"Gene"sis: Hope, Hype & the Hippocratic Oath

Introduction:

"Of all the words of tongue or pen, the saddest are," according to John Greenleaf Whittier, "it might have been." How many billions of us have had health-related "if only" moments in our lives? How many of us have wanted to cure a child or a parent, or even oneself from chronic conditions like Down’s Syndrome or diabetes (Rondal)? Humanity has been fighting a futile battle against such shapeshifting monsters since the beginning of time, all the while seeing hopes annihilated, dreams asphyxiated, livelihoods destroyed, and families bankrupted.

Until now.

As Siddhartha Mukherjee writes in The Gene: An Intimate History, the first half of the 20th century was the age of the atom and the latter half, that of the byte (Mukherjee). Now, we are in the age of another fundamental, foundational element of life: the gene. The "Genetic Age" began with the cloning of Dolly the sheep, in 1995 (Fridovich-Keil). Two years later, Craig Venter mapped the entire human genome. Subsequently in 2012, Nobelist Jennifer Doudna and her team refined the CRISPR technology at UC Berkeley. In the decade since then, genetic engineering has exploded, along with a commensurate use of computational techniques, including AI.

The holy trinity of mRNA, stem cells, and gene therapy are closely related and have combined to become both cause and catalyst to the development of many new treatment options, palliatives, and even cures to previously intractable, and even "fatal" diseases. Today, the fast-evolving field of gene therapy offers viable pathways to a better, healthier and happier tomorrow—a future where people can overcome their congenital limitations, escape from the clutches of fate and circumstance, and live one’s dreams. With the power of genetic engineering, medicine is finding ways to change things about ourselves that hold us back, that don’t work, or in some cases, that we don’t like. This emerging technology can cure diseases, solve major healthcare problems and change societal outlook about health and life.

The Hope:

Gene based medicine has improved so quickly, that scientists and society are gasping to keep pace. Genetics, coupled with advances in computer science, and molecular biology have shown us new ways to nurture nature. Healthcare, according to Statista, was 18% of US GDP in 2021, or 4.2 trillion dollars—an amount greater than the annual GDP of California and Texas combined. Every year, the US is spending the entire economy of the two biggest states in all of America on healthcare. How much of that money could be saved with health improvements via genetic engineering? How many families could be saved from bankruptcy? How many roads could be built? How many college tuitions could be paid for? It is not hyperbole to assert that gene therapy, therefore, ought to be an integral component of medical treatments going forward, as long as it is judicious and safe.

"Why shouldn't truth be stranger than fiction?

Fiction, after all, has to make sense."

— Mark Twain

Thanks to the magic of gene therapy, what was once the realm of fiction, is now routine.

A first-of-its-kind, CRISPR based, experimental, genetic treatment has recently been approved for sickle cell anemia (in Maryland) (Kolata). Separately, scientists recently "reconceptualized" Alzheimer’s, showing that at least 20% of cases have a clear genetic cause—the presence of two copies of a specific gene (APOE4) (Belluck). The FDA is reviewing gene based treatments for hemophilia, spinal muscular atrophy and cancer. Similar research is also being done worldwide relating to Down's Syndrome and allergies (Infante).

A dairy allergy (and, in general, allergies) and Down’s Syndrome are two ailments where gene therapies show great promise and potential. Drug maker Regeneron recently announced a trial to "eliminate" allergy causing IgE antibodies using gene immunotherapy (Gonzalez-Visiedo). Specific and targeted viral vectors have been designed to neutralize allergen specific antibodies, as well as suppressing anaphylactic responses. CRISPR also offers groundbreaking methods to edit allergen genes, potentially preventing allergy onset and improving disease management. Genetic engineering techniques can—and will—improve the quality of life for the over 220 million known allergy sufferers worldwide (true numbers are almost certainly a lot higher).

In conjunction with its fraternal twin, stem-cells, gene therapies can be godsend for "growing" new organs to help those with, say, heart-disease or facilitate mechanisms to grow artificial livers through 3-D printing. The wonderful and humane potential for gene therapies to help humanity is incredible and constantly growing.

As exciting as such examples are, they are of the past.

Nobelist Dr. Doudna and her team focused on editing genes—analogous to spell-checking and correcting an essay. Their goal was fixing or adding or deleting gene(s). CRISPR is like changing a car’s tail-light or the sound-system. Now, however, scientists are focused on gene synthesis. We’re now creating genes from scratch. This is like building a brand new car from scraps. This is like building a new house, brick by brick. We have now progressed from saving lives … to making lives. It is one thing to make something better, but it is another to make something from scratch. Slowly and in spurt, genetics progresses and heals.

Hope is an eternal cure.

The Hype:

For all its promise and potential, gene therapies do have plenty of portent and peril. And therein, as the Bard says (via Hamlet), lies the rub.

Famously, the internet was invented by the US Department of Defense as a tool to share scientific research and national security data safely. Today, it has devolved into a platform for TikTok posts, illegal videos, pornography and for anonymously yelling at strangers. Likewise, for all the highfalutin uses of gene-therapies, there is an inbuilt risk that eventually, it is going to be abused for nefarious purposes.

In 2018, Chinese scientist He Jiankui "synthesized" identical twin girls, in a lab—entirely via CRISPR based genetic engineering (Georgiou). As with most first attempts, the twins didn’t survive long. However, the precedent—and the possibility—has been established, despite Dr. Jiankui’s three-year sentence for his "crime." The next time, the process will obviously be better and the babies will live longer. What will we do when we have a class of babies, all made without parents, and all without support systems? What will stop unethical doctors from creating a designer baby in a petri-dish? Will we then start to make babies that have certain genes to look a certain way? Athletic genes, academic smartness, beauty, hair, and more can all be cherry-picked. Are such babies human anymore? Is Blade Runner … reality?

In the wrong hands, genetic engineering can facilitate eugenics. Imagine a modern-day Dr. Mengele in a dystopic quest to make a "super race." In a time when every ethnicity and every race is using false metrics and irrelevant measures to claim artificial superiority over everyone else, genetic engineering can foolishly fuel societal passions (Gorvett). Or, consider the insidious "Tuskegee Project," where the US military secretly infected ~600 African American men with the syphilis virus (non consensually) to "study" the disease. Thirty died; all survivors had lifelong consequences, including infertility ("The Untreated Syphilis").

Gene therapies frequently use viruses as "vectors." The jokes write themselves. Whether the fictitious Jurassic Park, or the all too real Covid pandemic, society is well aware of the foreboding law of unintended consequences. There are several unknown unknowns relating to our genomes and introducing viruses intentionally is similar to playing with flamethrowers around bales of cotton.

Between false-dawns, fake cures, abuse, and misapplications, society can easily be victimized by the lure of genetics. Medical practices and especially, laws need to be updated to handle the metamorphosing risks stemming from genetic treatments. Society needs to understand gene therapies are not a panacea. No genetic machinaton can correct unrealistic hopes.

Hippocrates & Health:

"Is gene therapy better than traditional medicine?"

This question, as Ms. Mona Lisa Vito notes in My Cousin Vinny, is a trick question. Rhetorically, are electric vehicles better than gasoline cars? The answer seems obvious, until one realizes that 75% of the electric power to charge all those EV batteries are made from coal plants (in the US). What’s "traditional" today was not traditional not too long ago. Science evolves, in fits and starts. Gene therapy is an additional toolkit—for doctors to nip some diseases in utero or alleviate pain subsequently and, if possible, cure the patient altogether. The global success of Covid vaccines show how gene therapy (using mRNA), in conjunction with traditional medicine and general hygiene can be most effective to treat pandemics and major diseases.

However, gene therapy can never be a panacea. Science can never fully delineate the combustible and consequential mix of nature, nurture and random chance that is destructively centrifugal sometimes and beneficially centripetal at other times. The intractable challenge here is that genes are not isolated or uniform in their import and impact. 

"We of the craft are all crazy.

Some are affected by gaiety, others by melancholy.

But all are more or less touched."

— Lord Byron

Some patients—say, someone with high-functioning autism—could struggle with so-called normal activities, but may excel in other fields and may even have critical skills for society’s survival. As Johns Hopkins’ Victor McKusick noted, genetic disorders are "a relative incongruence between a genotype and the environment" (Mukherjee 285-289). A particular genetic combination that is venom in one situation can be a vitamin in another. What is called illness in one situation can very easily be "exceptional ability" in another. For example: bringing a rake, instead of a shovel. Tool mismatch is an issue, but there is no denying that rakes are useful under different circumstances. Assuming treatment is even needed, is gene therapy the right "tool"? Or, do we move the person mentally and/or physically to a different location? Which among these two choices is ethical? And which is economical? And what if ethics and economics diverge? These are germane questions that have to be analyzed across scientific, social, ethical and moral prisms.

Psychologist Kay Jamison links varying degrees of mental illness to creativity in luminaries as disparate as Byron, Mozart, van Gogh, Isaac Newton, and John Nash (Jamison 96-97). People who are barely functional in the "normal" world can, demonstrably, be geniuses who discover gravity, write about "cloudless climes and starry skies," paint a Starry Night or reset the world’s equilibrium.

Every December, my mother and I bake pistachio cookies. The same recipe, in the same kitchen, somehow always ends with her batch invariably being tastier and crunchier than mine (a gooey, over-sugared mess). In different hands, recipes yield different results, in unpredictable ways. Some alterations are foreseeable; swap, say, regular milk for almond milk, and the cookie will be almondy. But, halving the sugar, say, or doubling the salt, for example, will lead to random and inconsistent results. Genes are recipes. The same ingredients lead to dissimilar manifestations. A plethora of uses, causes and triggers (including parental, prenatal, environmental, and providential) latently, and idiosyncratically, interact inside every gene. As such, precision is key: incorrect sampling and undue extrapolations lurk as significant risks with all genetic manipulations.

Gene therapies are incredibly effective, but they are not an elixir. Professionals and patients alike should understand that unreasonable hope is an incurable cancer. 

Conclusion:

Genetics is rife with frightening clichés. References to Pandora, Bob Dylan's "The Times They Are A-Changin'," and Orwell's "1984" serve as mere appetizers in this discourse. Despite the pearl-clutching and the hand-wringing, science marches on. Whether for diagnostic, therapeutic or preventive uses, gene therapy is here to stay. Scientific barriers are ephemeral and while progress may be asymptotic, societal benefits are real and undeniable.

Mengele’s Nazis lost. Tuskegee was shut down. Abuse will happen, for evil is real. Mistakes will happen, for humans are fallible. But snowstorms and accidents don’t stop driving. Growth and change necessitate trade-offs. There are social, economic, and ethical questions raised by the exploding advances in genetics. With proper controls and guidelines, society will progress. Science, one hopes, is ultimately its own patron, and police.

Hope is the greatest medicine.