We asked Dr. Parry Guilford what it was like finding the gene mutation that has affected so many families worldwide. What was that “Eureka moment” like?
Dr. Parry Guilford:
We were watching the sequence of CDH1 coming up on the DNA sequencing machine’s screen as it was being read real time, letter by letter. In this case, it was a fragment of the CDH1 gene belonging to members of a large New Zealand Māori family with generations of stomach cancer. Worst case scenario was that it would take us 20,000 years at our current rate to look at the whole genome and find the bloody thing. But the week before, we had run a different type of DNA test that told us something wasn’t right in this fragment of CDH1, a piece of DNA somewhere near the middle of the gene, a fragment that measured about one tenth of one millionth of the human genome.
CDH1 was a top candidate. There are 20,000 genes in the human genome, but this one, along with a handful of others, made really good sense (although it’s easy to tell yourself something makes good sense when the alternative is super tedious). So, we broke the CDH1 gene from people with stomach cancer into bite sized fragments and started to check each fragment one by one, looking for an error, a mistake, a mutation.
This fragment was 176 letters long (the whole genome has 3 billion letters). We were watching each letter appearing on the DNA sequencer’s screen, clicking down one by one, like something from the old Space Invaders video game. What we were looking at resembled a long, long bar code (176 bars long), with each bar being revealed at the top of the screen about every three seconds.
On the sequencer, beside the fragments from the stomach cancer families, was a fragment from someone else, someone who had no history of cancer. What we were hoping to see was those two barcodes diverge, one bar of the code from the cancer families to look wrong.
At 175 letters I gave up. I pushed back in my chair and said ‘nooo (words to that effect), it’s not there’. Then I heard my colleagues yell ‘No, look!’ And there it was, the barcode at position 176, exon 7, in the CDH1 gene, in the wrong place, all askew. We had it.
Moral of the story is: watch everything to the end, the real end.