  This technique involves modifying genes in the egg or the embryo and thus creating genetically modified newborns.   This technology holds tremendous promise for understanding and potentially treating, complex conditions such as autism or schizophrenia.  It could dramatically accelerate both the understanding and treatment of a host of conditions that are not well understood.  These types of experiments have already been conducted in the monkey model.

Some firms are exploring genetically modifying animal genes, such as those in the pig, in order to “humanize” their organs for use in the treatment of human disease.  Imagine genetically engineering a pig heart to have the same immunologic markers of an individual in need of a heart transplant.  In theory, this pig heart could then be transplanted into a human without fear of rejection.

The Promise

This new technology can be used to genetically engineer somatic cells.  The aim is to repair or eliminate a mutation in cells that cause disease.  An example would be the harvesting of bone marrow from a child with sickle cell disease.   These stem cells would then be modified by CRISPR to correct the mutation causing sickle cell, and then infused back into the child.  The aim is to correct a sufficient number of cells that carry the mutation.  Thus altered, these cells would be fixed for their lifetime as well as the lifetime of their progeny cells.  This treatment would have the potential, in a single step, to cure individuals of a terrible disease.  This line of treatment could be used for any disease with a known genetic etiology where somatic stem cells can be modified.

The use of CRISPR in human eggs or sperm (germ-line) and embryos with in vitro fertilization (IVF) has the potential to wipe out the infliction of a host of genetic diseases by correcting affected embryos.  It may also be possible to insert or modify genes to deliver life-long protection from such diseases as cancer, HIV, Alzheimer’s, and possibly extend one’s life expectancy.

The Fear

The fear is that human germ-line or embryonic genetic engineering will spark the quest to create designer babies or super-humans.  Why not design children for intelligence, looks, and athletic ability?  Could a country create superior soldiers or a group of people with superior aptitude to offer them a competitive advantage?

A dozen countries, excluding the U.S. have banned germ-line or embryonic cell genetic engineering.  Several scientific societies and industry trade groups have unanimously concluded that it would be too risky to allow.  The European Union’s convention on human rights and biomedicine has called gene pool tampering a crime against human dignity and human rights. However, in 2012,  Europe’s Committee for Medicinal Products for Human Use, approved a gene therapy for a rare genetic disease.  Although the U.S. does not officially prohibit germ-line genetic engineering, the U.S. National Institutes of Health’s Recombinant DNA Advisory Committee explicitly states that it “will not at present entertain proposals for germ line alterations.”

Early attempts with gene therapy in the U.S. ended in disaster. An early setback to gene-therapy occurred in 1999 with the well-publicized case of 18-year-old Jesse Gelsinger, who died after receiving an experimental gene therapy.  These initial problems were a result of the early gene delivery methods that involved using a virus. Most complications were attributed to reactions to the virus.  CRISPR  offers the availability of a much safer and accurate method of genetic engineering.

What’s Next?

The recent alarm raised concerning these activities  is understandable.  Given the broad implications of this therapy; in addition to, the unknown short and long-term side effects as well as the risks of tinkering with the early human genome.  On the other side of the argument is the incredible potential of CRISPR to revolutionize medicine.   Think of the countless individuals who suffer from genetic disorders, debilitating or life-threatening infections, cancer, and degenerative somatic and neurologic diseases.  The potential impact on quality of life and alleviation of human suffering is breathtaking.  While the implications of this new technology are mind-boggling, they are also terrifying.

CRISPR is likely another medical Pandora’s box, once it is out (and it is out!), it will be impossible to stop.  These revelations remind me of another new technology (IVF) that made its debut in the 1970’s.   One of the leading ethicist of the day, Paul Ramsey of Princeton University, referred to IVF as “…unethical medical experimentation on possible future human beings, and therefore it is subject to absolute moral prohibition.”  Similarly, the Nobel laureate and discoverer of DNA, James Watson, publicly remarked, “You can only go ahead with your work if you accept the necessity of infanticide.  What are you going to do with your mistakes? ” Well, we certainly have come a long way since then, largely due to the vision, fortitude, and courage of the pioneers of IVF, Robert Edwards, and Patrick Steptoe.  In retrospect, their vision has turned into a beautiful reality for countless infertile couples.

It makes me wonder where this new technology will take us.  Can we be trusted to allow it to fulfill its great promise or will we regret ever taking this path.  Like in vitro fertilization (IVF), will we be having the same conversation about the genetic engineering of human eggs, sperm, and embryos 50 years from now…

Links:

http://www.nature.com/news/don-t-edit-the-human-germ-line-1.17111

http://www.nytimes.com/2015/03/20/science/biologists-call-for-halt-to-gene-editing-technique-in-humans.html?ref=health&_r=0

http://www.technologyreview.com/featuredstory/535661/engineering-the-perfect-baby/

http://www.npr.org/blogs/health/2015/03/20/394311141/scientists-urge-temporary-moratorium-on-human-genome-edits?sc=17?f=1001&utm_source=iosnewsapp&utm_medium=Email&utm_campaign=app

http://www.nytimes.com/2014/03/04/health/a-powerful-new-way-to-edit-dna.html

http://www.addgene.org/CRISPR/guide/#

Ref:

Vogel, Gretchen. Embryo engineering alarm. Science 347(6228), 1301. 3-20-2015

Bibikova, M., Golic, M., Golic, K. G., and Carroll, D. Targeted chromosomal cleavage and mutagenesis in Drosophila using zinc-finger nucleases. Genetics 161(3), 1169-1175. 2002

Li, T., Huang, S., Zhao, X., Wright, D. A., Carpenter, S., Spalding, M. H., Weeks, D. P., and Yang, B. Modularly assembled designer TAL effector nucleases for targeted gene knockout and gene replacement in eukaryotes. Nucleic Acids Res. 39(14), 6315-6325. 2011.

Qi, L., Haurwitz, R. E., Shao, W., Doudna, J. A., and Arkin, A. P. RNA processing enables predictable programming of gene expression. Nat.Biotechnol. 30(10), 1002-1006. 2012.

Tebas, P., Stein, D., Tang, W. W., Frank, I., Wang, S. Q., Lee, G., Spratt, S. K., Surosky, R. T., Giedlin, M. A., Nichol, G., Holmes, M. C., Gregory, P. D., Ando, D. G., Kalos, M., Collman, R. G., Binder-Scholl, G., Plesa, G., Hwang, W. T., Levine, B. L., and June, C. H. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 370(10), 901-910. 3-6-2014.

Cathomen, T. and Ehl, S. Translating the genomic revolution – targeted genome editing in primates. N.Engl.J Med. 370(24), 2342-2345. 6-12-2014.

Niu, Y., Shen, B., Cui, Y., Chen, Y., Wang, J., Wang, L., Kang, Y., Zhao, X., Si, W., Li, W., Xiang, A. P., Zhou, J., Guo, X., Bi, Y., Si, C., Hu, B., Dong, G., Wang, H., Zhou, Z., Li, T., Tan, T., Pu, X., Wang, F., Ji, S., Zhou, Q., Huang, X., Ji, W., and Sha, J. Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos. Cell 156(4), 836-843. 2-13-2014.

Doudna, Jennifer A. and Charpentier, Emmanuelle. The new frontier of genome engineering with CRISPR-Cas9. Science 346(6213). 11-28-2014.

Kim, H. and Kim, J. S. A guide to genome engineering with programmable nucleases. Nat.Rev.Genet 15(5), 321-334. 2014.

Empowering Fertility: An educational blog for patients & healthcare professionals that empowers individuals to take charge of their fertility. Visit us at http://empoweringfertility.com.

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