By Nancy M.P. King
Science news is exploding these days with novel, exotic, and amazing-sounding research, ranging far and wide across the spectrum from science fiction to the bedside: making mini-brains in petri dishes, using baby pigs to grow human organs for transplant, employing "gene drives" to eliminate mosquito-borne and tick-born diseases, even inheritable genome editing to create "designer babies". We the public have become accustomed to reading about the prospect of medical miracles, and have been conditioned to believe that newer, better treatments for all human ailments are right around the corner. "Regenerative medicine" - a broad new field that includes research into future treatments as diverse as induced pluripotent stem cells, 3-D bioprinting, spray-on skin, bioartificial organs and regrowing organs and tissues, from fingertips to livers - lies at the heart of this biotechnological revolution and cultural phenomenon. Should we believe the hope, or shun the hype?
Answering that question may be more complicated than it seems. Let's examine how new treatments are developed through research. After learning about a potential new treatment in the lab, and from research with animals, researchers must study it in humans. For many years, the model for all research in humans has been drug development, and research to develop most drugs follows a familiar pattern. First, a drug is given to healthy volunteers, starting with very small doses and then increasing the dose for later research subjects until the side effects become too bad. This first step tests the drug's safety and finds the "maximum tolerated dose", which is the dose below the one with "intolerable" side effects. But it does not test whether or how well the drug works in humans, because the subjects are healthy.
This drug testing model assumes that two things are generally true. First, it assumes that the higher the dose, the more effective the drug is and the worse its side effects are. Second, it assumes the healthy volunteers are the best subjects to go first. When cancer drugs were first introduced, however, the second assumption changed. Chemotherapy is poisonous, so it seemed cruel to test chemotherapy drugs on healthy volunteers, since even low doses could be toxic. (Similarly, when surgery research became more common, it didn't seem either fair or useful to perform surgery on healthy volunteers.) Thus, the first subjects in cancer research became the sickest patients, for whom nothing else had worked. This seemed fair because if patients like these joined a research study of a new drug, being in the study would not keep them from getting some already available drug that might help them.
As a result of this change, many patients, physicians, and even researchers started to think that joining a first-in-humans research study might benefit patients for whom nothing else had worked, precisely because nothing else had worked and the study drug was new. Cancer patients and others started seeing research as a good way to try new treatments, which they hoped might work better than available standard treatments.
This "newer is better" viewpoint - which, if you think about it, pervades all of American culture, especially in this age of smartphones, fast computers, and smarter, faster cars - has been reinforced by the changes to the first assumption of our drug testing model. When researchers started looking not for new pharmaceutical drugs but for new so-called biologics, like potential treatments using genes and stem cells, they learned that increasing the doses being tested didn't always increase both the benefits and the side effects in a straight line. Instead, a low dose might be more effective than a higher dose, or there might be no effects at all until a high dose was reached. That is, researchers knew very little about what the effects would be, and some benefit -- and/or harm -- might be possible even for the very first patient-subjects. They also learned that in this kind of research it could sometimes be much harder to measure benefit in patient-subjects who were older and had received standard treatments. Instead, they could learn more by starting with younger patients, who had not had a lot of treatment. But that created a difficult ethical dilemma: Is it fair to start research using younger patients as subjects, if that means they can't start standard treatment right away? That would mean not providing a standard treatment that we know a lot about, and instead giving an experimental intervention about which we know very little.
Faith in the value of novel biologics solves that problem if patients are willing to postpone standard treatment in hopes of a better outcome from receiving an experimental intervention. Today, infants and young children may well be the first humans in genetic or regenerative medicine research. But the need for speed complicates matters. Faith in these new types of treatments generally assumes that progress will come quickly, because the early results of laboratory and animal research seems so promising. However, good results have taken a lot longer than expected. For example, gene transfer research, which enrolled its first subjects in 1990, has only recently begun to produce outcomes good enough to be truly called "gene therapy" for a few diseases. And the hope of regenerating and repairing failing organs is slowly being replaced by the knowledge that there is a lot more we need to learn before we can regrow organs successfully.
And now there is a new research debate to think about: Germline genome editing using CRISPR.
Without going into much scientific detail, the development of the CRISPR/Cas9 system of gene editing made it seem that designer babies and the elimination of inheritable genetic diseases were just around the corner. CRISPR/Cas9 - and newer versions of CRISPR, which are being developed almost daily it seems - makes genetic alteration much easier than before, by using a sort of bacterial scissors to remove certain genes, and then, if necessary, inserting new ones. This technique is already in wide research use for some genetic disorders. But many conditions cannot be treated unless every single cell in the body can be altered - and that isn't possible unless CRISPR is used on embryos that have been created in the laboratory. Using CRISPR on a very early embryo works because the effect persists in every cell as the embryo grows. This also means that an altered embryo could grow into an adult able to pass the CRISPR alteration to offspring through altered eggs or sperm - thus eliminating the disorder from any future offspring (if the effect persists, that is).
This sounds like a great result, doesn't it? After all, most genetic and regenerative medicine treatments affect only the person being treated. But if we can use CRISPR to avoid having to treat every future generation shouldn't we do just that?
Actually, there are several reasons why it isn't such a good idea. First, although this is no well known, it is already possible to accomplish the same goal, in almost every instance, without editing embryos. In order to edit an embryo, it first has to be created in the laboratory though in vitro fertilization (IVF). then it has to be tested, using preimplantation genetic diagnosis (PGD), to see whether it has a genetic mutation that needs to be corrected and can be corrected. Both of these steps - IVF and PGD - are already in common use to help couples get pregnant and select embryos who do not have a genetic disorder that can be tested for. These steps enable couples to give birth to healthy children when they know that they might pass a genetic disorder or disorders on to a child. They simply create and test more than one embryo and implant one without the disorder(s) tested for. That embryo will develop into an adult who never had the disorder and so cannot pass it to any future child.
Because IVF and PGD are needed before using CRISPR (or any other genome editing) on the embryo, why would anyone choose to use CRISPR instead of just choosing a healthy embryo? Every edited embryo would be a research subject for life. We also know that CRISPR isn't perfect, and that some edits might get into the wrong places in some genes, posing unknown risks of harm - not only to the embryo itself, but potentially to the future offspring of an edited embryo-turned-adult. This is a major reason not to use gene editing when it can be avoided.
And even if as a society we were to decide that we should try to edit embryos and thus alter future generations, it would still take a lot longer than we currently imagine to get to where we could agree it was safe to allow edited embryos to develop to birth. The few genome editing experiments that have proceeded with early human embryos have not only been controversial but also confusing - there is still an awful lot to learn before we could know enough to really try for "designer babies".
Finally, the need to learn more points us in a different direction - one that is being carefully and successfully pursued by some researchers. A very important use of CRISPR research is to increase our understanding of conception and embryology. Using CRISPR in the laboratory to learn more about human reproduction, by altering genes in order to test our understanding of human development, will ultimately help researchers understand better how to treat infertility and problems of early development. Simply planning to stay in the lab rather than hoping to move into human studies enables researchers to learn a lot without the distracting pressure of understandable but unwarranted hopes for rapid biotechnological progress.
So, regarding the question: Should we hope, or shun the hype? I think we have to do both. We the public need to get better at understanding that the pace of science can't be made to fit our hopes, but responsible research can move us forward nonetheless. The occasional apparent medical miracle raises everyone's hopes - but the beautiful and stunning complexity of living organisms demands our patience and commands our deep respect. The very idea of regenerative medicine is awe-inspiring. No, it can't meet the needs of every patient and family who fervently hope for faster cures, but it will ultimately provide us with some answers, if we are humble enough to ask good questions and willing to listen.
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