RUTHFULLY YOURS

Dr. Baltimore is emeritus president of the California Institute of Technology and the Millikan professor of biology. Dr. Berg is Cahill professor of biological chemistry, emeritus, at Stanford University. Both are Nobel laureates.

Let’s Hit ‘Pause’ Before Altering Humankind

Modern biological research continues to generate new technology at a staggering pace, bringing to society new challenges and new opportunities. A recent appearance is the so-called CRISPR/Cas9 technology for altering genes in the body’s cells, including, most troublingly, early embryonic cells.

To understand the challenge brought by this technology it is important to make a distinction between somatic cells and germ-line cells. Somatic cells are the run-of-the-mill cells of our bodies: muscles, nerves, skin and the like. Germ-line cells are the egg and sperm cells that, when joined, give rise to offspring. Making gene changes in somatic cells can have dramatic effects, but they are not transmitted to the next generation and therefore fall comfortably into the category of pure therapeutics and generate minimal controversy. It is changes in germ-line cells that create heritable alterations.

The advent of CRISPR/Cas9 again sees a biomedical technology challenging norms and raising concerns. CRISPR/Cas9 makes it comparatively easy to modify germ-line inheritance by inserting, deleting or altering bits of DNA. It may be possible to make these alterations quite precise, with no undesired changes in the genome. Nevertheless, such changes would be inherited not only by the next generation but by all subsequent generations. Thus the decision to alter a germ-line cell may be valuable to offspring, but as norms change and the altered inheritance is carried into new genetic combinations, uncertain and possibly undesirable consequences may ensue.

It is important to put this new capability and its potential applications into context. There are two types of germ-line modification to think about. One aims to eliminate a defect responsible for a serious disease, an outcome most would view as an unalloyed good.

If we could assure that a child of afflicted parents did not inherit Huntington’s Disease, for example, that would be a blessing to the child, to the parents and to society. At present, there are several conceivable paths to achieving this end. One scenario might be to make the necessary genome modifications in cells that can be converted to eggs or sperm, where the desired changes can be verified before they are used to create embryos by conventional in vitro fertilization and implantation.

However, germ-line modification is not the only way to avoid inheritance of a Huntington’s gene; there are embryo-selection methods that achieve the same end. In fact, only in rare circumstances are germ-line alterations the only way to achieve avoidance of passing on a deleterious gene.

The other, more unsettling kind of germ-line modification would involve attempts to modify inheritance for the purpose of enhancing an offspring’s physical characteristics or intellectual capability. We can call this voluntary modification in that there is no compelling medical need. Choosing to transmit voluntary changes to future generations involves a value judgment on the part of parents, a judgment that future generations might view differently.

This can be seen as eugenics, thought by earlier generations to be desirable but now generally considered abhorrent. Also, we often do not know well enough the total range of consequences of a given gene alteration, potentially creating unexpected physiological alterations that would extend down through generations to come. For these reasons and others, voluntary genome alteration might well be outlawed, at least at the present stage of knowledge.

The nature of these issues causes us to recall an earlier instance, in 1975, when members of the biological-science community expressed concerns about possible dangers of the newly emerged recombinant DNA technology. In response, scientists who were engaged in the research accepted a moratorium until the safety issues could be evaluated. A conference was then held at the Asilomar conference center in California, which we helped to organize, where scientists and others debated the potential risks and benefits of the technology and crafted a way forward.

Although somatic-gene therapy was viewed at that time as having become possible, the prospect for germ-line therapy seemed so far in the future that it was not seriously discussed. Responding to the current concerns about the potential applications of the CRISPR/Cas9 capability, scientists—including some carrying out the research—have again called for a moratorium on the most problematic application of the technology, germ-line modification, and for the convening of a new international meeting to consider a way forward.

We would support a move to hold such a conference. Those of us in the scientific community need to think carefully about the implications of our actions in both practical and ethical dimensions. Biomedical research offers hope for the alleviation of human disease, yet to address complex diseases like cancer we must carry our investigations to the most fundamental elements of living systems. This gives researchers powerful capabilities that can be used for reaching desired goals. We need to ensure that we have widespread agreement about what is desirable.