Engineering Heritable Changes in the Human Genome: Implications for Clinical Research

Clinical Researcher—February 2019 (Volume 33, Issue 2)


Daniel Kavanagh, PhD




This article will provide a brief overview of the state of genome-editing technologies as they relate to human genetic modifications that can be passed from parent to offspring (called “germline” genetic modifications). We will first look at what we can do with gene editing technology, and then look at approaches to the question of what we should do with such technology.

The answer to the former question can be reliably provided by molecular biologists and genetic engineers. The answer to the latter question must come from broad engagement of the scientific community, persons affected by heritable diseases, and the public at large. We will also consider recent reports from China regarding the alleged birth of human babies subjected to unethical gene-editing procedures by a rogue scientist.

Gene Editing Technology and Potential Applications

Genetic engineering—the deliberate modification of DNA to produce changes in an organism—has been around for decades, with early applications in the biology of microbes or isolated cells in culture, and later applications in animals and plants for research and agriculture. Some applications of genetic engineering are being used to modify cells in the human body for the treatment of disease.

As of this writing, the U.S. Food and Drug Administration (FDA) has already given marketing approval to several medical products whose mechanism of action involves genetic modification of patients’ cells. These include two Chimeric Antigen Receptor T cell (CAR-T) products for the treatment of B cell malignancies, and a gene replacement therapy to treat certain forms of inherited retinal disease.

A recent study suggests that there will be more than 40 such approvals by the year 2022.{1} Importantly, all of these therapies are intended to treat disease in individual patients; none are intended to induce genetic changes that will be passed on to future generations.

There are many techniques available to deliberately modify DNA; some of the most exciting recent developments in genetic engineering have been enabled by a set of technologies known as “gene editing” or “genome editing.” Genome editing technologies allow the genetic engineer to arbitrarily rewrite the sequence of chromosomal DNA with a degree of precision potentially comparable to a text editor or word processor. (Keeping in mind: texts produced with word processors frequently still contain errors.)

Of the various genome editing technologies, the ones receiving the most attention are those that involve CRISPR-based approaches. CRISPRs (clustered regularly interspaced short palindromic repeats) are a type of genetic sequence naturally found in bacteria. Bacteria use CRISPRs to naturally edit their own DNA to protect themselves from viruses.

Around 10 years ago, scientists first began to demonstrate that artificial CRISPR systems could be used to alter and edit the DNA of animal cells. Because functional CRISPR systems are relatively easy to design, it became apparent that various CRISPR-based systems could potentially be used to treat a wide variety of inherited diseases, and perhaps be brought to clinic much more quickly than preceding technologies. It is expected that some of the gene transfer medicines that will achieve FDA approval in the next few years will make use of CRISPR technology. It also became apparent that CRISPR techniques might be used not only to treat disease by targeting specific tissue such as lung, liver, or bone marrow, but also to induce genetic changes in cells that produce sperm or ova, or in living embryos. Such germline alterations in the human chromosome would potentially be passed on to children, grandchildren, and future generations.

In 2015, global experts met for the First International Summit on Human Gene Editing. As the conclusion to several extensive reports, the summit released a consensus statement on human germline gene editing.{2} Six areas of special concern were identified:

  • the risks of inaccurate editing;
  • the difficulty of predicting harmful effects;
  • implications for the individual and for future generations;
  • the fact that over multiple generations, genetic alterations might cross national and cultural borders;
  • broad social justice implications; and
  • moral and ethical considerations for purposefully altering human evolution.

The report concluded that it would be irresponsible to proceed with intentional germline human genome editing until safety and efficacy issues have been addressed, until there is broad social consensus on appropriate applications, and until appropriate regulatory oversight is in place.

“CRISPR Babies” in China

In late 2018, a Chinese biophysics researcher named He Jiankui announced to the world that he had intentionally altered the genome of viable human embryos, at least two of which had been carried to term, resulting in a live twin birth. As of this writing, the scientific community has not seen definitive proof that such live births actually occurred. Recent statements from the Chinese government seem to indicate that the live births are real, and that the researcher is facing potential criminal charges in China as a result of his actions in this matter.

Almost all of what we know about this activity comes from the researcher’s own statements, as well as a few leaked documents from the hospital where the work was done. Based on this information, his actions are irredeemably flawed and inexcusable from the standpoints of science, medicine, and ethics. The defects in his approach are so comprehensive that there is no space to list them here. (For a list of important concerns, see Ed Yong’s article in The Atlantic.){3}

The molecular results presented by the researcher are technically deficient; the available version of the informed consent is deceptive; the scientific rationale is misinformed; and the medical justification is specious. Every aspect of this case is so tragically compromised that there is little we can draw from as part of an informed discussion of potential future legitimate germline gene editing projects.

This incident has raised strong feelings within both the bioethics community and the genetic research scientific community. Nevertheless, we can take comfort from the fact that, based on available information, there is a reasonable chance that the children produced from this rogue activity may live normal lives without significant ill effects.

Potential Legitimate Future Applications of Germline Editing

Millions of people around the globe are affected by inherited genetic diseases, and medical databases list thousands of genetic mutations that are associated with these diseases. Many of these inherited diseases result in death in early childhood, or in lifelong disability for surviving individuals.

As whole genome sequencing becomes more routine, increasing numbers of prospective parents are faced with the knowledge that any children they conceive as a couple will face the risk, and sometimes the certainty, of a devastating congenital condition. Current existing avenues available to such couples include options such as adoption, sperm or ova donation, or in vitro fertilization (IVF) with pre-implantation selection of disease-free embryos.

Understandably, many couples wish for the option to conceive and bring to term children who are free from the risk of inherited disease; some couples may not wish to utilize these options, and some options may be impractical for medical or social reasons. Genome editing offers a plausible alternative approach; nevertheless, the three criteria mentioned above (safety and efficacy, societal consensus, and regulatory frameworks) remain to be fulfilled.

As one example, a couple may discover that both prospective parents carry one copy of a disease-associated recessive allele for cystic fibrosis (i.e., both parents are asymptomatic carriers). This means that, on average, one-fourth of the embryos conceived by this couple will be free of disease alleles, one-half of such embryos will be carriers like the parents, and one-fourth will be homozygous (receiving both copies) for the disease allele, and thus afflicted with cystic fibrosis, a devastating disease. The parents may plan to generate zygotes by IVF, test them for a disease allele, and then implant only disease-free embryos. Sometimes, however, too few viable zygotes are produced, and no disease-free option is available. As an alternative, parents might propose to use gene editing to attempt to alter the affected chromosomes and produce a disease-free child.

A Challenge for Scientists, Regulators, and the Public

At this point, the medical research community should be prepared to address crucial questions. Does the evidence indicate that this procedure is safe enough and effective enough to proceed? Is there a sufficient consensus in the community to allow such a procedure to go forward? Is there a regulatory framework in place to provide adequate oversight?

Further questions would include: How will researchers secure meaningful informed consent? Who would be liable for any social, psychological, or medical harm experienced by the child, or children in subsequent generations, that is possibly related to the gene editing procedure?

According to many authorities, the barriers posed by these concerns are essentially insurmountable. In other words, there are no foreseeable cases in which human germline gene editing would be justifiable. Other researchers are more sanguine, and feel that, as with IVF, initial public objections will fade away as new technology becomes more familiar, and that society has the tools to cope with risks associated with this and other emerging technologies.

Given the relative accessibility of the basic technology, and aside from the issue of legitimate research, society should prepare for the likelihood that increasing numbers of genetically altered children will be born in the coming decades, irrespective of popular opinion and regulatory oversight. The potential effects on the future of human society are profound. All participants in this discussion must do their best to maintain transparency regarding their own interests and biases, and research in this area must be guided by the basic principles of Respect for Persons, Beneficence, and Justice{4} at each step of the process.


  1. Existing Gene Therapy Pipeline Likely to Yield Dozens of Approved Products Within Five Years.

Daniel Kavanagh, PhD, is senior scientific advisor, gene therapy at WCG (WIRB-Copernicus Group). Previously he was on the faculty at Harvard Medical School, where he conducted gene therapy research and was vice chair of an Institutional Biosafety Committee overseeing human gene transfer studies.