By Kevin E. Noonan –

Idealism is a wonderful and at the same time frustrating character trait, because the world is not ideal as it is and is unlikely to ever be, but the motivation to achieve a more ideal world (or at least a more equitable one) is universal in human cultures (if only as a hope for a better world for our descendants).  A professor at the University of California/Berkeley, Fyodor Urnov (at right), recently expounded on the dream of using CRISPR gene editing to cure disease in a New York Times article and addressed the real-world challenges and obstacles faced in trying to use this breakthrough technology broadly enough for that ideal world to come a bit closer to reality (and for a change the NYT did not invoke patent protection as the all-purpose bogeyman thwarting such more idealistic outcome).

Dr. Urnov begins his essay with real-life examples of the types of genetic diseases faced by many (albeit a minority) of Americans (that statistical demographic playing a significant role in the story he is telling), in children and young adults, either from birth or in sudden onset or as a ticking timebomb of consequences determined by their faulty genes.  The initial promise of "DNA fixes" was gene therapy beginning in the 1980's, as the fruits of the revolution in molecular biology and the identity of genes responsible for these diseased began to be elucidated.  While there have been some successes in these efforts, the mechanisms for achieving them (usually involving virus-mediated gene insertion into an affected cell or tissue) have been both uncertain and "jaw-droppingly expensive" as Dr. Urnov relates (citing the $3.5 million price tag for Hemgenix, CSL Behring's cure for Hemophilia B).

An improvement with tremendous promise is CRISPR (which stands for "clustered regularly interspaced short palindromic repeats" in homage to how it was initially found in bacteria).  As Dr. Urnov explains, CRISPR technology can specify repair of a genetic mutation "right where the 'typo' occurs" in an affected gene.  He recites the recent uses of CRISPR technology for providing treatment for congenital blindness, sickle-cell disease, certain heart diseases, nerve disease, cancer, and HIV.  These successes engender in Dr. Urnov the hopeful prospect that CRISPR-based genetic medicine could be achieved in future for a variety of ailments, wherein its genetic specificity could provide directed and tailored cures for many diseases.  His vision for a future child afflicted with genetic disease is that:

A dedicated CRISPR ‌cures ‌‌center at a university-affiliated hospital . . . takes the diagnosis [of a genetic disease] and morphs it into an order form for a manufacturing facility to create the medication that will repair the faulty gene.  After a month of testing and data review by hospital clinicians and university scientists, the physician does a simple IV injection of the resulting CRISPR medicine, and after a three-day stay at the hospital to confirm‌ the gene editing went according to plan, the child is sent home.

He cites several examples, in the U.S. and abroad, of CRISPR successes and companies like CRISPR Therapeutics, Vertex, Intellia Therapeutics, and Regeneron who have achieved them in recent years, with other examples of on-going work by other companies.

But then Dr. Urnov explains the realities that create real impediments to this genetic utopia.  There are 7,000 known genetic diseases (caused by a defect in a single gene) and 400 million people worldwide affected by them.  While he posits a simple experimental path from diagnosis to treatment, he also acknowledges that this would be "only the first step in a four-year journey likely to cost at least $8 million to $10 million."  The first reason for this situation is the regulatory requirements in the U.S. and Europe aimed at "ensur[ing] safety and efficacy of the experimental medicine," Dr. Urnov laying out the time- and money-consuming path from beginning preclinical studies to actually producing the "CRISPR medicine," which itself is subject to well-deserved demanding specifications.  These efforts can cost more than $1 million and take years when animal testing is included in the calculus.  As a result, the hypothetical child having a genetic disease amenable to CRISPR treatment "stands little chance of timely treatment," he writes.  Added to the complexities of bringing the CRISPR drug to market, Dr. Urnov recognizes that the investment can easily be over $10 million and could (in some instances) be capable of treating only a single patient (for idiosyncratic mutations not shared by a class of patients such as with sickle cell disease where a particular shared mutation converts a glutamic acid residue to valine in the hemoglobin protein).  And the doctor notes that many patients do not have the luxury of time for all these processes to play out, making the theoretical possibility of the CRISPR magic bullet even more frustrating and tragic.

There also have been examples of actual therapies (in "conventional" gene therapy) that have hit the roadblock of investment failure by private companies trying to commercialize university-created inventions (one involving UCLA being mentioned specifically in Dr. Urnov's article).  But while there is an economic justification for the cost of these drugs (cited here, that "a one-time cure saves the health care system years of costly supportive care"), "[f]or diseases with fewer than 100 patients, such prices [$2-3 million per patient] are still not enough for these efforts to make commercial sense."  The doctor cites cases where companies have discontinued clinical studies due to the cost of bringing the drug to market, and the dim or at least insufficient prospects of a return on investment, that have made the economic proposition untenable.

Dr. Urnov proposes that as a first step towards improving this situation is for the regulatory regime to be revised; while it makes sense for diseases having tens of thousands of patients for a proposed treatment, for "one-of-a-kind genetic typo" cases there should be a "streamlined" process (akin to what was employed for CAR-T therapies in their infancy).  As for the role of who develops and pays for the treatments, he recognizes that private biotechnology companies cannot bear the burden.  "Tapping into federal and state funding could provide a path forward," Dr. Urnov posits, citing recent clinical trial collaborations between UCLA, UCSF, and UC/Berkeley for a gene-editing approach to curing sickle cell disease.

But recognizing the zeitgeist he asks:  "Why should the average taxpayer contribute to building medicines for rare diseases?  Would the money be better spent on finding treatments for common ailments?"  His answer is that helping people with rare diseases will foster development of CRISPR-based treatments for more common ones.  He acknowledges that, for now, ethical considerations will limit CRISPR therapies to those patients with diseases like cancer and "devastating genetic ailments."  He expresses hope that development of these treatments will eventually produce in genetic medicine the types of advances that have been achieved in other industries.  And he advocates that while "[u]nless things change dramatically, the millions of people CRISPR could save will never benefit from it," "[w]e must, and we can, build a world with CRISPR for all."

This essay raises a fundamental ethical question, should we and must we do what we can to achieve CRISPR-based and other revolutionary treatments in the face of the economic realities that there is no short-term economic justification for them?  History is replete with examples of seemingly fruitless efforts (Columbus, the space program) that turned out to have unappreciated (or at least unexpected) benefits, economic and otherwise.  The long-term view is that developing CRISPR and other medical technologies will produce a more robust, more productive populace, which will inure to our benefit and well-being.  The question Dr. Urnov raises is whether we will have the vision to leave behind the short-term view of present-day dollars and cents and see and act upon that possibility for a better, healthier world.