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Nov 21, 2023

Cells, Not DNA, Are The Master Architects Of Life

Far from being a blueprint for an organism, genes are mere tools used by life’s

Far from being a blueprint for an organism, genes are mere tools used by life's true expert builders: cells.

Alfonso Martinez Arias is ICREA Research Professor in the department of systems bioengineering of the Universitat Pompeu Fabra in Barcelona.

This essay is adapted from his upcoming book, "The Master Builder: How the New Science of the Cell Is Rewriting the Story of Life" (Basic Books, 2023).

For you formed my inward parts; you knitted me together in my mother's womb. I praise you,for I am fearfully and wonderfully made.— Psalm 139: 13–14

Every animal and plant on Earth has an awesome beauty: the majesty of an oak, the delicate fabric of a butterfly, the grace of a gazelle, the imperious presence of a whale and, of course, us humans, with our mixture of wonders and fatal flaws. Where does it all come from? In Mayan tradition, the answer is corn; other cultures suggest various forms of egg as the source. In many stories, the origin is some clay-like material shaped by the might and imagination of a powerful entity that breathes life into it. From such starts, multiplication follows and the Earth is populated, though the details of how this happens are scant.

Over the past century, scientists have discovered a material explanation for the source of life, one that needs no divine intervention and provides a thread across eons of time for all beings that exist or have ever existed: deoxyribonucleic acid — DNA. While there is little doubt that genes have something to do with what we are and how we come to be, it is difficult to answer precisely the question of what their exact role in all of this is.

A closer look at how genes work and what they can accomplish, compared to what they are said to achieve, casts doubt on the assertion that the genome in particular contains an "operating manual" for us or any other living creature. When it comes to the creation of organisms, we’ve overlooked — or, more accurately, forgotten — another force. The origin and power of that force are cells.

What makes you and me individual human beings is not a unique set of DNA but instead a unique organization of cells and their activities. The story of Karen Keegan, a 52-year-old woman in desperate need of a new kidney, is an example.

After consulting with doctors, Karen knew that a donor's kidney would have to be a very close genetic match to reduce the chances that her immune system would reject it as a foreign invader. She was lucky, the doctors had told her. As the mother of three adult sons, she was very likely to find a match within her immediate family. By the rules of genetic inheritance, each of her kids would share about half of their DNA with her, which would make them all good donors. It was just a matter of doing a test to see which son was her best match based on exactly which DNA he’d inherited from her. But when the test results arrived from the lab, Karen was in for a shock: Two of her three sons could not be hers, the doctors said, because they did not share enough DNA.

There had to have been a mistake in the test, Karen protested. She’d been pregnant and given birth to all three of her sons; she had felt them growing (and kicking!) inside her.

Lynn Uhl, a specialist at the hospital, knew Karen, and she knew that Karen had given birth to the children. The chances that not just one but two of Karen's sons had been mistakenly switched at birth was astronomically unlikely. So too was the chance that there had been a mix-up in the blood lab. On a hunch, Uhl decided to check Karen's blood sample against some tissue from another part of Karen's body. This test solved the riddle: Karen did not have one DNA sequence, or genome, in her cells. She had two.

Fifty-three years before, early in Karen's mother's pregnancy, two separate eggs had been independently fertilized, giving rise to two separate balls of cells, each with its own DNA. At some point in the rush of cell division and multiplication that follows fertilization of the egg by sperm, the two groups of cells fused into one. Instead of developing into twins, they developed into Karen, with cells from both balls randomly distributed throughout her body. While most of Karen's body had cells from one of the groups, it just so happened that two of her sons came from eggs that had been generated by the other.

People who carry more than one complete genome are called chimeras, after the fire-breathing lion of Greek mythology with the head of a goat growing out of its back and the head of a snake growing out of its tail. The term denotes that they are combinations of more than one creature. Karen is not alone in being a natural chimera. Indeed, the first human chimera was identified in 1953, the same year that the double helix structure of DNA was discovered. And today, some scientists estimate that about 15% of people are chimeras. Sometimes only blood cells are mixed up, but other times, as in Karen's case, two separately fertilized eggs start to develop and then get fused together.

Ever since the day when James Watson and Francis Crick unveiled their model of the double helix to account for the structure of DNA, we’ve been in thrall to genes. We think of every aspect of ourselves as being determined by our DNA, from the color of our eyes to our propensity for a particular disease.

In the minds of some, DNA even sets the parameters for a person's intellectual ability or temperament: It's in her genes, a parent will say about a child. We take a swab of cells from the cheek and get our DNA tested to learn "who we are," as if tracing which genes we inherited from whom tells us anything about ourselves in that moment. DNA has become so central to our sense of identity that we even use it as a metaphor for social organizations: It's in our DNA as a company, a CEO will say, or as a team, says a coach.

Yet chimeras are just one way in which nature shows us that DNA does not define who we are. Karen is not defined by a DNA sequence; she has two. The publication of the human genome ushered in an era in which people think that most noninfectious diseases have some genetic basis, underscoring the connection between DNA and identity. For conditions linked to a mistake in a single gene — like cystic fibrosis, hemophilia or sickle cell anemia — a focus on DNA will almost certainly allow scientists to develop cures.

Recently developed cutting-edge technologies like CRISPR — the so-called genetic scissors that allow the editing of DNA at will — have produced a range of potential treatments. For example, gene-editing interventions using CRISPR have been shown to repair a single change in the DNA for the beta-globin gene that produces sickle cell anemia and thereby restore the health of individuals. Other uses and treatments are in the pipeline.

But even in instances like this, there are problems. The relationship between changes in a gene and a dysfunction is not usually as straightforward as in the case of sickle cell anemia. Having mutations in the breast cancer type 1 (BRCA1) or type 2 (BRCA2) genes makes it more likely that the body can't produce the functional proteins needed to effectively destroy cancer cells in breast tissue, but it does not say you will get cancer.

Mapping gene mutations to cell malfunctions may help us understand what happens when a gene is faulty or absent, but more often than you think, the observation doesn't tell us how cells use the normal form of the gene to make normal tissues and organs. In fact, over 60% of birth abnormalities cannot be linked to specific genes. Many chronic diseases are caused not by genetic predisposition but by how cells respond to their environment — including in breast cancer, where only 3% of people diagnosed have a mutation in their BRCA1 or BRCA2 genes.

Of course, genes do carry information that contributes to our being. Identical twins are the classic example — they share all of their DNA at birth and look uncannily similar. At the same time, identical twins raised in the same home can develop different personalities, different medical conditions and, sometimes, different physical traits. The question is not whether DNA has something to do with the way we look or behave, but rather what exactly its role is.

It's strange how completely we’ve given in to a gene-centric view of life. We’ve been aware of the workings of cells for well over a century, and through years of study, we have come to know their content and organization in detail. Some we know as essential functional entities. The immune system comprises an army of cells that fight infections and heal injuries, while neurons process information to generate and control our movements and thoughts.

Recent advances in our ability to scrutinize cells’ contents and activities have revealed them to be dynamic entities capable of creating and destroying time and space. We have filmed their interactions and observed how they work in groups to build and maintain organisms. We have learned that our bodies are in constant flux because the cells that make them up are themselves in constant flux. When we consider life from the perspective of the cell, the result is a breathtaking vista of spatial and temporal choreographies.

I have devoted my career to studying how cells come together to generate organs and tissues in animals from fruit flies to mice to human beings. And I have grown increasingly uneasy about how much genes are blamed for things that they have nothing to do with. Genetics provided important glimpses into the processes of animal and plant development, but we have overstretched what genes can explain.

The reason is simple. Geneticists have been so successful at finding changes in genes associated with dysfunction that we’ve fallen into the trap of equating correlation with causation. We’ve transformed method into explanation. We turned tools for studying life into the architects and builders of life. As the famed French mathematician Henri Poincaré might have phrased it, cells are no more piles of genes than a house is a pile of bricks.

Critics might argue that there is nothing here to challenge the gene-centric view of development and evolution. After all, cells are an inevitable consequence of the activity and interactions of the genes that lie in their genomes. There is some truth in this, but cells have powers that DNA cannot dream of. DNA cannot send orders to cells to move right or left within your body or to place the heart and the liver on opposite sides of your thorax. DNA cannot measure the length of your arms or instruct the placement of your eyes symmetrically across the midline of your face. We know this because each and every cell of an organism generally has the same DNA in it, with the same monotonous structure.

Cells can send orders, measure lengths and much more beyond that. In chimeras such as Karen Keegan, cells negotiate the differences between the two genomes coming together to create one body. To do their masterful handiwork, cells use genes, choosing which will or will not be turned on and expressed to determine when and where the products of genes are deployed.

An organism is the work of cells. Genes merely provide materials for their work.

Over years of experiments in my lab and elsewhere, cells have displayed astonishing abilities. Our experiments started by trying to understand why cells behave differently in culture versus in embryo. We found that when a particular type of mouse stem cell — that is, cells that can give rise to any type of organ or tissue — are left to roam on a Petri dish in certain conditions, they will become different from each other; they generate the different types of cells that make up the embryo but do so in a disorganized manner.

If the same cells, with the same genes, are placed in an early embryo, however, they will faithfully contribute to the embryo. Same cells, same genes. So, something other than genes must be involved in making an embryo.

We went on to prove this by developing conditions in the lab in which the cells will imitate many of the processes that lead to the first organization of a body plan in an embryo. The ability to use cells to build structures resembling tissues and organs and even embryos in the lab represents the birth of a new kind of engineering, one that allows cells to show us what they need to build organisms, using their tools and following their rules.

Through this research, I have come to recognize a creative tension between genes and cells that lies at the heart of biology. Cells don't merely multiply, regulate, communicate, move and explore; they also count, sense force and geometry, create form and even learn.

You have never been just a gene or even a set of genes. Instead, you can safely trace your origins back to a first, single cell within your mother's womb. Once this first cell came into existence, it began to do things that are not written in DNA. As it multiplied, it created a space in which the emerging cells assumed identities and roles, exchanged information and used their positions relative to each other to build tissues, sculpt organs and eventually produce a whole organism — you.

The 20th century was the century of the gene. It dawned with the rediscovery of the work of Gregor Mendel and confirmation that the essence of heredity lies in discrete units of biological information passed on from one generation to another. As the century progressed, an exhilarating sequence of discoveries placed those units into chromosomes and showed that they could be altered or mutated, and that some of these changes are linked to our health. Most significantly, genes were shown to be made up of DNA within that iconic double helix.

This was followed in quick succession by the elucidation of the genetic code and of the mechanism that translated genes into proteins and how these perform functions like carrying oxygen around the body or configuring a cytoskeleton. Later, genes were linked with development, and the century closed with the unveiling of a draft of the human genome and a sense of triumph that we now could read the "book of life" — and, more recently, even rewrite it.

These discoveries invited exalted claims that we now held "the complete set of instructions for our development, determining the timing and details of the formation of the heart, the central nervous system, the immune system and every other organ and tissue required for life," as Charles DeLisi once said. With such an amazing story to tell, it is little wonder that the gene has exerted such a spell on us.

But the genome is not actually a blueprint for an organism or its architect. Insofar as it contains any design, it is the design for another genome, not for an organism.

It would, of course, be foolish to argue that genes have nothing to do with who and what we are; they do. But they are not the masters of our being and fate that they have been made out to be. The notion of a toolbox is often bandied about without ever answering the question of who or what is selecting and using the tools. That elusive entity is the cell.

Nevertheless, the gene-centric view has established a form of tyranny where genes reign supreme over not only our past and present but also our future. At one extreme of this mindset, psychologist and geneticist Robert Plomin has said that pretty much everything about who and what we are, and who and what we will become, is written in our genes from the moment of our conception. He has suggested that social interactions or environment can do little to override the power of genes; we can only acknowledge our genetic selves and work around them. Such views are a natural extension of the idea that the genome contains our operating instructions.

But without a cell, a genome doesn't mean much. For creatures ranging from a virus to a human being, it is cells that give meaning to those sequences of nucleic acids by translating stretches of them into proteins. It is cells that use those proteins to take care of and repair themselves. Most importantly, it is cells that work with other cells to construct an organism. The cell decides which genes are used for what purposes and when, rather than being at the mercy of the genes, a feat on most magnificent display during the development of an embryo.

Late in the 19th century, it was established science that the cell was the fundamental basic unit of biological systems. The consequences of this realization were ignored, however, first because of a lack of understanding of how cells worked and later because of our obsession with genes. This is finally being righted with the discovery that we can coax cells to build embryo-like structures in a lab, without tinkering with their genomes, just using their language to communicate with them and steer their actions where we want.

It's remarkable, really: If you grow cells on a flat surface, they will spread out or round up, depending on the culture in which they are being grown, maybe even following programs of gene expression and adopting different cellular fates. But they will not engage in making an organ, much less an embryo.

Place the same cells in three dimensions, and depending on the initial numbers, they will generate either chaos or an embryo-like structure, weaving sheets that they can mold into different shapes — the tubes of the gut and spinal cord, the chambers of the heart, the furls of the brain.

When we obtain embryo-like structures, we are able to see why cells with the same genes use those genes differently, creating different spaces in different amounts of time and thus building the various tissues and organs of which we are made. Same genes, different outcomes, depending on the cells’ immediate environment. Out of the interactions and communications of trillions of cells, we emerge. The cell is the architect, the master builder.

A critic might protest that by highlighting the power of cells over that of genes, I am endowing cells with mystical abilities that do not advance our understanding of life any more than reductionist genetics. And it's true that these are early days in our understanding of the workings of groups of cells, how they contribute to gastrulation, to the building of an arm or a heart.

But it is clear that we are not going to make progress simply by cataloging the genes that cells express; we need to engage with the emergent properties that give rise to cells and that arise from the workings of cells, find the elements that drive them and learn to control them. Cells can't always be easily enumerated, measured and compared in the way that DNA and gene mutations can, but we do have some techniques for observing cells’ activities, particularly how they communicate and coordinate with each other.

The electrical activity of networks of neurons can be recorded in electroencephalograms and other scans; the performance of the heart can be monitored through electrocardiograms; the work of the immune system can be measured in specific outputs as body reactions. While we currently lack comparable techniques for monitoring the activities of cells in embryos and our tissues, let alone for quantifying how cells generate space and time during embryonic development, we are learning.

As we study embryo-like structures and come to better understand the operations of our cells, we will be able to explore in more detail the nature of the relationship between cells and genes and write new pages in the history of biology. It may be that cells lose or cede control to genes in cases other than cancer. What a remarkable thing that would be: a Faustian pact that is continuously being renegotiated in each living organism. But until we recognize the power of cells, such dynamic aspects of biological systems will remain invisible to us.

Cells hold a creative potential that genes cannot dream of. Whereas genes provide a substrate for transcription and replication, cells display a broader repertoire of activities in the versatile and complex work of proteins, when sculpting tissues and organs into embryos and fully-fledged organisms.

It is often asked how such similar genomes can build such different animals as flies, frogs, horses and humans. However, the real wonder is how the same genome can build such different structures as eyes and lungs in the same organism. Let us give cells their due.

Taking a cell's-eye view of life may at times feel messy. It will definitely be messier than the digital, abstract view of ourselves that we get from studying our genes, but we should remember that this is the start of a new period in the history of biology and that, as in other periods of science, there will be some fog in the beginning.

A cell's-eye view of biology will provide a rich understanding of our being and our past. It will articulate the tussle that went on when animals appeared on the face of the Earth, the tension between selfish genes and the intrinsic cooperative nature of cells. This was resolved with the cells taking control of the genome to explore the creativity inherent in their powers and creating a divide — the germ cells — for a safe passage of the genes to the next generation, where the story repeats itself.

Looking at us from the perspective of cells brings us closer to other animals — far closer than the overlap in genomes — and the uncannily similar sketch of the early body suggests a grand design to life that we are just beginning to uncover.

A shift in our understanding of how we are made and who we are is underway: Genes, rather than determining every detail of biology, are integrated into the activity of cells. I can see a future in which a cell-based understanding of biological systems promises to help us tackle diseases and improve our lives with even more benefits than are being afforded by our current understanding of the gene. We can get a glimpse of this in the success of immunotherapy, where immune system cells are trained to hunt down and destroy tumors, as well as in the promises ahead in understanding how cells age and how this process can be reversed.

As cells spill their secrets, revealing the ways in which structure and function develop side by side, the possibilities for regenerative medicine will be nearly boundless. We do not yet know much about how cells come together to use the genome, but the answers are out there, starting to come out in the workings of our embryo-like and organoid cellular marvels. The century that is now well underway is, and will be, the century of the cell.