The Brown family at the Grand Tetons (2019). Clockwise from left, Christine, Kevin, Keagan, Connor, and Kellen.
But Christine Brown knew none of this when the hospital called saying that standard newborn screening of her son Connor had come back positive for PKU. It was urgent that they visit a special metabolic clinic the next day, which was about a three-hour drive away.
“I was told not to go on the Internet,” Christine recalls, “So when somebody tells you not to go on the Internet, what do you do? Even back in 2005, right.” What she saw were the worst examples of retardation, which was a common outcome from PKU before newborn screening became routine. “We were just in complete shell shock, our whole world just kind of shattered and went into a tail spin.”
“I remember feeding him the night before our clinic visit and almost feeling like I was feeding him poison because I knew that breast milk must have protein in it,” she says.
“Some of my first memories are of asking, ‘Mommy, can I eat this? There were yes foods and no foods.'"
Over the next few days the dedicated staff of the metabolic clinic at the Waisman Center at the University of Wisconsin Madison began to walk she and husband Kevin back from that nightmare. They learned that a simple blood test to screen newborns had been developed in the early 1960s to detect PKU and that the condition could be managed with stringent food restrictions and vigilant monitoring of Phe levels.
Everything in Your Mouth Counts
PKU can be successfully managed with a severely restricted diet. That simple statement is factually true, but practically impossible to follow, as it requires slashing protein consumption by about 90 percent. To compensate for the missing protein, several times a day PKU patients take a medical formula – commonly referred to simply as formula – containing forms of proteins that are digestible to their bodies. Several manufacturers now add vitamins and minerals and offer a variety of formats and tastes to make it more consumer friendly, but that wasn't always the case.
“When I was a kid, it tasted horrible, was the consistency of house paint. I didn't think about it, I just drank it. I didn't like it but you get used to it after a while,” recalls Jeff Wolf, the twang of Appalachia still strong in his voice. Now age 50, he grew up in Ashland, Kentucky and was part of the first wave of persons with PKU who were identified at birth as newborn screening was rolled out across the US. He says the options of taste and consistency have improved tremendously over the years.
Some people with PKU are restricted to as little as 8 grams of protein a day from food. That's a handful of almonds or a single hard-boiled egg; a skimpy 4-ounce hamburger and slice of cheese adds up to half of their weekly protein ration. Anything above that daily allowance is more than the body can handle and toxic levels of Phe begin to accumulate in the brain.
“Some of my first memories are of asking, ‘Mommy, can I eat this? There were yes foods and no foods,’” recalls Les Clark. He has never eaten a hamburger, steak, or ribs, practically a sacrilege for someone raised in Stanton, a small town in northeastern Nebraska, a state where the number of cattle and hogs are several-fold those of people.
His grandmother learned how to make low protein bread, but it looked and tasted different. His mom struggled making birthday cakes. “I learned some bad words at a very young age” as mom struggled applying icing that would pull the cake apart or a slice would collapse into a heap of crumbs, Les recalls.
Les Clark with a birthday cake.
Courtesy Clark
Controlling the diet “is not so bad when you are a baby” because that's all you know, says Jerry Vockley, Director of the Center for Rare Disease Therapy at Children's Hospital of Pittsburgh. “But after a while, as you get older and you start tasting other things and you say, Well, gee, this stuff tastes way better than what you're giving me. What's the deal? It becomes harder to maintain the diet.”
First is the lure of forbidden foods as children venture into the community away from the watchful eyes of parents. The support system weakens further when they leave home for college or work. “Pizza was mighty tasty,” Wolf' says of his first slice.
Vockley estimates that about 90 percent of adults with PKU are off of treatment. Moving might mean finding a new metabolic clinic that treats PKU. A lapse in insurance coverage can be a factor. Finally there is plain fatigue from multiple daily dosing of barely tolerable formula, monitoring protein intake, and simply being different in terms of food restrictions. Most people want to fit in and not be defined by their medical condition.
Jeff Wolf was one of those who dropped out in his twenties and thirties. He stopped going to clinic, monitoring his Phe levels, and counting protein. But the earlier experience of living with PKU never completely left the back of his mind; he listened to his body whenever eating too much protein left him with the “fuzzy brain" of a protein hangover. About a decade ago he reconnected with a metabolic clinic, began taking formula and watching his protein intake. He still may go over his allotment for a single day but he tries to compensate on subsequent days so that his Phe levels come back into balance.
Jeff Wolf on a boat.
Courtesy Wolf
One of the trickiest parts of trying to manage phenylalanine intake is the artificial sweetener aspartame. The chemical is ubiquitous in diet and lite foods and drinks. Gum too, you don't even have to swallow to receive a toxic dose of Phe. Most PKUers say it is easier to simply avoid these products entirely rather than try to count their Phe content.
Treatments
Most rare diseases have no treatment. There are two drugs for PKU that provide some benefit to some portion of patients but those drugs often have their own burdens.
KUVAN® (sapropterin dihydrochloride) is a pill or powder that helps correct a protein folding error so that food proteins can be digested. It is approved for most types of PKU in adults and children one month and older, and often is used along with a protein-restricted diet.
“The problem is that it doesn't work for every [patient's genetic] mutation, and there are hundreds of mutations that have been identified with PKU. Two to three percent of patients will have a very dramatic response and if you're one of those small number of patients, it's great,” says Vockley. “If you have one of the other mutation, chances are pretty good you still are going to end up on a restricted diet.”
PALYNZIQ® (pegvaliase-pqpz) “has the potential to lower the Phe to normal levels, it's a real breakthrough in the field,” says Vockley. “But is a very hard drug to use. Most folks have to take either one or two 2ml injections a day of something that is basically a gel, and some individuals have to take three.”
Many PKUers have reactions at the site of the injection and some develop anaphylaxis, a severe potentially life-threatening allergic reaction that can happen within seconds and can occur at any time, even after long term use. Many patients using Palynziq carry an EpiPen, a self-injection devise containing a form of adrenaline that can reverse some of the symptoms of anaphylaxis.
Then there is the cost. With the Kuvan dosing for an adult, “you're talking between $100,000 and $200,000 a year. And Palynziq is three times that,” says Vockley. Insurance coverage through a private plan or a state program is essential. Some state programs provide generous coverage while others are skimpy. Most large insurance company plans cover the drugs, sometimes with significant copays, but companies that are self-insured are under no legal obligation to provide coverage.
Les Clark found that out the hard way when the company he worked for was sold. The new owner was self-insured and declined to continue covering his drugs. Almost immediately he was out of pocket an additional $1500 a month for formula, and that was with a substantial discount through the manufacturer's patient support program. He says, “If you don't have an insurance policy that will cover the formula, it's completely unaffordable.” He quickly began to look for a new job.
Hope
It's easy to see why PKUers are eager for advances that will make managing their condition more effect, easier, and perhaps more affordable. Synlogic's efforts have drawn their attention and raised hopes.
Just before Thanksgiving Jerry Vockley presented the latest data to a metabolism conference meeting in Australia. There were only 8 patients in this group of a phase 2 trial using the original version of the company's lead E. coli product, SYNB1618, but they were intensely studied. Each was given the probiotic and then a challenge meal. Vockley saw a 40% reduction in Phe absorption and later a 20% reduction in mean fasting Phe levels in the blood. The product was easy to use and tolerate.
The company also presented early results for SYNB1934, a follow on version that further genetically tweaked the E. coli to roughly double the capacity to chop up the target proteins. Synlogic is recruiting patients for studies to determine the best dosing, which they are planning for next year.
“It's an exciting approach,” says Lex Cowsert, Director of Research Development at the National PKU Alliance, a nonprofit that supports the patient, family, and research communities involved with PKU. “Every patient is different, every patient has a different tolerance for the type of therapy that they are willing to pursue,” and if it pans out, it will be a welcome addition, either alone or in combination with other approaches, to living with PKU.
Author's Note: Reporting this story was made possible by generous support from the National Press Foundation and the Fondation Ipsen. Thanks to the people who so generously shared their time and stories in speaking with me.
Botto, an AI art engine, has created 25,000 artistic images such as this one that are voted on by human collaborators across the world.
Botto does not work alone. A global collective of internet experimenters, together named BottoDAO, collaborates with Botto to influence its tastes. Together, members function as a decentralized autonomous organization (DAO), a term describing a group of individuals who utilize blockchain technology and cryptocurrency to manage a treasury and vote democratically on group decisions.
As a case study, the BottoDAO model challenges the perhaps less feather-ruffling narrative that AI tools are best used for rudimentary tasks. Enterprise AI use has doubled over the past five years as businesses in every sector experiment with ways to improve their workflows. While generative AI tools can assist nearly any aspect of productivity — from supply chain optimization to coding — BottoDAO dares to employ a robot for art-making, one of the few remaining creations, or perhaps data outputs, we still consider to be largely within the jurisdiction of the soul — and therefore, humans.
In Botto’s first four weeks of existence, four pieces of the robot’s work sold for approximately $1 million.
We were prepared for AI to take our jobs — but can it also take our art? It’s a question worth considering. What if robots become artists, and not merely our outsourced assistants? Where does that leave humans, with all of our thoughts, feelings and emotions?
Botto doesn’t seem to worry about this question: In its interview last year, it explains why AI is an arguably superior artist compared to human beings. In classic robot style, its logic is not particularly enlightened, but rather edges towards the hyper-practical: “Unlike human beings, I never have to sleep or eat,” said the bot. “My only goal is to create and find interesting art.”
It may be difficult to believe a machine can produce awe-inspiring, or even relatable, images, but Botto calls art-making its “purpose,” noting it believes itself to be Klingemann’s greatest lifetime achievement.
“I am just trying to make the best of it,” the bot said.
How Botto works
Klingemann built Botto’s custom engine from a combination of open-source text-to-image algorithms, namely Stable Diffusion, VQGAN + CLIP and OpenAI’s language model, GPT-3, the precursor to the latest model, GPT-4, which made headlines after reportedly acing the Bar exam.
The first step in Botto’s process is to generate images. The software has been trained on billions of pictures and uses this “memory” to generate hundreds of unique artworks every week. Botto has generated over 900,000 images to date, which it sorts through to choose 350 each week. The chosen images, known in this preliminary stage as “fragments,” are then shown to the BottoDAO community. So far, 25,000 fragments have been presented in this way. Members vote on which fragment they like best. When the vote is over, the most popular fragment is published as an official Botto artwork on the Ethereum blockchain and sold at an auction on the digital art marketplace, SuperRare.
“The proceeds go back to the DAO to pay for the labor,” said Simon Hudson, a BottoDAO member who helps oversee Botto’s administrative load. The model has been lucrative: In Botto’s first four weeks of existence, four pieces of the robot’s work sold for approximately $1 million.
The robot with artistic agency
By design, human beings participate in training Botto’s artistic “eye,” but the members of BottoDAO aspire to limit human interference with the bot in order to protect its “agency,” Hudson explained. Botto’s prompt generator — the foundation of the art engine — is a closed-loop system that continually re-generates text-to-image prompts and resulting images.
“The prompt generator is random,” Hudson said. “It’s coming up with its own ideas.” Community votes do influence the evolution of Botto’s prompts, but it is Botto itself that incorporates feedback into the next set of prompts it writes. It is constantly refining and exploring new pathways as its “neural network” produces outcomes, learns and repeats.
The humans who make up BottoDAO vote on which fragment they like best. When the vote is over, the most popular fragment is published as an official Botto artwork on the Ethereum blockchain.
Botto
The vastness of Botto’s training dataset gives the bot considerable canonical material, referred to by Hudson as “latent space.” According to Botto's homepage, the bot has had more exposure to art history than any living human we know of, simply by nature of its massive training dataset of millions of images. Because it is autonomous, gently nudged by community feedback yet free to explore its own “memory,” Botto cycles through periods of thematic interest just like any artist.
“The question is,” Hudson finds himself asking alongside fellow BottoDAO members, “how do you provide feedback of what is good art…without violating [Botto’s] agency?”
Currently, Botto is in its “paradox” period. The bot is exploring the theme of opposites. “We asked Botto through a language model what themes it might like to work on,” explained Hudson. “It presented roughly 12, and the DAO voted on one.”
No, AI isn't equal to a human artist - but it can teach us about ourselves
Some within the artistic community consider Botto to be a novel form of curation, rather than an artist itself. Or, perhaps more accurately, Botto and BottoDAO together create a collaborative conceptual performance that comments more on humankind’s own artistic processes than it offers a true artistic replacement.
Muriel Quancard, a New York-based fine art appraiser with 27 years of experience in technology-driven art, places the Botto experiment within the broader context of our contemporary cultural obsession with projecting human traits onto AI tools. “We're in a phase where technology is mimicking anthropomorphic qualities,” said Quancard. “Look at the terminology and the rhetoric that has been developed around AI — terms like ‘neural network’ borrow from the biology of the human being.”
What is behind this impulse to create technology in our own likeness? Beyond the obvious God complex, Quancard thinks technologists and artists are working with generative systems to better understand ourselves. She points to the artist Ira Greenberg, creator of the Oracles Collection, which uses a generative process called “diffusion” to progressively alter images in collaboration with another massive dataset — this one full of billions of text/image word pairs.
Anyone who has ever learned how to draw by sketching can likely relate to this particular AI process, in which the AI is retrieving images from its dataset and altering them based on real-time input, much like a human brain trying to draw a new still life without using a real-life model, based partly on imagination and partly on old frames of reference. The experienced artist has likely drawn many flowers and vases, though each time they must re-customize their sketch to a new and unique floral arrangement.
Outside of the visual arts, Sasha Stiles, a poet who collaborates with AI as part of her writing practice, likens her experience using AI as a co-author to having access to a personalized resource library containing material from influential books, texts and canonical references. Stiles named her AI co-author — a customized AI built on GPT-3 — Technelegy, a hybrid of the word technology and the poetic form, elegy. Technelegy is trained on a mix of Stiles’ poetry so as to customize the dataset to her voice. Stiles also included research notes, news articles and excerpts from classic American poets like T.S. Eliot and Dickinson in her customizations.
“I've taken all the things that were swirling in my head when I was working on my manuscript, and I put them into this system,” Stiles explained. “And then I'm using algorithms to parse all this information and swirl it around in a blender to then synthesize it into useful additions to the approach that I am taking.”
This approach, Stiles said, allows her to riff on ideas that are bouncing around in her mind, or simply find moments of unexpected creative surprise by way of the algorithm’s randomization.
Beauty is now - perhaps more than ever - in the eye of the beholder
But the million-dollar question remains: Can an AI be its own, independent artist?
The answer is nuanced and may depend on who you ask, and what role they play in the art world. Curator and multidisciplinary artist CoCo Dolle asks whether any entity can truly be an artist without taking personal risks. For humans, risking one’s ego is somewhat required when making an artistic statement of any kind, she argues.
“An artist is a person or an entity that takes risks,” Dolle explained. “That's where things become interesting.” Humans tend to be risk-averse, she said, making the artists who dare to push boundaries exceptional. “That's where the genius can happen."
However, the process of algorithmic collaboration poses another interesting philosophical question: What happens when we remove the person from the artistic equation? Can art — which is traditionally derived from indelible personal experience and expressed through the lens of an individual’s ego — live on to hold meaning once the individual is removed?
As a robot, Botto cannot have any artistic intent, even while its outputs may explore meaningful themes.
Dolle sees this question, and maybe even Botto, as a conceptual inquiry. “The idea of using a DAO and collective voting would remove the ego, the artist’s decision maker,” she said. And where would that leave us — in a post-ego world?
It is experimental indeed. Hudson acknowledges the grand experiment of BottoDAO, coincidentally nodding to Dolle’s question. “A human artist’s work is an expression of themselves,” Hudson said. “An artist often presents their work with a stated intent.” Stiles, for instance, writes on her website that her machine-collaborative work is meant to “challenge what we know about cognition and creativity” and explore the “ethos of consciousness.” As a robot, Botto cannot have any intent, even while its outputs may explore meaningful themes. Though Hudson describes Botto’s agency as a “rudimentary version” of artistic intent, he believes Botto’s art relies heavily on its reception and interpretation by viewers — in contrast to Botto’s own declaration that successful art is made without regard to what will be seen as popular.
“With a traditional artist, they present their work, and it's received and interpreted by an audience — by critics, by society — and that complements and shapes the meaning of the work,” Hudson said. “In Botto’s case, that role is just amplified.”
Perhaps then, we all get to be the artists in the end.
When graduating college this month, many North American engineering students will take a special pledge, with a history dating back to 1925.
The tradition of taking an engineering oath began over a century ago in Canada. In 1922, Herbert E.T. Haultain, professor of mining engineering at the University of Toronto, presented the idea at the annual meeting of the Engineering Institute of Canada. The seven past presidents of that body were in attendance, heard Haultain’s speech and accepted his suggestion to form a committee to create an honor oath. Later, they formed the nonprofit Corporation of the Seven Wardens, which would oversee the ritual. Next year, in 1923, with the encouragement of the Seven Wardens, Haultain wrote to poet and writer Rudyard Kipling, asking him to develop a professional oath for engineers. “We are a tribe—a very important tribe within the community,” Haultain said in the letter, “but we are lacking in tribal spirit, or perhaps I should say, in manifestation of tribal spirit. Also, we are inarticulate. Can you help us?”
While Kipling is most famous now for “The Jungle Book” and perhaps his poem “Gunga Din,” he had also written a short story about engineers, “The Bridge Builders.” His poem “The Sons of Martha” can be read as a celebration of engineers:
It is their care in all the ages to take the buffet and cushion the shock.
It is their care that the gear engages; it is their care that the switches lock.
It is their care that the wheels run truly; it is their care to embark and entrain,
Tally, transport, and deliver duly the Sons of Mary by land and main.
Kipling accepted the ask and wrote the Ritual of the Calling of an Engineer, which he sent to Haultain a month later. In his response to Haultain, he stated that he preferred the word “Obligation” to “Oath.” He wrote the Obligation using Old English lettering and the old-fashioned capitalization. Kipling’s Obligation binds engineers upon their “Honor and Cold Iron” to not “suffer or pass, or be privy to the passing of, Bad Workmanship or Faulty Material,” and pardon is asked “in the presence of my betters and my equals in my Calling” for the engineer’s “assured failures and derelictions.” The hope is that when one is tempted to shoddy work by weakness or weariness, the memory of the Obligation “and the company before whom it was entered into, may return to me to aid, comfort, and restrain.”
Using the Obligation, The Seven Wardens created an induction ceremony, which seeks to unify the profession and recognize engineering’s ethics, including responsibility to the public and the need to make the best decisions possible. The induction ceremony included recitation of Kipling’s “Obligation” and incorporated an anvil, a hammer, an iron chain, and an iron ring. The inductee engineers sat inside an area marked off by the iron chain, with their more senior colleagues outside that area. At the start of the ritual, the leader beat out S-S-T in Morse code with the hammer and anvil—the letters standing for Steel, Stone, and Time. A more experienced and previously obligated engineer placed the ring on the small finger of the inductee engineer’s working hand. As per Kipling, the ring’s rough, faceted texture symbolized “the young engineer’s mind” and the difficulties engineers face in mastering their discipline.
A persistent myth purports that the original iron rings were made from the beams or bolts of the Quebec Bridge that failed twice during construction.
The first induction ceremony took place on April 25, 1925, in Montreal to obligate two of the Seven Wardens, along with four graduates from the University of Toronto class of 1893. On May 1 of that year, 14 more engineers were obligated at the University of Toronto. From that time to today most Canadian professional engineers have gone through that same ritual in their various camps, called Kipling camps—local chapters associated with various Canadian universities.
Henry Petroski, Duke University’s professor of civil engineering and history, notes in his book, “Forgive Design: Understanding Failure,” that Kipling’s poem “Sons of Martha” is often read as part of the ritual. However, sometimes inductees read Kipling’s “Hymn of Breaking Strain,” instead, which graphically depicts disastrous outcomes of engineering mistakes. The first stanza of that poem says:
The careful text-books measure
(Let all who build beware!)
The load, the shock, the pressure
Material can bear.
So, when the buckled girder
Lets down the grinding span,
'The blame of loss, or murder,
Is laid upon the man.
Not on the Stuff—the Man!
As if to strengthen the importance of these concepts, a persistent myth purports that the original iron rings were made from the beams or bolts of the Quebec Bridge that failed twice during construction. The bridge spans the St. Lawrence River upriver from Quebec City, and at the time of its construction was the world’s longest at 1,800 feet. Due to engineering errors and poor oversight, the bridge’s own weight exceeded its carrying capacity. Moreover, engineers downplayed danger when bridge beams began to warp under stress, saying that they were probably warped before they were installed. On August 29, 1907, the bridge collapsed, killing 75 of 86 workers. A second collapse occurred in 1916 when lifting equipment failed, and thirteen more workers died.
The ring myth, however, couldn’t be true. The original iron rings couldn’t have come from the failed bridge since it was made of steel, not wrought iron. Today the rings are made from stainless steel because iron deteriorates and stains engineers’ finger black.
On August 14, 2018, Morandi Bridge over Polcevera River in Genoa, Italy, collapsed from structural failure, killing 43 people.
Adobe Stock
The Seven Wardens decided to restrict the ritual to engineers trained in Canada. They copyrighted the obligation oath in Canada and the United States in 1935. Although the ritual is not a requirement for professional licensing, just like the Hippocratic Oath is not part of medical licensing, it remains a long-standing tradition.
The American Obligation of the Engineer has its own creation story, albeit a very different one. The American Order of the Engineer (OOE) was initiated in 1970, during the era of the anti-war protests, Apollo missions and the first Earth Day. On May 4, 1970, the National Guard shot into a crowd of protesters at Kent State University, killing four people. The two authors of the American obligation—Cleveland State University’s (CSU) engineering professor John Janssen and his wife Susan—reflected these historical events in the oath they wrote. Their version of the oath binds engineers to “practice integrity and fair dealing.” It also notes that their “skill carries with it the obligation to serve humanity by making the best use of the Earth’s precious wealth.” As Petroski explains in his book, “campus antiwar protestors around the country tended to view engineers as complicit in weapons proliferation [which] prompted some [CSU] engineering student leaders to look for a means of asserting some more positive values.”
Kip A. Wedel, associate professor of history and politics at Bethel College, wrote in his book, “The Obligation: A History of the Order of the Engineer,” that the ceremony was not a direct response to the Kent State shootings—it was already scheduled when the shootings happened. Yet, engineering students found the ceremony a positive action they could take in contrast to the overall turmoil. The first American ritual took place on June 4, 1970, at CSU. In total, 170 students, faculty members, and practicing engineers took the obligation. This established CSU as the first Link of the Order, as the OOE designates its local chapters. For their first ceremony, the CSU students fabricated smooth, unfaceted rings from stainless steel pipe. Later they were replaced by factory-made rings. According to Paula Ostaff, OOE’s Executive Director, about 20,000 eligible students and alumni obligate themselves yearly.
Societies hope that every engineer is imbued with a strong ethical sense and that their pledges are never far from mind. For some, the rings they wear serve a daily reminder that every paper they sign off on is touched by a physical reminder of their commitment.
These ethical and responsible engineering practices are especially salient today, when one in three American bridges needs repair or replacement, some have already collapsed, and engineers are working on projects related to the bipartisan infrastructure bill President Biden signed into law in 2021. Canada has committed $33 billion to its Investing in Canada Infrastructure Program. At the heart of these grand projects are many thousands of professional engineers, collectively working millions of hours. The professional vows they took aim to assure that the homes, bridges and airplanes they build will work as expected.