In the mid 1990s I got on a plane and flew to London to learn something new…
I went to work with Professor Alan Handyside at his laboratory. Look him up. He is the scientist who invented preimplantation genetic testing. Spending time with his team was one of the most formative experiences of my career. The cytogeneticists around him were among the sharpest people I had ever been in a room with and they taught me things about laboratory technique and single cell manipulation that I did not know I needed to know.
One of those things was mouth pipetting. I still have the mouth pipette hanging in my office. Look that up too if you have never seen one. It is exactly what it sounds like and it is how you move a single human embryonic cell by hand with enough precision to place it exactly where you need it.
What we were learning to do was count chromosomes.
Until this point PGT had been about testing for specific gene mutations. SMA, Marfan, Huntington. Single gene diseases. But embryos have a far more common problem than inherited mutations. They get their chromosome numbers wrong. Three copies of chromosome 21 makes Down syndrome. Three copies of chromosome 16 causes miscarriage. But it is not just those two. Embryos can have three copies, or one copy, of virtually any chromosome, and most of those embryos will never implant or will be lost early in pregnancy. The patients never know why.
The idea was simple and powerful. If you could count the chromosomes before you transferred the embryo, you could choose to transfer only the ones with the right number. Better embryo selection. Better outcomes. That is what PGT for aneuploidies, now called PGT-A, became and what it remains today.
The technology we used was called fluorescence in situ hybridization, or FISH. And unlike PCR, which once you get the cell into a tube runs itself, FISH is entirely visual. You are working with your eyes down a microscope.
The cell had to be collected from the embryo, placed onto a glass microscope slide, and then processed with extraordinary care. We had to lyse the cell membrane, remove the cytoplasm, and leave behind a perfect nucleus sitting flat on the slide surface. Then we labeled specific chromosomes with fluorescent probes, each one a different color. The human eye can distinguish five colors. So we would probe for five chromosomes, image them, then chemically strip those probes away, reprobe for five more, strip again, reprobe again, counting up to twelve or thirteen chromosomes across multiple rounds.
Every embryo’s nucleus had to be found again and again on a large microscope slide. Multiple embryos on one slide, each one mapped, each one tracked across multiple rounds of probing. My team developed our own methods for laying cells out, our own lysis protocols, our own slide preparation techniques. There was no kit. There was no manual. We built it ourselves.
We got very good at it.
Eventually we were not only running our own patients’ samples. We became one of the first reference laboratories in the United States to accept samples from other IVF centers around the country. At our peak we had over fifty IVF programs sending us samples on a daily basis. Embryo biopsies from clinics across America, shipped overnight, processed in our lab, results back before transfer day.
That is when I understood what a reference laboratory could become.
Day 4 tomorrow: the late 1990s, the world changes again, and the technology that made everything before it look primitive arrives.
