FRONTLINE presents Organ Farm
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Bishop is the president of Infigen, Inc., a private biotechnology company, which specializes in cloning and gene mapping. In this interview, he explains how the company is working on creating and cloning genetically modified pigs and the impact this will have on xeno-transplant technology. (Interviewed Winter 2001)

Michael, tell me, when you want to clone a pig, what do you have to begin with?

To clone a pig, you need to start with two pieces of material. One is you need a carrier egg that you've removed the DNA materials from, and then you need a cell that you want to clone that will develop in to the animal that you desire.

How do you actually get the eggs to begin with?

The eggs are retrieved from ovaries that are brought in to the laboratory from abattoirs throughout the community. We extract those eggs directly from the ovaries. . . We mature the eggs in a petri dish until they reach appropriate time in development, and then we remove the DNA materials from those eggs, and replace it with the cell containing the DNA that we want to clone, and make an animal from. . .

How is [the DNA] removed?

The DNA is removed from the cell by making a small hole in the side of the egg with a small fine tool, an instrument that we make specially in the lab. Basically the DNA is sucked out of the egg using a vacuum. We hold the egg in place with vacuum and then we withdraw the DNA material with a vacuum.

So you then have an egg that is, in a sense, a blank canvas, looking for instructions. Where do you get those instructions from?

. . . [The] DNA is fused in with a short electrical fusion stem, and then allowed to sit and incubate in the cytoplasm of that egg for a set period of time, before we jump start, as it were, the division of that cell in a process we call activation. That is done chemically. At that point, the cell begins to divide, pig cells multiple and develop in to a developing embryo, and eventually a fetus, and then hopefully in to a live piglet.

So the moment of activation is the moment at which that empty egg accepts the new instructions.

The activation process is a critical step in the overall process of embryo development. At that point, the cell begins to take its commands from the cellular material surrounding it, the DNA nucleus driving it, and it starts to divide, which is critical for it to become an embryo.

So that division goes on in the laboratory until what stage?

In pig, once the activation process is initiated, those embryos are immediately transferred to an embryo transfer site, where a recipient animal is waiting, properly synchronised in her own . . . cycle to receive these eggs. And these eggs are surgically implanted in a recipient animal for the process of pregnancy initiation takes place, and the animal acts as an incubator and develops these embryos in to fetuses and eventually live piglets are born.

The work we're doing hereÉ will create a system that within a few hundred days you could create an animal of the correct genetic geno type whose organs could be compatible to any human being that had a specific need. There is also a step where you would like to introduce some information in to the system. Give me a sense when in the cell culture stage you try to influence events.

. . . Once we've established the primary cell culture, we take a sub culture of those cells, and introduce a human gene in to the DNA material of those cells by electro proration step. That allows the nucleus of those cells to be more porous, so that DNA will drive in to the chromosomes and the DNA material of the porcine or pig cell. And then under selection pressure, in the culture media, we're able to differentiate the cells that took up the human gene, or did not take up the gene. . . And then [we can] create a culture of cells that did take up the gene, and use those cells in the cloning process. . .

You are trying to provoke a novel genetic event. How can you find the cell that's done what you want?

The real art in the selection process is to be able to identify that cell that took up that specific DNA. And there is the technology challenge: to create subculturing systems that allow you to after you have done the gene transfer, array those cells in such a culture situation that they can grow up and you can identify individual cell cultures, and identify which cell has taken up the DNA correctly. In an event that happens maybe once in every 100,000 or 1 million cells it takes a lot of screening of various populations of cells in order to identify which cell, and cell culture is specifically taken up the correct humanised DNA.

But you can do it.

With basically brute force, by covering several petri dishes, a mass array, if you have lots of incubators full of petri dishes that can handle large volume scale screening capabilities, with lots of assistance, and some robotics, you can quickly screen through many thousands of cell cultures, and identify the cell culture that's correctly taken up the specific gene of interest. . .

Give me a sense of the animal husbandry.

Cloning accelerates the production of these animals by saving the traditional generations of breeding, which can amount to literally thousands of days of hard work of breeding animals, selecting, rebreeding. Once you have identified the correct cell that has the humanised DNA, then you can make the same pig over and over and over again.

Give me a sense in the overview of what cloning can offer xeno transplant technology.

Cloning offers xeno transplantation technology the opportunity to explore to a greater extent the number of genes that may want to be inserted in to these pig cells, or to be knocked out in the pig cells, to make them more immuno acceptable. The cloning process, with its sub culture process, allows one, in the petri dish, to knock out not just one or two cells, but as many cells as possible, and to place in humanised cells in the same cell, in multiple realms of technology. . .

In the broad sense, cloning offers xeno technology a shorter time to the realisation of pig organs or animal organs being used directly as transplants for human patients.

You are able to humanise the organs, is that right?

In effect, we're able to humanise those organs by making certain genetic modifications, by adding certain genes to the cells that we clone, or knocking out certain genes so that they don't express, so that you have greater immuno acceptance of those organs. Once you've identified the correct culmination of genes to put in, and genes to knock out, then you have a cell culture that has an unlimited genetic source of material from which you can make piglets of the same genetic geno type over and over again. . .

Do you think the work you're doing here, if it succeeds, will impact on people's lives?

The work we're doing here will very much impact on people's lives, because it will create a system that within a few hundred days you could create an animal of the correct genetic geno type whose organs could be compatible to any human being that had a specific need.

So is the end goal a universal donor organ?

The end goal is to produce organs that are acceptable on a universal basis for all mankind, as for organ donors. . .

Do you need to take the public with you on this journey of science?

. . . We need to be responsible stewards of the science and technology that we're developing, and to include the public in the knowledge and understanding of, in an educational sort of way, as we develop this technology, so that they become comfortable with it, and understand its meaning to their human health, and the potential it has for improving the quality and length of life of people who vitally need these organs to live. ...

If a company like Infigen was to produce a litter of cloned transgenic piglets, what would be the significance of that event?

. . . The importance of putting a cloned transgenic pig on the ground, would mean that we would finally have the tools, the physical tools to explore a multiple array of genes that could be inserted in to the genom of the pig, and animals produce, so that we could explore opportunities for organ transfer in to human patients.

Do you think that event is a very long way away?

I think that event is likely to occur very, very soon. . .

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