From the Editor-in-Chief

How many times can a piece of paper be folded in half? The widely accepted limit is 7, and I invite you to take a sheet of paper and see whether the assertion is correct. As you can see from my attempt in the right photo on this JVRD issue’s cover, that last fold is difficult and partial at best. Most people who toy with this problem make a few attempts and then give up.

Nevertheless, something as innocuous as paper folding offers the opportunity for insight and innovation. In 2002, when Pomona, California high school student Britney Gallivan was given the challenge in math class to disprove the long-accepted sevenfold limit, she smashed it by folding paper 12 times.

Britney Gallivan not only demonstrated that 7 was not even close to an absolute limit, but she amazingly derived scalable formulas that link the number of folds to the paper’s thickness, length, and width. Armed with her brilliant mathematical sorcery and a 1.2-kilometer (!) roll of special toilet paper, she demonstrated a full 12 folds and promptly entered the record books; headlines and videos of her accomplishment were circulated around the world.

Her book, How to Fold Paper in Half Twelve Times: An Impossible Challenge Solved and Explained, ¹ would clearly be a prize winner for both a science fair submission and for its crisply informative title. Ironically, it is no longer available in a paper version.

We ourselves are creatures of folding. Amino acids are progressively coded into chains by mRNA passing through a ribosome, and when this growing peptide chain grows to include 50 or more amino acids, it is termed a protein. Proteins need to fold into a certain precise shape to function appropriately as enzymes, structural elements, and myriad other components indispensable to life.

How a given amino acid chain folds quickly and accurately is one of the central questions in biology and is fiendishly complex because there are an infinite number of possible shapes for a freshly synthesized protein. Attaining the final shape depends on pH, temperature, and a host of choregraphed influences including chemical, electrochemical, and Van Der Waals forces, as well as aptly named chaperone proteins that rapidly guide the contortions of the new amino acid chain into its final form.

Remarkably, proteins arrive at the desired shape in a mere fraction of the predicted time. This highly complicated system, fortunately, works correctly most of the time, but misfoldings, unfoldings, and refoldings all occur and are implicated in disease.

In recent news, ² a London-based effort called Deep Mind has employed neural nets and other advanced artificial-intelligence techniques to determine the shape of 350,000 proteins, including all known proteins in the human genome. Their AlphaFold technology can predict the shape of any amino acid chain with an accuracy of 63% compared to more laborious laboratory methods.

This powerful tool promises a new era of designer proteins applicable not only to biological processes like diseases and antibiotic therapy, but also to widely varied industrial, chemical, and food production processes. Indeed, an early application being explored is the removal of plastic debris from the oceans by the enzymes designed to degrade the plastic.

The present issue of JVRD contains an article in which protein folding has gone awry, with severe visual consequences. Ms. Chiya Abramowitz and Drs. Eric K. Chin and David R.P Almeida describe a patient with bilateral vitreous opacities that persisted despite prior vitrectomy, enlarged intraconal optic nerves, and other ocular findings; this patient was belatedly recognized to have systemic amyloidosis. The diagnosis was confirmed through demonstration of amyloid by Congo-red stain in a fat-pad biopsy, and the authors emphasize the need for a high level of suspicion to avoid a delayed or missed diagnosis.

Amyloid is a durable residue of protein or protein fragments that becomes folded into forms such as beta sheets that do not function as intended and resist further decomposition. Amyloidosis comes in many varieties—inherited or sporadic, systemic or localized, etc.—and more than 30 specific forms have been characterized.

Symptoms can be remarkably diverse and may present in vague or bizarre combinations due to amyloid deposits almost anywhere in the body; internal organs such as the heart, kidneys, and liver as well as the peripheral nervous system bear major damage in the more common forms.

Indeed, the complexities of the amyloidosis forms can be so varied and baffling that only the most rarified experts can master every form and presentation. This vast array of confusing clinical manifestations can prove to be perversely advantageous to those struggling during case presentations, grand rounds, or even high-profile visiting professorships; if you are on the spot and desperate for a comment that will seem relevant and not idiotic, simply lock eyes with the presenter and confidently ask, “Have you considered amyloidosis?” You will throw everyone off balance and be confidently assured that no one in the audience will be able to dismiss your question out of hand.

The misfoldings of amyloids can even be infectious and fatal. Creutzfeldt-Jakob disease, Kuru, and other exotic neurodegenerations in humans and animals are caused by prions, a subset of misfolded proteins that can transmit their abnormal shape on contact with normal proteins.

Creutzfeldt-Jakob disease can be spontaneous, inherited, or acquired through contact with contaminated tissue including—most rarely—by ophthalmologists transplanting contaminated corneal tissue. Kuru was transmitted by ritual cannibalism in a remote area of New Guinea; the cessation of this practice many years ago and the passing of infected individuals mercifully eradicated the disease over a decade ago.

The idea that an unliving shape such as a prion can self-propagate and aggressively transmit a destructive influence is both unexpected and terrifying. Remarkably, spreading devastation by an inanimate form was foreseen. The image of prions progressing across the brain and relentlessly forcing normal tissue to acquire their abnormal folds is strangely reminiscent of the mythical form of water known as Ice-nine, a substance that features in the final destruction of the world in Kurt Vonnegut’s 1963 satirical novel, Cat’s Cradle. ³ Vonnegut conjured Ice-nine as a form of ice that was solid at room temperature and acted like a seed that, when coming in contact with water, would instantly freeze it into more Ice-nine.

Through a variety of plot twists and turns, fragments of this dangerous substance, kept safely in special containers, accidentally enter the oceans and instantly freeze all the world’s water into Ice-nine. Only a handful of individuals escape the initial catastrophe and survive for several months. Let’s hope the prions are not so successful with their contaminating forms.

Donald J. D’Amico, MD
Editor-in-Chief
Journal of VitreoRetinal Diseases