What is Germline Genetic Engineering and why we need to pay attention to it? by Don Simborg

By Guest Contributor Don Simborg

Author of The Fourth Great Transformation, Don Simborg, explains what Artificial General Intelligence is (AGI) and what The Fourth Great Transformation could mean for us all and a new human species.

In The Fourth Great Transformation I have made what I thought was a bold prediction. I state that it is inevitable that germline genetic engineering in humans will become legally available somewhere in the world. By germline genetic engineering, I mean the deliberate genetic modification of human germline cells with the intention that those modifications will be passed on to future generations of the individuals involved. Although that could be done by modifying sperm or eggs (or their precursors), the most likely way this will be performed is with zygotes (fertilized eggs) during the process of in vitro fertilization (IVF). My timing for this in the book suggested this would happen near the end of this century.

There is a lot of news lately that makes we wonder if my prediction timeline was overly cautious.



First, the United Kingdom already allows what some might categorize as germline genetic engineering. To refresh your memory on basic genetics, humans have somewhere in the range of 20,000 to 25,000 genes contained in our 23 pairs of chromosomes housed in the nucleus of every one of our cells, including our germline cells like sperm and eggs. In addition to those genes, we also have a small number of genes – 37 to be exact – that are contained in the mitochondria of each of our cells. In rare occasions, there are mutations in those mitochondrial genes that cause serious disease or miscarriages.

During the 1990s in the US, Dr. Jacques Cohen at the St. Barnabas Institute in New Jersey pioneered an IVF technique that allowed the substitution of normal mitochondria (with their genes) from a donor to be substituted for the abnormal mitochondria of a mother undergoing IVF. The subsequent child born from such a procedure would not only have disease-free mitochondrial genes, but those genes would be passed on to all future female offspring of that person (mitochondria come only from the mother during normal procreation.) Although this procedure was subsequently banned in the US, a similar procedure was legalized in the United Kingdom in 2015 and is also performed in multiple other countries. It is currently one of the reasons for medical tourism for people from countries like the US where the procedure is not available. (1)

One could reasonably argue that this form of mitochondrial gene treatment is not truly germline genetic engineering even though it does change the genes that are passed on to future generations. It does not involve an actual procedure that changes a gene using a genetic engineering tool. Rather, it is a mitochondrial transplant which happens to contain normal genes.



Unfortunately, true germline genetic engineering has already occurred in humans illegally. By now, many of you may have read about the scandal in China in which a biophysicist, He Jiankui, genetically engineered embryos during IVF that were subsequently implanted in two women resulting in the live births of twins in one of the women and a single child in the other. This was done without approval from the regulatory agencies in China and without the normal informed consent procedures that would be required of any experimental procedure. (He Jiankui insists that he did follow ethical informed consent procedures with the involved hospital and patients, but this has been disputed.) Jiankui used CRISPR (see below) to perform the genetic engineering. What he changed was a gene that would make these children resistant to HIV infection. At this time, as far as we know, the three children are apparently normal although information about them is highly restricted.

Further, we have no idea at this point whether the genetic changes were actually successful. Although making future children resistant to HIV may one day be a desirable goal, no responsible person today would suggest that such a procedure should be allowed with our current state of genetic engineering capability. The authorities in China clearly agree and He Jiankui is current serving a jail sentence for his activity. (2)  Germline genetic engineering of IVF embryos intended for implantation is currently banned worldwide. Experimentation with embryos NOT intended for implantation is still allowed in the US and elsewhere.



Since the discovery of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) as a tool for genetic engineering, (3) research has progressed rapidly to the point where today there are dozens of human clinical trials underway in the US alone to use this tool to cure a wide spectrum of genetic disorders, including many cancers. None of these initiatives are germline genetic engineering. Rather they are somatic genetic engineering which alters the genes only of the individuals treated and cannot be passed on to their offspring.

Clearly, we need to perfect our understanding and capabilities of somatic genetic engineering before we risk proceeding to germline genetic engineering which risks not only the individuals involved but future generations. Why are we even risking individuals today with somatic genetic engineering? As with all new medical interventions, at some point in their development the known and even unknown risks of a procedure become outweighed by the severity of the problem they are designed to cure. At that point, it becomes a legitimate and ethical choice of the individual involved as to whether to attempt using that intervention. That is where we are today with somatic genetic engineering used to cure disabling or life-threatening genetic disorders. The threshold for making such a choice is certainly lower than a decision that will affect a person’s children, grandchildren, and all future generations. At this point in our knowledge, we don’t know the long-term risks of these procedures that might accrue to future generations.



The more important question is who will have the right to make such a decision when it comes to germline genetic engineering? Is it up to the individual that carries a defective gene or does the broader society have a role in regulating such decisions? Let me use as an example, the gene that causes Huntington’s Disease. This neurological disease is debilitating and deadly for those who have a single copy of the abnormal gene. The manifestations do not appear until later in life so people carrying this gene have a 50% probability of passing it on to their children long before the disease manifestations become apparent. Clearly, if genetic analysis detects this abnormality in a young person, and there is a possible somatic genetic engineering cure for that individual, he or she has the right to decide to choose it. But does that individual have a right to alter their germline cells as well or IVF embryos they might create?

One might ask why not? What harm can be done in preventing this individual’s offspring from developing Huntington’s Disease. The answer is we don’t know. One of the problems with using CRISPR and other genetic engineering tools is that they are not as precise as we’d like them to be in altering a genome. They sometimes create what is known as “off-target” mutations which means they alter the genome in some unintended location in addition to the one that is targeted. The impact of these “off-target” mutations is unpredictable, but in some cases, we know can be very harmful. That’s the risk. It is one thing to risk that in a single individual and quite another to risk it for future generations.

When I wrote The Fourth Great Transformation, I believed it would be many decades before we were confident enough to move on to germline genetic engineering. Advances, however, are moving at an unbelievable pace is this area. For example, new forms of CRISPR (and its associated “cutting” enzyme Cas9) are being discovered or developed at a rapid pace. Each of these new versions brings improvements in accuracy or capability for specific genetic engineering needs. (4)  Even more dramatic is the report of a tool called RLR (Retron Library Recombineering) Technique. (5)  Retrons are small snippets of DNA that can be inserted into cells causing them to replicate a desirable gene without altering the genome of the treated cells. Although retrons are a long way from being ready for clinical use, they could achieve the same genetic engineering goals without the concern for off-target mutations. These are just a couple of examples of the rapid progress in this area.

Germline genetic engineering may come sooner than we think.


References and Footnotes:
  1. For a description of this “3-genetic parent” procedure, see Appendix 5 of my book, What Comes After Homo Sapiens?
  2. For an excellent report about the He Jiankui scandal and related issues, see CRISPR People: The Science and Ethics of Editing Humans, Henry T. Greely, The MIT Press, Cambridge, 2021
  3. Jennifer Doudna and Emmanuelle Charpentier received the 2020 Nobel Prize in Chemistry for discovery of the use of CRISPR for genetic engineering. For a beautifully written description of Doudna’s life and work, see The Code Breaker, Walter Isaacson, Simon & Schuster, New York, 2021
  4. For a list of some of these new versions of CRISPR, see Table 3, p.200 of The Fourth Great Transformation.
  5. https://wyss.harvard.edu/news/move-over-crispr-the-retrons-are-coming/

If you’d like to find out more information about The Fourth Great Transformation, please see Don’s previous blogs.


DON SIMBORG is a graduate of the Johns Hopkins School of Medicine, and former faculty member at both the Johns Hopkins and University of California San Francisco schools of medicine. He is the founder of two electronic medical records companies and is a founding member of the American College of Medical Informatics. He served on the Computer Science and Telecommunications Board of the National Academics of Science. He and his wife, Madeleine, have two children and four grandchildren and live in California.

LinkedIn: https://www.linkedin.com/in/don-simborg-293678/


Suggested Reading

A new human species will soon come to co-exist with us. This new species, ‘Homo nouveau, will be created using artificial intelligence and genetic engineering; both important tools which are in their infancy. Not only are the science and technology relatively new, but their implications in the mind of the general public are also only just beginning to enter our collective consciousness. This book expands on the research done for the author’s pervious book, What Comes After Homo Sapiens?

Written by a medical professional and independent consultant to healthcare IT companies, The Fourth Great Transformation explores the questions of what this new species will look like, how we as humans will get along with them, and the potential threats and opportunities that will come along with genetically modified humans.

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