The Right to Try is an ongoing and hot debate that centers around patients requesting to try thoroughly-untested medications because they have determined that the attempt at treatment is better than the course of disease or disorder. Of course, the FDA and all international regulatory agencies exist to ensure that medicines released to the public have been properly vetted in a structured way to balance the benefit of treatment with its risks. Where you are on this debate is a matter of perspective.

It surprised me that in mid-June, the newswires lit up with fear-mongering stories about how CRISPR-Cas9 gene editing was a cancer risk. Surprising because even a basic understanding of cellular biology and genetics makes clear the fact that these gene-edited cell lines are necessarily more prone to tumorigenesis. Is CRISPR-Cas9 bad? Is cancer ‘bad’? Surely it facilitated CRISPR-Cas9 gene edits. It’s reducible to this: We have a terrible tendency as humans—and really, probably all sentient animals have this too—of making un-nuanced binary judgments about most everything we encounter. For example, when you think of friends or acquaintances or just people that you know, they are more likely to fall into two categories: Liked or disliked. You don’t often hear someone, who if you ask them if they know and/or like “Bob” or “Alice,” respond with, “Well, across personality dimensions, Bob is my friend—just barely—by virtue of his average scoring of 7.2; Alice is a great friend, ranking at 9.4.”

Part of this is a decision-making heuristic that makes it easier to parse out content we experience and then move on without wasting valuable cognitive resources on over analysis. But, for example, with CRISPR-Cas9, the technology can lead to preferential selection of cells which lack a mechanism for repairing DNA damage as these cells are easier to gene-edit. So not only should it have been patently obvious that CRISPR-Cas9 technology outputs would have a higher likelihood of a prevalence of cancer, but the presence of cancer and whether it’s ‘good’ or ‘bad’ also falls into the realm of one’s perspective.

Subjectivity of Right to Try
Which brings me to the broader point of this article: What’s good or bad/right or wrong is often totally subjective and personal. Who should decide the right to try? Is it on an individual-by-individual case? Can patients really make an informed decision? Is it up to the government? Medical panels? Ethicists?

The Right to Try bill would allow terminally-ill patients the right to seek drug treatments that have passed Phase I approval, but are still deep within clinical trials. It is currently waiting for senate approval, where it has already passed the House 267 to 149. Keep in mind that this is the Federal plan; 38 states currently have their own right to try laws. Should patients have this right? Are drugs ‘good’ or ‘bad’?

I should note that Wisconsin senator Ron Johnson wrote the Right to Try law, and from his perspective, “This law intends to diminish the FDA’s power over people’s lives, not increase it,” he wrote in a letter to FDA Commissioner Scott Gottlieb.

You’re ok, but your reaction to your medication is not
Every medical treatment has alternative effects. Whether these are side effects, treatment effects, or adverse events—usually ‘Type A’ in this case—none are 100% specific (0% off-target) for a particular disease or disorder without having adjunctive physiological impacts.

For example, if you had a runny nose and took pseudoephedrine, you’d note on the packaging if you bothered to read it that side effects could include anxiety, tremors, increased heart rate, diaphoresis (that’s sweating), hypertension, etc. These aren’t terrible drug effects when taken in context. In fact, they’re necessarily present because pseudoephedrine is a central nervous system stimulant. It’s not that pseudoephedrine has a list of positive effects, and then a separate list of ‘bad’ things that it does to you. It’s part of the success of the drug is that it does do these things. In fact, it acts on  α-adrenergic receptors and to some extent,β2-adrenergic. If you didn’t have other off-target effects, you should be suspicious that what you took was really not pseudoephedrine, and if there wasn’t requisite and adequate CNS stimulation, you wouldn’t have its decongestant effects, either. It’s all about perspective, how one perceives a particular drug, its ability to resolve symptoms, and its pantheon of other effects. The approval of such medicines are based on the balance of benefit and risk.

Now, back to CRISPR-Cas9 and it’s “frightening” tendency to cause cancer (the media’s word, not mine). The ability of C-C9 to do what it does is predicated on its ability to make edits. There are certain cells within which this is more probable and more effective. It’s specifically by doing what it does in the way that it does that the cell line has a higher tendency than baseline to become cancerous. Again, it’s perspective, and should we withhold making treatments like this available to individuals because of potential effects?

The Right to Try: Ethics and morality
Like many ethical and moral dilemmas which are taught in business schools and bioethics programs, perspective is a powerful mediator. One example is the Heinz Dilemma, a parable where a fellow has a wife who falls gravely ill. The treatment for her disease, most often called a form of cancer in these thought experiments, is a new medication that is very, very expensive. Heinz cannot afford it, and considers robbing the pharmacy to obtain the treatment. So the moral and ethical dilemma here is: Protect the life of his wife vs. subvert society’s laws which prohibit stealing, and only work if almost everyone follows them. In these examples, the difficulty as with many bioethicist’s decisions is that there is no objective right (correct) answer. It depends on perspective.

Why cancer loves being cancer… most of the time
Similarly, cancer is a terrible thing for people and animals to develop, because it interferes with survivability. But for certain cells, cancer is a great thing. The cellular modifications in cancerous cells allow the cells to proliferate very quickly (high mitotic index) in many cases, and indeed even encourage new fresh supplies of blood vessels to help feed their growing needs. So the relative ‘badness’ of tumorigenesis is subjective.

Now, even if you’re a cancer cell, the outlook isn’t always good. Contrary to popular (i.e., false) belief, cancer cells are not all immortal. In fact, the research done on this shows that many cancer cell types don’t fit this criterion. In fact, many cancer cells hit a “telomere crisis” and stop dividing at some point in the future. After a varying number of divisions, many appear to hit a “telomere crisis” and stop dividing. In these cases, the telomere tips become so short that the cell mistakes the fragment for a DNA break and attempts to repair them. The result of this is a cell that either dies or becomes dormant. The cancer cells that are capable of relative immortality activate telomerase reverse transcriptase (TERT), which is a telomere-repairing enzyme. Incidentally, in 2011, Cancer Research UK began a clinical trial to halt the spread of pancreatic cancer using a vaccine composed of fragments of TERT. The TERT would elicit an immune response, and any pancreatic cancer cells with active TERT would also be targeted.

Another example, and this may be a line of thinking that only resonates with parasitologists: The form of parasitism that doesn’t fall into the categories of commensalism or mutualism is one in which one species benefits at the disadvantage of the other species. So for example, a tick bite is an unwelcome event for a person—and becoming more and more dangerous with increasing occurrences of Lyme disease, Bartonella, Babesia, and other tick-associated diseases—but from the perspective of the tick it’s a great thing. The tick gets food on a warm host, shelter, and travel. We can even go one additional recursive layer down in this analogy for yet another perspective: The transmitted bacteria or parasites from the tick to host also love the fact that they can continue on with their lifecycle because they were taxied there by an intermediate vector (the tick). 


References

• Kohlberg, Lawrence (1981). Essays on Moral Development, Vol. I: The Philosophy of Moral Development. San Francisco, CA: Harper & Row.
• Centers for Disease Control & Prevention (2017). Tickborne diseases of the United States. https://www.cdc.gov/ticks/diseases/index.html

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Ben Locwin

Ben Locwin, PhD, MBA, MS, MBB is a widely-acclaimed author and speaker. He has been featured in The Wall Street Journal, The Associated Press, Forbes, and other media. He writes the Clinically Speaking column for Contract Pharma and is a member of several industry Advisory Boards and Boards of Directors.