So if a single isoform is used to switch on VEGF then you do get increased vasculature and you get increased vessels but they leak and you get a bloody mess. Literally, you can see it in the mouse ear; it's very easy to see. So the... but with VEGF which switches on the gene, gene expression which produces the precursor messenger RNA, precursors of the... and the precursor messenger RNA is split into the different messengers and they produce this splicing isoforms. And if you do that, switching on the endogenous gene, the vessels don't leak. So clearly you need a cascade, it's very clear that you need these other isoforms, for either strengthening the walls of the capillaries or whatever... moving onto the next stage for maturing them and so on. And it's known that angiopoietin would be the next in the list, but that's yet another gene, that hasn't been studied yet.

So the next experiment was to try in a rabbit. The rabbit's skeletal muscle, the hind limbs of rabbits and this was done, as I said, by Yale and also by a group at Duke, using Sangamo's zinc fingers for switching on VEGF. Well, both experiments showed that if, in the ischemic – ischemic means lack of blood supply – in artificially ischemic rabbits, it's rather cruel, but they tie off the arteries and so there's no blood supply but that's how medicine progresses. The rabbit's injected with VEGF, grew new blood vessels and you can measure the amount, you can measure the blood flow and so that was regarded as a success, in fact the rabbits were cured. They grew new blood vessels. And there were other experiments of this sort, so the... Sangamo applied to the FDA, Food and Drug Administration, who license trials and this was in last... 2004 in March... April 2004 the FDA sanctioned the use of clinical trials and having the money, as I said, from Edwards Life Sciences, they were able to start recruiting patients and people are eager to come to try there for their... apparently the people with peripheral and arterial disease have great pain, they can't work... it's very debilitating. So they enrolled patients and the trials were planned and they've all been executed by somebody at NIH, nothing to do with either Edwards or Sangamo, these are totally independent trials and not with either Frank Giordano or the man at Duke, that's how these things are done. And they... it's a double blind with placebo trial and started last August by which time they'd recruited sufficient patients for a what's called a phase one/phase two trial. So that's nearly a year now and as I say double blind, nothing is reported, however if in trials of this kind there's an adverse event, it's called a serious... an adverse event AE and SAE, not a stamped addressed envelope, but a serious adverse event... then the trials are stopped. That's the way it works, they're monitored all the time.

Well, nothing's been reported so whether they're doing any good or not, I don't know. You would have heard if they... We would have heard. Now if they'd been doing miraculously with people jumping up and saying their lives had been transformed, you might have heard as well. Because if that happens and that happens very rarely then the ethics is... because some patients are getting the drug and other are not, but if you have enough patients saying we're getting better, then it looks as though the drug is working. It's a pity but they have to then stop the trials and give it to everybody. That's unfortunate in a way if you think, taking a hard, cold look at it, because if you still have to do the dosing, can see the dosing hasn't been improved and see when people get a bit better, they might be a lot better if the trials were to go and be able to establish the dosing issue. So people aren't encouraged to leap up and say I'm cured or I'm feeling better, so I know this from other... experience I've read about. So that is number one, so zinc fingers are in patients. And the number of patients is several hundred, 400, 500. But various degrees of peripheral and arterial obstructive disease. There are many ways of approaching this when you plan these trials. I know this from my experience with Cambridge anti-body technology, you sometimes take moderately disturbed... moderately affected people in the beginning but the pressure is, if you've got a serious disease, the pressure is to give them to the most seriously affected, because they're the ones who need it most. But you can see... you can't learn much from that. As much as you learn from only moderately handicapped people. So... so the patients chosen for the PAD trials actually involve a spectrum. Whether there were enough people I don't know, I don't know enough about it.