The Day We Thought Our Genes Changed
Imagine being told that every biology textbook gets something fundamental wrong about your genes—that rather than having identical DNA throughout your body, your different tissues might actually contain surprising genetic variations. This is exactly what a team of scientists proposed in 2009, setting off a scientific controversy that would challenge core principles of genetics and reveal how scientific knowledge evolves through rigorous debate. At the center of this controversy was a gene called BAK1 and a mysterious condition called abdominal aortic aneurysm—a deadly bulging of the body's main blood vessel that can rupture with catastrophic consequences.
Abdominal aortic aneurysms affect approximately 4-8% of men over 65 and are often asymptomatic until rupture, which has a mortality rate exceeding 65% 5 .
This is the story of how a single scientific paper ignited a firestorm of debate, forcing geneticists to reconsider some of their most fundamental assumptions about the relationship between our genes and our health. It's a tale that takes us to the very heart of how science self-corrects and advances.
For decades, a fundamental principle has guided our understanding of genetics: with few exceptions, every cell in your body contains the exact same DNA. This concept forms the bedrock of genetic medicine—the idea that we can diagnose genetic conditions through a simple blood test because the DNA in your blood cells perfectly matches the DNA in your brain, your liver, and your heart.
Same DNA in every cell (with few exceptions)
Blood samples used to diagnose conditions affecting any tissue
This principle made practical sense. Doctors couldn't routinely sample tissue from every organ, but if DNA was consistent throughout the body, they could use accessible blood samples to diagnose and understand genetic conditions affecting any tissue. This assumption underpinned decades of genetic research and clinical practice 9 .
Abdominal aortic aneurysm (AAA), the disease at the center of this controversy, represents a serious vascular condition where the main blood vessel supplying blood to the body gradually widens and weakens. Like a weak spot on an overinflated inner tube, the aortic wall can eventually tear, causing massive internal bleeding. AAAs are particularly insidious because they typically develop without any symptoms until catastrophe strikes. By the time symptoms appear, the mortality rate exceeds 65% 5 .
In 2009, Dr. Bruce Gottlieb and his colleagues at McGill University published a paper that would challenge the genetic status quo. They were studying the BAK1 gene, which produces a protein that promotes programmed cell death (apoptosis). Since excessive cell death in the aortic wall had been linked to aneurysm development, BAK1 seemed a logical candidate for investigation 1 6 .
Do BAK1 gene sequences differ between blood samples and aortic tissue samples from the same individuals?
What they found was startling: specific variations in the BAK1 gene sequence appeared in aortic tissues (both diseased and healthy) that were completely absent from matching blood samples 1 . These same variations were extremely rare in genetic databases, appearing in less than 0.06% of recorded sequences 6 .
The researchers proposed that multiple gene variants might preexist in "minority" forms within specific tissues, and certain conditions could cause these minority variants to be selected and amplified. In AAA, perhaps mechanical stresses on the aortic wall created an environment that favored certain BAK1 variants 1 .
To understand both the original findings and the subsequent controversy, we need to examine exactly how the researchers conducted their work:
The team collected matching blood and abdominal aortic tissue samples from 31 AAA patients and 5 individuals with healthy aortas 1 6 .
From blood samples, they extracted genomic DNA—the complete genetic blueprint. From aortic tissues, they extracted RNA (which reflects active genes) and converted it to complementary DNA (cDNA) for comparison 3 .
Using sophisticated laboratory techniques, they determined the exact genetic sequence of BAK1 in each sample, specifically looking for single nucleotide polymorphisms (SNPs)—tiny variations at individual positions in the genetic code 1 .
Critically, they compared sequences between:
| Sample Type | Genetic Material Analyzed | Number of Cases |
|---|---|---|
| Blood from AAA patients | Genomic DNA | 31 |
| Aortic tissue from AAA patients | RNA converted to cDNA | 31 |
| Blood from healthy controls | Genomic DNA | 5 |
| Aortic tissue from healthy controls | RNA converted to cDNA | 5 |
When Gottlieb and his team compiled their results, they discovered something unprecedented: the BAK1 gene sequences from aortic tissues showed consistent differences from those in blood samples. These weren't random mutations, but specific SNP patterns that appeared systematically in aortic tissue while being absent in blood 1 .
| Genetic Position | Variant Type | Found In | Frequency in Databases |
|---|---|---|---|
| Codon 42 | G>A change | Aortic tissue | <0.06% |
| Codon 52 | T>C change | Aortic tissue | <0.06% |
| Codon 81 | C>T change | Aortic tissue | <0.06% |
The aortic tissue had acquired unique mutations not present in blood cells
The process of reading genes and creating RNA messages had been modified in aortic tissue
Multiple BAK1 variants preexist in tissues at low levels, and certain conditions cause specific variants to be selected and amplified 2
The researchers leaned toward the third, most radical explanation—that our tissues might contain multiple genetic variants and that certain conditions can drive the selection of particular variants, almost like evolution happening within our own bodies 1 .
The genetics community reacted to Gottlieb's provocative findings with skeptical interest. While the idea was intriguing, many researchers identified what they considered significant methodological problems. The debate played out in the pages of Human Mutation through a series of letters between the original authors and their critics 7 .
The most serious criticism concerned a genetic "doppelganger"—a pseudogene called BAK2 located on a different chromosome. Pseudogenes are evolutionary relics that resemble functional genes but have lost their protein-making capacity 3 .
Dr. Eli Hatchwell was first to raise this concern, noting that the variant sequences Gottlieb found in aortic tissue perfectly matched the BAK2 pseudogene sequence rather than rare BAK1 variants. He suggested the researchers might have accidentally sequenced BAK2 while thinking they were sequencing BAK1 3 .
The original authors defended their methods, noting they had used RNAse treatment to eliminate genomic DNA contamination and had designed their experiments to distinguish between BAK1 and BAK2. They pointed to specific nucleotide positions where their sequences matched true BAK1 rather than the pseudogene 2 .
Critics also questioned the proposed mechanisms behind the genetic differences. Küry and colleagues noted that the types of DNA-to-RNA changes observed (G>A and T>C) didn't match known patterns for RNA editing, a process where cells modify RNA sequences after genes have been read. Only one of the three changes (C>T) corresponded to known RNA editing mechanisms 3 .
Gottlieb's team countered that new forms of RNA editing were being discovered, including exactly the types of changes they had observed in other genes from brain tissue samples 2 .
Skeptics noted several puzzling aspects of the findings. How could all five healthy control subjects have the same rare variants if these variants were disease-related? Why were the variant sequences completely homozygous (identical on both chromosome copies) in aortic tissue but entirely absent from blood? 3
The original authors acknowledged these puzzles but maintained they reflected genuine biological phenomena rather than methodological artifacts 2 .
| Research Tool | Primary Function | Importance in BAK1 Study |
|---|---|---|
| RNAse Enzymes | Degrade RNA while leaving DNA intact | Prevent RNA contamination in DNA samples |
| Reverse Transcriptase | Convert RNA to complementary DNA (cDNA) | Allow comparison of RNA sequences to genomic DNA |
| PCR Primers | Target specific gene sequences for amplification | Selectively copy BAK1 gene regions for sequencing |
| DNA Sequencers | Determine exact nucleotide sequence | Identify specific genetic variations |
| BAK1-specific Probes | Distinguish BAK1 from similar sequences | Avoid cross-reaction with BAK2 pseudogene |
Though the specific claims about BAK1 tissue-specific variations remain unconfirmed, the debate itself advanced genetic science in several important ways:
The exchange emphasized the critical importance of careful controls when comparing sequences across tissues and using different molecular templates (DNA vs. RNA) 3 .
While not proving tissue-specific genetic variation, the debate encouraged researchers to be more open to exceptions to genetic uniformity 9 .
The episode demonstrated science's self-correcting nature—how bold claims face rigorous community scrutiny, leading to refined understanding 7 .
The journal's editors ultimately called for additional research to resolve the questions raised, noting that "further comment on this study must be accompanied with thorough, original research aimed to either validate or refute the original findings" 7 .
The BAK1 gene controversy represents science in its most dynamic state—a cycle of claim, counterclaim, and methodological refinement. While the original theory of tissue-specific BAK1 variants hasn't gained widespread acceptance, the debate pushed geneticists to examine their assumptions and improve their methods.
What makes this story particularly compelling is that neither side was entirely right or wrong. The critics successfully identified methodological weaknesses, but they couldn't definitively prove the pseudogene explanation. The original authors couldn't convince the scientific community, but they raised important questions about genetic heterogeneity that continue to resonate in genetics research.
This episode reminds us that scientific knowledge doesn't advance in straight lines but through a messy, contentious process of challenge and response. The next time you read about a "groundbreaking" discovery, remember the BAK1 story—the initial claim is just the beginning of the conversation, not the final word.
Perhaps the true lesson of the BAK1 controversy is that our genes still hold many mysteries, and as one group of researchers noted, we may need "next-generation genetic databases" and new analytical tools to truly understand the complex relationships between our genes and our health 9 .