For decades, the central dogma of biology has shaped our understanding of life. It asserts that DNA, as the blueprint of life, dictates everything—our body, mind, and behavior. But what if this foundation is fundamentally flawed? Picking up from our earlier blog, this blog (6) will explore why the gene-centric approach to biology has failed to predict common diseases and what might work instead.
We’ll start with a question: If genes aren’t the blueprint for life, why have we focused so heavily on them? Based on the works of Professor Dennis Noble, I’ll walk you through why measuring genes and their associations with diseases often doesn’t work. We will also explore an alternative approach—one that focuses on the functional networks that control the genome and even allow it to be edited.
But before diving into those complexities, let’s begin with a simple explanation of the genome itself. For readers who may not be familiar with the technical details, the genome is a long thread of molecules within our cells, made up of four nucleotides—A, T, G, and C. In humans, the genome contains around three billion of these nucleotides. This number will become significant later on. Every cell in our body (except red blood cells) contains a complete set of DNA.
Image Credit: genome.gov
Here’s the critical point: as molecules, these nucleotides can only act in predictable, chemical ways. They pair up—A with T, G with C—following simple rules of chemistry. They have no choice in this pairing. When we zoom in too much on the genome and its sequence, we lose the bigger picture.
According to professor Noble, It’s like trying to understand a sentence by focusing on individual pixels of each letter. The genome has been famously described as the "book of life"—the blueprint for creating us, body and mind. But if this were true, all the logic of life would have to be encoded in the genome itself—and it’s not.
if you look for the "if-then" conditional logic that controls biological processes, you won’t find it in the genome. Yes, there are genetic switches—small DNA sequences that turn genes on or off—but those switches are controlled by larger physiological networks, and not by the genome itself.
So, where are the real control mechanisms of life? They’re in our cells. Cells are complex, packed with structures formed from lipid (fat) membranes and protein channels. These channels respond to chemical and electrical signals from the environment, allowing cells to make decisions—to turn on or off specific functions. These are the true conditional processes that enable organisms to behave in ways that are much more dynamic than genes alone could explain. This is crucial because it highlights a significant flaw in 20th-century biology—the belief that genes alone shape life. The reality is far more intricate.
The Genome: A Blueprint or a Dynamic System?
The genome is often described as the "blueprint of life," but this analogy is misleading. While the genome contains the genetic information necessary for building and maintaining an organism, it does not provide the complete instructions for life's complexity. So what drives the activity in our cells?
Proteins are the true drivers of activity in living organisms. It’s a basic chemical fact: DNA makes RNA, and RNA makes proteins. But while this process is simple, it doesn’t stop an organism from editing its own genes. Some biologists argue that it’s impossible to reverse this process—from protein back to DNA—but you don’t need to. The body knows how to control its genes without reversing the chain.
Image Credit: NIH
Living Organisms Can Change Their DNA
One of the most striking contradictions to the central dogma is that organisms can and do change their DNA. A clear example comes from our immune systems. During the pandemic, for instance, our immune cells altered their DNA to create millions of new protein shapes (immunoglobulins) that could fight off viral invaders. This is a critical function of our immune system and shows that the rigid, one-way direction of DNA → RNA → Protein is not a barrier to adaptive changes in DNA when necessary.
The New Focus: Functional Networks, Not Genes
Cells, not genes, are the fundamental units of life. They are complex structures that contain a variety of organelles and molecules that interact in intricate ways. These interactions, rather than the genetic code alone, control the behavior of cells and organisms.
So, where do we go from here? The answer lies in studying the functional physiological networks that govern life. These networks—interconnected systems of cells, proteins, membranes, and electrical signals, are the true drivers of biological processes. Genes, on the other hand, are merely one component of these networks.
What’s fascinating is that these functional networks are highly sensitive to external factors such as diet, environmental changes, and social interactions. These influences can modify how our networks function, independent of any changes in our genetic code. Understanding these dynamic, living processes is crucial for tackling diseases that don’t respond to gene-centric approaches.
Image Credit: Dennis Noble
Can We Study These Networks? Two Breakthrough Examples
Let’s look at two examples of research that show how functional networks control genetic expression:
Calcium Signaling Pathways: A study led by Dick Chen at New York University demonstrated how tiny calcium molecules entering the cell surface can create a signal that is transported along molecular "tubulins" to the nucleus, where it regulates gene expression. This rapid communication between the cell membrane and DNA takes only seconds, showing that external signals can control genetic activity through complex cellular networks.
Calcium-Controlled Gene Expression: At Oxford University, researchers led by Anant Parekh uncovered how calcium entering the cell at two different sites generates signals that travel via tubulins to the nucleus. This process results in changes to gene expression, showing that the cell’s functional architecture is intimately involved in regulating the genome.
These findings demonstrate that living cells possess intricate systems for controlling gene expression in real-time, a concept entirely ignored by the central dogma.
A Call to Scientists: Unravel the Functional Networks
We are at the cusp of a new understanding of biology, one that prioritizes the study of living networks over static gene sequences. The task for the next generation of scientists is to unravel how these functional networks operate and how they mediate communication between the environment and our DNA. This is where the future of medicine lies.
The Flawed Assumption of DNA Self-Replication
Another significant assumption in evolutionary biology is that DNA is the self-replicator of life, autonomously responsible for making copies of itself. While it's true that nucleotide pairing—A binds with T, and G binds with C—helps ensure that DNA replicates, it’s not an error-free process. In fact, if left unchecked, hundreds of thousands of replication errors would accumulate every time a cell divides. This is where proteins in the cell step in, actively cutting and correcting these mistakes. Therefore, DNA replication is not an autonomous process; it depends on the cell’s machinery to maintain its integrity, further undermining the notion that DNA can operate independently of living cells.
The Replicator-Vehicle Distinction
The final dogma we must challenge is the belief that DNA (the "replicator") is distinct from the cell or organism (its "vehicle"). In reality, DNA is inseparable from the living cell. It requires the cellular environment to replicate and function. This fact highlights a core misunderstanding: genes cannot be viewed as isolated entities controlling life from a distance. Life’s processes are deeply embedded in the structures and networks that surround and interact with the genome.
Genome Sequencing: A Broken Promise
Thirty years ago, the Human Genome Project promised a revolution in medical treatments by decoding the human genome. The expectation was that once we knew which genes caused specific diseases, we could cure them by correcting or replacing faulty genes. However, this promise has only materialized for a few rare, monogenic diseases—conditions caused by a single gene. These diseases, such as cystic fibrosis, account for less than 5% of all human ailments.
Robustness, or the ability of biological systems to remain stable despite disruptions, further complicates matters. When one gene or pathway fails, other systems often compensate, masking the effect of any single gene. This robustness is why genome sequencing cannot offer the predictive power it promised. In contrast to single-gene disorders, the vast majority of diseases are resilient to genetic perturbations, and this resilience makes it difficult to predict outcomes based solely on genetic data.
Professor Dennis Noble's Experiment on Heart Rhythm
Professor Dennis Noble, conducted an experiment to investigate the role of a specific pacemaker protein in regulating heart rhythm. This protein, known as HCN4, is responsible for approximately 80% of the heart's rhythm.
Noble and his team blocked the HCN4 protein in heart cells and observed the resulting changes in heart rhythm. Surprisingly, they found that blocking this protein only reduced heart rate by 10%. This unexpected result challenged the prevailing view that HCN4 was the primary driver of heart rhythm.
The experiment demonstrated that heart rhythm is a complex process involving multiple factors, not solely dependent on a single protein. This finding highlights the importance of a systems biology approach, which considers the interactions between various components of a biological system, in understanding complex physiological functions.
The following video, which might seem unrelated, however encapsulates this whole adaptable nature of our cells, rather perfectly!
In conclusion, the promise of the Human Genome Project has not been fulfilled because it was built on flawed assumptions. Genes are not the blueprint for life; they are part of a larger, more complex system. If we want to tackle the diseases of the 21st century, we must move beyond the gene-centric view and focus on the networks that truly control life, which is what we will look into in our subsequent blogs.
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