Earlier this year, I had breakfast with George Church, professor of genetics and director of the Center for Computational Genetics at Harvard Medical School. (Click here to read my profile of Church in the New York Times.)
A pioneer in developing DNA sequencing technologies, and in researching everything from epigenetics and microbiomics to synthetic biology, Church has co-founded or advises over 20 companies. He also has launched the Personal Genome Project with a goal of sequencing the complete genomes of 100,000 volunteers.
When I asked Church what he was most excited about right now, he answered without hesitation: “I’m thinking a lot about using regeneration as the key to treatments and keeping people healthy.”
TR: You mean regeneration using stem cells?
Church: Yes, induced pluripotent stem (IPS) cells (see, “Growing Heart Cells Just for You”). This is where I’m putting almost all of my chips these days, because it combines many of my interests–genomics, sequencing, epigenetics, synthetic biology, stem cells. I don’t think people have fully appreciated how quickly adult stem cells and sequencing and synthetic biology have progressed. They have progressed by orders of magnitude since we got IPS. Before that, they basically weren’t working.
Is this because IPS cells are relatively easy to create and to engineer?
You can use them to reprogram genomes–not sequence them, but to reprogram them genetically and epigenetically. In other words you make the minimum changes it takes to get them where you want them to be genetically and epigenetically and then you program the cells into tissues.
What do you mean?
Let’s use stem cells in bone marrow as an example. They are easy to use and to get to work when you implant them in bone marrow. You might one day have three choices. You can have bone marrow from someone else that is matched to you, or that is from you, or bone marrow that is matched to you and comes to you, but is better than you. This better bone marrow might be [engineered to be] resistant to one virus, or to all viruses. It could have a bunch of alleles that you picked out of super centenarians, alleles that you have reason to believe are at least harmless and possibly helpful. So now you have choice, a patient who can take a good bone marrow that he might reject and you’ll be on immunosuppressants your whole life. Or you might use your own, or your own that might fix the cancer, or your own enhanced bone marrow. And you will be able to do that for almost every stem cell population. Some of them are a little bit harder to replace, though.
Does IPS really work to accomplish this regeneration?
We have good evidence that you can create an entire mouse from IPS cells.
Has this been done?
This has been done. They have used IPS cells to grow a mouse, and they made IPS cells from that mouse. They’re totipotent [able to make an entire organism], not merely pluripotent. We haven’t done this for humans for obvious ethical reasons, but we will do it. As far as I know the mice have done fine.
But haven’t there been some problems with mutations occurring with IPS-generated tissue?
We have a recent paper in Nature that shows that when you make human induced pluripotent stem cells you actually do get mutations in coding regions at a slightly elevated level. But I think this is temporary. We’re going to use this information as an assay to make the process work better, to correct problems. You will be able to use this to improve the quality of gene therapy because that’s been the problem with gene therapy the last ten years.
How far are we from testing that in humans?
Almost everything I’ve described has been done in rodents, so we’re talking about years, not decades. It’s shorter than the Human Genome Project [which took 13 years], not less expensive, but definitely shorter.
Could this technology be used to support personalized genomics, and can it verify a personal risk factor?
That’s why we do IPS. We want to establish an IPS line for every single person who gets sequenced in the PGP [Personalized Genome Project, which aims to sequence 100,000 people].
When is regeneration likely to happen in humans?
There is much to be worked out. But here’s the leap. If you want to accelerate this, you have to pick an intermediate target that doesn’t sound so scary. So you’ll start out with bone marrow patients. And you’re going to basically make a synthetic version of that patient’s bone marrow using IPS, which is going to work much better than the diseased bone marrow. And once this works that’s going to catch on like wildfire. And then you’ll do skin, and then you’ll do every other stem cell you can get.
Who is going to do this?
The only way people are going to get this is through some brave soul. It will start with a sick person, and they will end up getting well, possibly more well than before they got sick. So you didn’t just correct the sickness, you actually did more. And they’ll give testimonials, and someone from the New York Times will interview them, and tell this appealing anecdote.
Will people who are, say, aging but not yet sick ever be able to use this technology?
I don’t consider this medicine, it’s preventive. I expect somebody who is truly brave, who has nothing wrong with them other than maybe the usual aging, saying: ‘I want a bone marrow transplant’, or intestinal, or whatever. And it will gain momentum from there.
Won’t this cost a lot?
Initially it will be wealthy people who will try this. Ironically, wealthy people are often willing to be the guinea pigs that are really in a sense the front line of new technologies. They’re the foot soldiers. They’re willing to put themselves at risk, and to spend money on it.
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