Does the grammar of life necessarily have to consist of 20 letters? Life on Earth makes proteins using 20 standard amino acids. This system is so ancient and universal that it has long been regarded almost like a natural grammar that all living organisms must follow. Yet synthetic biology is now beginning to ask a new question. If one letter is removed from the basic grammar of life, can a cell still remain alive and functional?

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The most familiar way to understand living organisms begins with DNA. DNA contains the blueprint of life, and that information is transferred to RNA and then translated into proteins. At this stage, the basic building blocks of proteins are amino acids. Almost all living organisms on Earth make proteins by combining 20 standard amino acids. Muscles, enzymes, parts of cell membranes, and countless molecular devices that send and receive signals are all ultimately structures created as these 20 materials fold and intertwine.

This is why the 20 amino acids are often called the alphabet of life. Just as letters form words and words form sentences, amino acids link together to create the sentences of life known as proteins. The question is whether this alphabet is truly absolute. Why did life on Earth choose exactly 20 amino acids? Would 19 have been insufficient? Would 18 have been impossible? Conversely, would living organisms using more amino acids have had an advantage?

For a long time, this question was closer to a theoretical speculation about the origin of life. Early life on Earth may have begun with simpler materials than those used today. It is unlikely that a complex biochemical system appeared in a fully completed form from the beginning. If so, today’s 20-amino-acid system may not be the starting point of life, but rather the result of a long evolutionary process.

In April 2026, a study published in Science by a joint research team from Columbia University, Harvard University, and MIT, including Liyuan Liu, Charlotte Rouchereau, Simon Cozlow, and Guillaume Urtecho, experimentally addressed the question of whether life could be created with a 19-amino-acid alphabet by combining generative artificial intelligence design with synthetic biology.

Synthetic biology has developed significantly in the direction of expanding the grammar of life. This has involved adding new nonstandard amino acids to the 20 amino acids used in nature, rearranging the genetic code, or designing cells to produce molecules that do not exist in nature. Such research has played an important role in turning living organisms into a kind of biological factory. This includes efforts to produce medicines, enzymes, new materials, and biofuels inside cells, especially substances that are difficult or inefficient to make through conventional chemical processes.

However, expanding the grammar of life and reducing it are different in nature. Adding a new letter is closer to placing a new function on top of an existing grammar. By contrast, removing one letter means rewriting an entire set of sentences that has been fixed over billions of years. To eliminate a specific amino acid embedded throughout proteins, it is not enough simply to change a few genes. The structural role, chemical properties, protein-folding behavior, and interactions with other amino acids that the amino acid had been responsible for must all be considered.

This study focused on isoleucine among the 20 amino acids. Isoleucine is a hydrophobic amino acid with chemical properties similar to leucine and valine. It is frequently used to stabilize the interior of proteins, but it may also be replaceable with amino acids that have similar characteristics. Still, this does not mean that isoleucine can simply be replaced with another amino acid. A protein is not merely a string of beads. Even when the same materials are used, a change in position can alter the way a protein folds, and when folding changes, function can disappear.

The target of the research team was the ribosome of Escherichia coli. The ribosome is the translation machine inside the cell that makes proteins. It plays a central role in the final stage where the information contained in DNA is converted into proteins. For a living organism to maintain and replicate itself, the ribosome must function. Therefore, whether a cell can survive even after a specific amino acid is reduced in ribosomal proteins becomes a powerful experiment for testing the minimum grammar of life.

An important tool in this study was protein design based on generative artificial intelligence. Proteins inside living organisms are composed of countless amino acid combinations. It is difficult to decide by simple intuition whether a particular isoleucine position should be replaced with valine, leucine, or another amino acid. The possible combinations are too numerous, and the effects of each change on protein structure and cell survival are complex.

At this point, protein language models and structure-based design models were used. Artificial intelligence predicts which substitutions are relatively stable based on vast amounts of protein sequence and structure information. Instead of having researchers test every possible case one by one in the laboratory, AI first narrows the field to designs that are more likely to work. This does not mean that life is fully designed on a computer screen. Life must still be verified in the laboratory. However, AI becomes a search tool that helps identify which designs are worth attempting, which changes are too risky, and which substitutions are likely to preserve function.

The research team began by replacing ribosomal proteins containing isoleucine with other amino acids, but simple substitution was not enough. Some proteins maintained their function, but in many cases cell growth was impaired or the proteins did not work properly. The researchers therefore used AI models not merely to perform one-to-one substitutions, but to redesign proteins in a way that also adjusted surrounding amino acids. In other words, they searched for compensatory mutations that could remove isoleucine from specific positions while preventing the overall protein structure from collapsing.

This process reveals a shift in the direction of synthetic biology. Whereas past biotechnology was closer to finding and using functions already created by nature, future synthetic biology is moving toward rewriting the grammar of life itself. Editing DNA alone is not sufficient. The principles by which living organisms operate must be calculated, possible design spaces must be explored, and the results must be verified in actual cells.

The point that requires the greatest caution in understanding this study is exaggeration. The researchers did not create a complete 19-amino-acid organism. Isoleucine was not removed from every protein in the entire E. coli cell, nor was the whole cell changed so that it could live using only 19 amino acids. The core achievement was showing whether cells could still function even after isoleucine was extensively removed from ribosomal proteins, the central translation machinery of E. coli.

In this study published in Science, the researchers systematically reduced isoleucine residues contained in ribosomal proteins. They then integrated some redesigned ribosomal components into their original genomic locations in E. coli and created viable cells. These cells did not function at exactly the same level as wild-type E. coli, but they were able to survive and proliferate. More importantly, the researchers showed that these changes were not merely short-term accidental survival, but could be maintained relatively stably across multiple generations.

This difference matters. Saying that a “19-amino-acid organism has been completed” would blur the scientific meaning. But saying that “it is meaningless because it is not yet complete” would also be inaccurate. The fact that part of life’s core machinery can function with a 19-amino-acid system rather than a 20-amino-acid system shows that the grammar of life may be more flexible than previously thought. The 20-amino-acid system of life on Earth is a powerful and universal standard, but it is no longer easy to conclude that it is the only possible way.

We tend to think of life as an extremely precise and fragile system. Indeed, even a small genetic mutation can cause disease or loss of function in living organisms. At the same time, however, life is remarkably flexible. It withstands mutations, adapts to environmental change, and finds detours even under unfavorable conditions. The history of life is less a history of perfect design than a history of finding workable solutions through countless trials and errors.

This study shows that flexibility again at one of the most fundamental levels of life. It is true that the 20-amino-acid system is the most familiar and stable standard for life on Earth today. But it cannot be assumed to be the only possible system. Perhaps life has a broader design space than we have imagined. Life on Earth may be only one successful version within that space.

This perspective also connects to research on the origin of life. Early life on Earth may not have possessed the sophisticated protein systems seen today. The types of amino acids may have been limited, and the genetic code may have been less complex than it is now. If a life-like system nevertheless functioned under such conditions, the current 20-amino-acid system may have been the result of gradual expansion rather than the original starting point. This study allows us to experimentally imagine the possibility that early life may have functioned with a simpler set of amino acids.

Another implication is connected to the search for extraterrestrial life. We often imagine life in the form of life on Earth. We judge the possibility of life based on the framework of DNA, RNA, proteins, and 20 amino acids. However, if the grammar of life does not have to be singular, life on another planet or moon may use an entirely different combination of materials. Of course, this study does not prove the existence of extraterrestrial life. Still, when trying to understand the phenomenon of life, it suggests that we should be cautious about treating the standard observed on Earth today as an absolute criterion.

Research on 19 amino acids is also deeply connected to minimal cell research. A minimal cell refers to the simplest possible cell, leaving only the components essential for sustaining life. It is a field that investigates which genes are absolutely necessary, which metabolic pathways can be removed, and which proteins are central to survival. The purpose of this field is not simply to make smaller cells. Its essence lies in discovering the minimum conditions required for life to operate.

What can be removed while life is maintained? How far can life be reduced before it can no longer be called life? Which functions are essential, and which are optional depending on the environment? These questions change the very way we understand life. This study expands the scope of minimal cell research from the number of genes or the size of a cell to the amino acid alphabet itself. In other words, it asks not only whether the number of parts required by a living organism can be reduced, but whether the kinds of basic materials used to make those parts can also be reduced. This is a more fundamental form of reduction.

Such reduction also has practical meaning. Cells with a simpler amino acid system may operate more predictably in certain environments. They may reduce unnecessary metabolic burdens and be designed to concentrate energy on producing specific substances. From the perspective of biomanufacturing, a cell becomes not merely a living organism but a precise production platform. The problem is that cells are too complex. Greater complexity makes prediction difficult, and when prediction is difficult, industrial application also becomes more challenging. Minimal cell research is precisely an attempt to reduce this complexity.

The more important possibility is a biological safety mechanism. If cells can be created that operate with a grammar different from that of natural organisms, such cells may have difficulty surviving freely in the outside environment. If they are designed to depend on a specific amino acid system or specific nutritional conditions, living organisms that cannot proliferate outside the laboratory could be created. As synthetic biology expands into industry, safety becomes a central challenge. Research that reduces or changes the grammar of life may become not just a matter of scientific curiosity, but a foundational technology for controllable biotechnology.

Biomanufacturing is a technology that uses cells to produce needed materials. Cells are already used as production factories in various fields, including insulin, vaccines, antibody medicines, enzymes, and fermentation-based materials. However, future biomanufacturing is unlikely to remain at the level of simply borrowing natural cells. It is moving toward designing cells that produce better, waste less, and can be controlled more safely.

The message offered by research on 19 amino acids is clear. Cells are not objects that must simply be used as given. Cells are systems that can be redesigned. If we can go beyond changing genes and alter the basic material system that constitutes proteins, the possibilities of biomanufacturing will become far broader. Cells that use less of a specific amino acid, protein systems optimized for producing specific substances, and cells with genetic codes different from those found in nature may emerge.

Of course, such a future will not arrive immediately. Changing the grammar of a living organism is extremely difficult and requires careful risk management. A cell is not a machine that moves exactly as desired simply because one part has been changed. Even if one particular protein works well, the cell’s overall metabolism, growth, stress response, and mutational stability must also be considered together. The future of synthetic biology may be promising, but it cannot be assumed that commercialization will happen quickly or automatically.

Even so, the direction is clear. Life science is expanding from a discipline that observes and interprets living organisms into a technology that designs and adjusts them. The question of whether life can be designed with only 19 amino acids is not simply a matter of removing one amino acid. It is a question about how far life can be rewritten. It is a starting point for testing whether humans can move beyond understanding the grammar of life created by nature and design a new grammar of life.

The greatest meaning shown by this study is that life may be more flexible than previously thought. The 20-amino-acid system is a highly successful standard for life on Earth, but it may not be an absolute limit. The result that part of the cell’s core translation machinery can function with a 19-amino-acid system shows that the basic structure of life may be an adjustable system rather than an unchanging rule.

This question will continue to expand. Beyond removing one specific amino acid, could the roles of multiple amino acids be rearranged? Could amino acids not found in nature be added stably? Could cells be made to live according to a protein grammar completely different from that of natural organisms? These questions lead to the origin of life, the search for extraterrestrial life, minimal cell design, biomanufacturing, and biological safety.

Ultimately, research on 19 amino acids is not an experiment in reducing life, but an experiment in expanding the possibilities of life. Because one letter was removed, a much larger question emerged. Does life have to exist only in the form we now observe? Is the grammar of life an immutable law once set by nature, or can it be rewritten in other ways? Synthetic biology has now begun to answer that question through experiment. And that answer is slowly opening toward the future of artificial cells, minimal life, and biomanufacturing.

Science, April 2026, Toward life with a 19?amino acid alphabet through generative artificial intelligence design