Vision for the Future: The Hunt for Factor X

Vision for the Future: The Hunt for Factor X


Laser continued on as the standard treatment
for diabetic retinopathy for decades, but the vision of the people getting the treatment
never really improved, it only stopped declining. And laser mainly treated proliferative diabetic
retinopathy, having little effect on the leaky veins of diabetic macular edema. People in
the diabetes eye care community wanted more than just halted destruction of vision. They
wanted to improve the vision of those with proliferative diabetic retinopathy, and find
better treatments for macular edema. Researchers started exploring at the molecular level,
to find what they referred to as ‘Factor X.’ The question of why do diabetic patients develop
so much blindness was thought to be due to Factor X. People proposed it in the 1940s
and 1950s. Factor X was thought to be a molecule produced in the eye, one that increased when
the eye was deprived of oxygen, due to high blood sugar, and prompted blood vessel leakage
and growth. With those criteria in mind, researchers ramped up efforts in the late 1970s. Labs
around the world, including the lab of Dr. George King, Research Director at Joslin Diabetes
Center, set up experiments to test any molecule that seemed to fit the bill. Over a few decades
they tested dozens of possibilities, but couldn’t pin down the elusive Factor X. Then, in the
mid 1980s, a researcher at Beth Israel Deaconess Medical Center named Harold Dvorak identified
a molecule 50 times more potent than histamine, a well known cause of blood vessel leakage.
Not long after, Dr. Napoleon Ferrara, of the biotech company Genentech was able to clone
the molecule, allowing him to hone in on it’s exact functionality. He found that not only
did the molecule cause blood vessels to leak, it also caused them to grow. He called it
vascular endothelial growth factor, or VEGF, for short. It was studied in cancer at first
in the lab of Dr. Judah Folkman at Children’s Hospital. Dr. Folkman published a paper showing
that VEGF increased in the oxygen deprived cancer cells, confirming that it fulfilled
two of the three criteria for the mysterious Factor X. So when the oxygen is going down,
the VEGF is being produced much more, and this VEGF then caused leakage and blood vessels
to grow. When we were looking at this and I saw that report, I looked at it and said
‘That’s exactly what we need in the eye to mediate the problems from diabetes.’ Dr. Aiello,
Dr. Beetham’s grandson, and then a research fellow in Dr. King’s lab, suggested they study
VEGF at Joslin to find out if it is produced in diabetic eyes. Their lab contacted colleagues
from around the world to gather enough eye fluid samples to study in culture dishes,
ranging from no diabetes to significantly uncontrolled diabetes. We were able to take
those fluids from the eye and measure the VEGF in them and also look at whether or not
this was a time when there was leakage or permeability or blood vessel growth going
on. Amazingly enough, particularly in diabetes when we had these complications, the levels
of VEGF in the eye were hugely high. Very very elevated. Either very early in the disease
or in non-diabetic eyes, the levels were very very low. The elusive Factor X had been confirmed.

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