Simple reductionist systems can serve as powerful catalysts for unlocking complex innovations in science and art. The evolution from simplicity to complexity is illustrated by the career journeys of the scientist Earl W. Sutherland, who discovered cyclic AMP and opened the field of cell signaling, and the artist Frank Stella, who pioneered geometrical patterns and shapes in both painting and sculpture. Their work profoundly influenced biomedical science and modern art. How one navigates the journey from simplicity to complexity is a fundamental challenge to scientists and artists who aim to identify fresh ideas that lead to insights with lasting impact.
Scientists and artists alike face a challenge in creating fresh, innovative ideas. Scientists strive to push the boundaries of knowledge, while artists aim to develop unique expressions that transcend established norms. In this essay, I explore how one scientist and one artist, working in vastly different fields, began their careers with a focus on simplicity. Their work evolved over time into complex, groundbreaking contributions, illustrating the power of starting simple as a prelude to deeper complexity. In the world of science, the biochemist Earl W. Sutherland (1915-1974) discovered cyclic AMP, which revolutionized our understanding of cell signaling and communication. In the world of art, the painter Frank Stella (1936-2024) invented and reinvented new forms of abstraction, which ranged from minimalist paintings to bold structural compositions.
Earl Sutherland’s Discovery of a Biological Principle
Biological systems are inherently messy, involving countless complex interactions among molecules, cells, and tissues — all operating in the context of changing environments. In recent decades, scientific research has increasingly relied on Big Data and technologies such as genomics, proteomics, metabolomics, imaging, and artificial intelligence. How scientists extract meaningful insights from these vast datasets presents a formidable challenge.
A time-tested way to address this challenge is by starting with simple systems that can strip away the nonessential elements. In the 1950s, Earl Sutherland sought to understand how the hormones epinephrine and glucagon induce glycogen breakdown in the liver to produce glucose. He began with liver slices, progressing to cell extracts and then to purified enzymes. His approach revealed a groundbreaking discovery: the existence of a small molecule called cyclic AMP (cyclic adenosine 3′-5′-monophosphate). This molecule acted as an intermediary “second messenger,” transmitting signals from hormones at the cell surface to target enzymes inside the cell (reviewed in ref. 1).
Fig. 1. Schematic representation of the first signaling pathway involving cyclic AMP, which was discovered and first published by Earl Sutherland in 1966 (2) and reprinted in his Nobel Lecture in 1972 (1). Image credit: Adapted from ref. 2, Nancy L. Heard (UT Southwestern Medical Center, Dallas, TX).
Fig. 2. Schematic representation of a current version of a signaling pathway involving cyclic AMP (shaded in yellow). Image credit: Illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com). For pathway, see https://media.cellsignal.com/www/pdfs/science/pathways/gpcr-overview.pdf.
Sutherland proposed an elegantly simple three-step mechanism: 1) the hormone (epinephrine or glucagon), referred to as the “first messenger,” binds to its hypothesized receptor on the cell surface; 2) this activates an enzyme called adenylyl cyclase, which produces cyclic AMP; and 3) cyclic AMP, the “second messenger,” activates enzymes that lead to glycogen breakdown and glucose production. Importantly, he discovered that cyclic AMP is formed within the cell membrane, suggesting that the hormone itself never enters the cell. Figure 1 shows a schematic representation of Sutherland’s second messenger concept (2).
The Impact of Sutherland’s Work
Sutherland’s minimalist concept, published in the mid 1960’s, inaugurated the field of cell signaling. It paved the way for numerous discoveries that rapidly followed, including cyclic AMP-dependent protein kinases, G-protein-coupled receptors (GPCRs), and other second messenger molecules, such as cyclic GMP, inositol trisphosphate, calcium, and nitric oxide.
Sutherland’s work had far-reaching implications, influencing scientific thinking about cellular communication and spawning 60 years of research by thousands of scientists who elucidated as many as 105 new signaling pathways – like Ras/MAPK/ERK, WNT/β-Catenin, Hedgehog, steroid hormones, JAK/STAT, TGF-β, NF-κB, mTORCs, SREBPs, cGAS/STING/γ-Interferon, etc. (3). These pathways govern virtually all cellular functions and physiological processes in living organisms. Much of the remarkable growth of the cell signaling field can be attributed to the biotechnology company, Cell Signaling Technology, Inc., which markets more than 16,000 products. These include antibodies, chemical reagents, recombinant proteins, and kits, which are available for probing the 105 signaling pathways (https://www.cellsignal.com). Figure 2 shows a schematic representation of one of these pathways – the “GPCR, Calcium, cyclic AMP Pathway” – the complexity of which is a far cry from Sutherland’s original minimalist cyclic AMP pathway shown in Figure 1.
For his pioneering scientific work, Sutherland received the Lasker Basic Research Award in 1970 and the Nobel Prize in Physiology or Medicine in 1971 (4).
Fig. 3. Examples of two of Frank Stella’s works in the original Black Paintings series. enamel on canvas. 1959. (A) Jill. 7.6 x 6.6 ft. (B) Die Fahne hoch. 10.5 x 6 ft. © 2025 Frank Stella / Artists Rights Society (ARS), New York.
Fig. 4. Evolution of Frank Stella’s style: from the minimalism of his early Black Paintings to his later paintings characterized by vibrant colors, canvases with altered shapes, and structural components extending from the canvas. (A) Jasper’s Dilemma (1962-1963). alkyd on canvas. 6.4 x 12.8 ft. (B) Gur III (1968). fluorescent alkyd on canvas. 10 x 15 ft. (C) Gobba, zappa e collotorto (1985). oil, fluorescent alkyd, acrylic, and printing ink on etched magnesium and aluminum. 11.4 x 10 x 2.9 ft. © 2025 Frank Stella / Artists Rights Society (ARS), New York.
Frank Stella’s Evolution from Simplicity to Complexity
Stella’s early works, known as the Black Paintings, were created between 1958 and 1960 when he was just 22 years old (5). Each of the 14 paintings in the Black Paintings series consisted of a different geometric pattern of uniform black stripes separated by thin pinstripes of unpainted canvas (Figs. 3A and B). Their stark simplicity, devoid of symbolism and depth, was a radical departure from the complex, multi-colored expressive style of artists like Jackson Pollack and Willem de Kooning, whose compositions dominated the art world at the time. The Black Paintings took the art world by storm.
Even though Stella’s minimalism gained widespread acclaim, he did not remain confined to this style. In the 1960s, he began painting on canvases with varied shapes, including concentric squares and polygons, and adorned them with sparkling colors. One notable work from this period, is his painting Jasper’s Dilemma (Fig. 4A), which features two identical panels — one in color, the other in grey tones. This painting was inspired by a statement from fellow artist Jasper Johns: “The more I paint in color, the more I see everything in black” (6). Jasper’s Dilemma became the stimulus for a monumental Stella sculpture (discussed below). In 1970, at age 34, Stella became the youngest artist to receive a full-scale retrospective at the Museum of Modern Art (5).
Stella’s creativity continued to evolve. By the 1970s, he introduced large-scale paintings with complex interlocking and overlapping patterns inspired by the curves of the protractor, a simple geometric tool for measuring angles. His use of fluorescent colors added a new level of vibrancy to the Protractor series (Fig. 4B)
Breaking Boundaries with Three-Dimensional Art
In the late 1970s and 1980s, Stella — the master of reinvention — changed course again, abandoning the flat canvas and moving towards three-dimensionality with structural components that extended out from the canvas (Fig.4C). These visually stunning pieces combined elaborate sculptural forms painted with ravishing colors (7). In 1987, the Museum of Modern Art gave Stella a second retrospective exhibition — unprecedented for a living artist.
Over a 12-year period from 1985 to 1997, Stella produced his iconic Moby Dick series, a set of 266 paintings, metal sculptures, collages, woodcuts, and prints inspired by Herman Melville’s novel (8). One of these works, The Fountain, is based on Chapter 85 of Moby Dick (9). It measures over 23 feet in length. It is one of the largest prints ever created and involves seven different artistic techniques, including woodcut, etching, collage, and painting with 67 colors (Fig.5). Stella used swirling black shapes and rainbow-like crescents to evoke Melville’s description of a whale’s spout.
Fig. 5. Frank Stella. The Fountain (1992). hand-colored woodcut, etching, aquatint, relief, drypoint, screenprint collage on three sheets of handmade paper. 7.6 x 23 ft. © 2025 Frank Stella / Artists Rights Society (ARS), New York.
In his later years, Stella integrated digital technologies into his creative process. His final exhibition in 2024 at age 87 featured three massive sculptures – each 16-18 feet tall supported by a single metal pole on a wheeled base and adorned with an explosive array of sparkling colors (Fig.6). Stella designed these sculptures with computer programs, which were fabricated with fiberglass and aluminum and then sprayed with car paint (10). These psychedelic sculptures are among Stella’s most inventive and extreme abstract works – a far cry from the simplicity of the Black Paintings.
Fig. 6. Frank Stella. K.144 Large Version (2014). fiberglass on foam core. 16.4 x 17.3 x 12.5 ft. © 2025 Frank Stella / Artists Rights Society (ARS), New York.
Fig. 7. Frank Stella. Jasper’s Split Star (2017). 6 solid aluminum sides / 6 painted open grids. 16.8 x 21.4 x 20.8 ft. Installed in front of 7 World Trade Center on Nov. 22, 2021. © 2025 Frank Stella / Artists Rights Society (ARS), New York.
Stella’s Legacy of Reinvention
In addition to his indoor artwork, Stella produced many large-scale outdoor works, including his Star series that features complex, geometric star shapes displayed in sculpture gardens and public places throughout the world. One such 21-foot-tall sculpture, Jasper’s Split Star, is constructed out of 12 geometric pieces with six solid unpainted aluminum sides and six open sides spray-painted in pale shades of blue, purple, and grey (Fig. 7). The work was installed in 2021 in the public plaza in front of 7 World Trade Center in lower Manhattan (12). The two split faces of the sculpture – one colored and the other unpainted – hark back to Stella’s 1962 painting Jasper’s Dilemma (described above; Fig. 4A).
Throughout his 66-year career, Stella mastered the art of reinvention, as his work evolved from minimalism to maximalism. His passion for innovation in color, shape, and technology continually redefined the relationship between art and perception (13). He famously stated, “What you see is what you see,” emphasizing the purity of visual experience (14). Stella’s work has been widely exhibited and collected by major museums throughout the world.
A Shared Journey: The Power of Simplicity
Both Sutherland and Stella began with reductionist approaches in their respective fields. Sutherland isolated specific cellular responses to hormones. His discovery of cyclic AMP spawned a new field of research in which thousands of scientists went on to reveal more than 100 new signaling pathways essential to life. Similarly, Stella reduced paintings to their most basic elements before expanding into increasingly intricate and dynamic works that combined painting with sculpture in a three-dimensional form.
The work of Sutherland and Stella embodies the sentiment captured by Leonardo da Vinci’s famous quote “Simplicity is the ultimate sophistication” (14). Through their groundbreaking contributions, they have left enduring legacies in science and art, inspiring future generations to explore the transformative power of simplicity as a stepping-stone to innovation.
2025 Lasker Awards: Various Paths to Innovation and Discovery
As described above, simple reductionist approaches can evolve increasingly into more complex dynamic work that leads to transformative ideas and discoveries. Various paths to innovation from the simple to the complex are exemplified by the discoveries of this year’s Lasker winners. For a detailed account of the 2025 Lasker Awards, please refer to the Lasker website at https://laskerfoundation.org and to the accompanying articles in this issue of the Proceedings of the National Academy of Sciences. A brief summary of the awards appears below.
Albert Lasker Basic Medical Research Award. The recipients of this award are Dirk Görlich (Max Planck Institute for Multidisciplinary Sciences, Göttingen) and Steven L. McKnight, University of Texas Southwestern Medical Center, Dallas). The awardees are recognized for their discoveries that exposed the structures and functions of low-complexity domains within protein sequences, revealing new principles of intracellular transport and cellular organization. Low-complexity domains (LCDs) are regions within proteins composed predominantly of a few types of amino acids rather than the diverse mix of 20 in most protein regions. These unstructured LCDs comprise 15-20% of the coding sequences in the human genome. Görlich discovered that LCDs in nucleoporin proteins containing phenylalanine-glycine (FG) repeats can form a hydrogel representative of the inside of the nuclear pore complex. This FG hydrogel acts as a highly selective permeability barrier. Transporter receptors penetrate the hydrogel and carry their cargo protein across the pore. Gorlich’s demonstration that LCDs can self-associate and phase separate provided early biochemical evidence for formation of membraneless compartments. McKnight characterized additional proteins with LCDs that form hydrogels (e.g., FUS, TDP43, the ribonucleoprotein hnRNPA2, and certain intermediate filaments). Importantly, he discovered that phase separation by these proteins is mediated by reversible cross beta interactions between LCDs, explaining how membraneless puncta appear and disappear. Genetic evidence showed that disease-causing point mutations can make these membraneless structures excessively stable, explaining protein aggregation in certain inherited neurological diseases. The work of McKnight and Gorlich has transformed our understanding of cellular organization by showing that a significant portion of the proteome — those 15-20% of proteins with LCDs – enables cells to create dynamic, reversible structures that organize and regulate cell function beyond traditional membrane-bound organelles.
Lasker~DeBakey Clinical Medical Research Award. The recipients of this award are Michael J. Welsh (University of Iowa), Jesús (Tito) González (Formerly of Vertex Pharmaceuticals), and Paul A. Negulescu (Vertex Pharmaceuticals, San Diego). The awardees are recognized for their key roles in developing a novel treatment for cystic fibrosis – a triple-drug combination that saves the lives of people with this lethal genetic disease. Cystic fibrosis (CF) is caused by autosomal recessive mutations that disrupt the function of CFTR, the protein channel that transports chloride and bicarbonate ions across cell membranes. Welsh made major contributions to understanding the function of CFTR and its dysfunction when mutated in CF. González developed a novel FRET-based voltage sensor assay that was used to screen for drugs that restore function to the mutant CFTR proteins. Negulescu, the leader and champion of the CF program for more than 20 years, assembled the people and expertise necessary for large-scale mutation-specific testing (Fred Van Goor) and medicinal chemistry (Sabine Hadida). The FDA-approved, triple-drug combination (Trikafta®) — identified by Negulescu’s team — corrects the folding, trafficking, and activity of mutant CFTR proteins. This orally administered drug is now used by tens of thousands of CF patients throughout the world. Its development represents a true milestone in the history of biomedical research and clinical medicine.
Lasker~Koshland Special Achievement Award in Medical Science. The recipient of this year’s award is Lucy Shapiro (Stanford University) for a 55-year career in biomedical science – honored for fundamental discoveries in bacterial genetics; for founding Stanford’s distinguished Department of Developmental Biology; and for exemplary leadership at the national level. In pioneering studies of the bacterium Caulobacter crescentus, Shapiro dissected the mechanism by which a dividing cell can produce two progeny with different developmental fates, generating one of the best understood systems of asymmetric cell division. In addition to her research and academic leadership at Stanford, she served as a key advisor to President Clinton and his Cabinet on bioterrorism threats and defense, antibiotic resistance, and emerging infectious diseases. She continued this advisory role at the Office of Homeland Security in the George W. Bush presidency. Her influence extends through her service on the Scientific Advisory Boards of Harvard University, Whitehead Institute/Massachusetts General Hospital, and the Pasteur Institute. With Steve Benkovic, she discovered a new class of boron-containing compounds. Together they co-founded two companies that are developing an antifungal drug for infections of the nail and nailbed, a topical PDE4 inhibitor for atopic dermatitis, and a boron-containing compound to combat banana fungal disease.
1. E. W. Sutherland, Studies on the mechanisms of hormone action (Nobel Lecture). Science, 177, 401-408 (1972).
2. E. W. Sutherland, G. A. Robison, Metabolic effects of catecholamines: the role of cyclic-3′,5′-AMP in response to catecholamines and other hormones. Pharmol. Rev., 18, 145-161 (1966).
3. Online catalogue for Cell Signaling Technology.
4. C. F. Cori, “Earl W. Sutherland 1915-1974” Biographical Memoirs of National Academy of Sciences, 1978.
5. W. S. Rubin, Frank Stella (The Museum of Modern Art, New York, NY, 1970).
6. M. Auping, Jasper’s Dilemma, 1962. Whitney Museum of American Art, Audio archive. October 30, 2015.
7. M. Auping, Frank Stella: A Retrospective (Yale University Press, New Haven CT, 2015).
8. S. Guberman, Frank Stella: An Illustrated History (Rizzoli International Publications, Inc., New York, NY, 1995).
9. P. Larson, Frank Stella: The Fountain (Tyler Graphics, Ltd., Mount Kisco, NY 1992).
10. https://deitch.com/new-york/exhibitions/frank-stella-recent-sculpture
11. M. H. Miller, Revisiting ground zero. New York Times. Nov. 23, 2021.
12. A. Russeth, “Frank Stella, American artist who moved from proto-minimalism to extreme abstraction, dies at 87.” May 4, 2024.
13. R. Mnuchin, M. McGinnis, Frank Stella (1936-2024) An Homage (Catalogue, Mnuchin Gallery, New York, NY, 2024).
14. https://www.inc.com/kevin-daum/20-quotes-from-leonardo-da-vinci-to-inspire-you.html
