Future Current

A pioneer in the field of stem cell research, Michael West, Ph.D., has served on the BioTime Board of Directors since 2002 and has extensive academic and business experience in age-related degenerative diseases, telomerase molecular biology and human embryonic stem cell research and development. At the free symposium organized by the Methuselah Foundation life-extension organization, he unveiled an online open sourced database, called the Embryome, whose purpose is to help identify the hundreds of cell types that can be made from embryonic stem cells.

The following transcript of Michael West’s presentation at the Methuselah Foundation symposium entitled “Aging: The Disease, The Cure, The Implications” has not been approved by the speaker. Video is also available.

The International Embryome Initiative

I want to circle back to the first talk Dr. Haseltine gave. I don’t know about you guys, but I noticed there was rapt attention during what he said. Certainly, it has attracted me. I am a gerontologist, and my interest in my career has been not only to understand the biology of aging, but how can we learn something to improve the human condition and maybe even extend human longevity?

I am going to talk today about the cells Dr. Haseltine was talking about—these immortal cells. He talked about life and death in the human life cycle. I remember growing up watching Ben Casey—I don’t know if any of you are old enough to remember that show? A couple hands. Remember the beginning? “Man, woman, birth, death, infinity.” I used to look at that, saying, that sounds profound.

Ever since then I have been entranced by the immortality of the species and how it’s accomplished. A simple way of putting it: we are made of cells, trillions of them, that have been proliferating backward in time all the way through hundreds of millions of years to the beginning of life on the planet, leaving no dead ancestors in their wake ever—or we would not be here. It is our somatic cells that are destined to die. All the cells in our body have this immortal legacy going backward in time millions of years and will face death for the first time ever in our lifetime.

What can we learn about the immortality of the species to transport those observations and discoveries of modern technologies into something that will really do something about human aging? That is what I am going to talk about today.

Aubrey mentioned I am an optimist. Maybe I am, because I am showing you a rising sun here. Actually, these are cells derived from these immortal cells, embryonic stem cells. Dr. Mark Perry here in the LA area took pictures of these some years ago.

There is a backdrop though, to talk about the properties. You probably all heard in the debate about embryonic stem cells, because they are from the root of human life, they can make everything in the human body. That is a first, ever. Medicine has never had a platform, a mechanism, to make and replace all of the cells in the human body. As odd as it sounds, we can replace your carburetor or the tires of your car, but the leading cause of death in the United States is the loss of heart cells in your heart. That does not make a lot of sense, does it? We keep an antique car around forever, but we cannot keep the human body around.

These are a first platform. They make every kind of cell. Because of their being an immortal cell, they open the door to merging them with DNA technology. It is a merger of two technologies: modern genomics and cell biology, married together with these cells. You see it where these cells have been used to make mice — then we can go in an do all kinds of sophisticated changes to the DNA. There are human therapeutic applications, which California is funding, and of course a lot of research can be done with these cells as well. One of the most significant things as a gerontologist is that we believe that for the first time we can really capture these immortal cells that are transported from generation to generation — keeping them from going on an immortal cycle, but they are showing this immortality.

How do we know these are the immortal cells? All the cells, grown in the laboratory dish from the human body, age. This has been used for years to study the biology of aging. We predicted, based on all this biology, that these cells would be the only exception of a normal human cell that would proliferate forever, like the Energizer bunny. Sure enough, it did. These are the first human cells that were cultured that have this property of replicating without limit.

Now I want to switch from all this optimistic stuff to the realities. As Dr. Haseltine said, you can imagine now some pretty dramatic inventions. If these are really the cells that keep making us, and we can take a cell from you or me and transport it back in time to make these cells, then there will be lots of opportunities — that is the optimistic side. Let’s delve into the challenges, and that is where I want to spend the rest of tonight talking about. I’m talking about it, because I’m excited. I think we know how to deal with the challenges, and I want to walk you through that quickly, because I find that very encouraging.

To balance the rosy sun, I’m showing the stark, cold reality of the moon to lay out the challenges. Number one — and this is really a problem — because these cells are so powerful, they turn into everything in the human body. That is thousands of different kinds of cells—that’s a problem. Few of us who study anatomy, the cells and cell biology, can remember all the cells in the human body.

A second thing, there are no precise markers. Different kinds of cells decorate themselves with proteins on their surface that tell you if that is a liver cell, a heart cell, and so on. We don’t even know what those are in the early developing human. Because President Bush and previous administrations have banned federal funding for early embryo research, we really don’t know very much about these cells. If we had these wonderful cells that could cure diabetes, we don’t even know what properties they would have.

There is enormous complexity and a very poor understanding of these markers. You may have noticed that when some of the early companies that approached the FDA saying they want to start human clinical trials with these cells, the FDA replied, “They aren’t pure enough.” These are some of the challenges.

The way we looked at this, here is a very complex tree. These cells would be at the base of this tree, branching out into all the cells that make you and me. Imagine the tree suddenly getting out at least a hundred times more complex. That is closer to the reality of you and me. “How do we make a beta cell?” “How do we make a heart cell?”

There are two different ways you can do it. One would be, I want that “apple” up there, I can make a stick and a catcher’s mitt and “get it,” so to speak. Early technologies were going to figure out how to make a beta cell, but some of us were thinking about this and said, “Look, a lot of this we want to do in our lifetime. Let’s put a tarp under the tree and shake it, and take everything that falls out.”

That was the way the sequencing of the genome was suddenly accelerated. That was the way this field was accelerated.

All of this complexity that leads to all the different zebra stripes—we actually have invisible stripes on our body—all this complexity is in the human body. We invented a technology to to shake the tree, to shotgun clone all these cells that make up you and me — embryonic stem cells, in a purified form — without knowing how a heart cell forms.

This is the tarp we put under the tree. It is a combinatorial matrix approach where we tried a bunch of random, different ways of growing the cells, then we looked for cells that could grow up from a single cell. We call it “shotgun cloning.” Only in the last five to ten years could all of this be done with the immense increase in computing power and a lot of other techniques that scientists have available. We were going to take all of these cells, and then get the expression (the genes that are turned on and off) for all the cells, and then let computers run 24 hours a day for weeks, and reassemble the tree.

It is hard to see, but up at the top there is a branching tree, and those red spots are generated by computer, showing the genes that are very highly expressed. You can see the enormous diversity of cell types we have made this way. Basically shaking the tree, suddenly falling out of this are over 140 early lineages that make up you and me. What we suddenly realized was the complexity problem. We thought this was where we would be thirty years from now. Now, we suddenly have all these early precursors of muscle, teeth and the inner ear. The computer is giving us all these charts of markers, these things we so desperately needed to tell one cell type from another.

We went under a stream to collect a glass of water and suddenly, Niagara Falls. There was this enormous flood of information and cell types — cell types like this, by the way. This in the upper left is a propagating, purified culture of precursors to the brain. It can incorporate and regenerate the telencephalon in the brain — really amazing stuff.

In the top panel you can see some of these cells lit up. They are 100% pure because they were clonally isolated. We had suddenly solved this problem of separating these cells out. The fun part is that all the cells in our body have a zip code built into them that tells the cells where they are. You can identify homeobox genes (when you look at them in a developing mouse, as you can see in the lower left there) in the developing jaw or wherever. These cell lines on the right, you can see the histograms, give us these very clear zip codes. We can even tell where they would have been in the developing human.

All of this data, all of these cell lines, all the history that research scientists have done into the development of the mouse, is an enormous opportunity, but way too complicated. The DNA was a very complicated problem, billions of letters — how do we deal with this? It led to a field called “genomics,” which is the study of all the regulatory, coding sequences of the DNA and how we make sense of all this.

There is a new field emerging now called “embryomics,” which is the study of all of these cell lineages that make up the developing human, their markers and their properties. It’s just that, like genomics, it is so complicated. How do we do this?

What we have launched is an international embryome initiative. We have opened up on the internet a database at embryome.com, open sourced so that the whole world can join in and help us build out this tree and all its complexity. It’s sort of like Wikipedia. Here you are looking at the frontpage. Click on this simplified tree and it takes you to a far more detailed analysis of gene expression and a very precise nomenclature of every cell, its markers and its properties.

This has all happened in the last year. A lot of the critics have said embryonic stem cells still have not cured a disease. What I want to tell you is that we had to invent all new technologies. We are excited about how this is building out.

These are these immortal germline cells. They keep making new people. We know that by studying the clock of aging, the telomere. The clock of aging is wound at the very beginning of life. You can see these growth curves — they have these long lifespans compared with normal cells.

How could these cells be used in the next ten years? There are numerous examples I could give you, but one hopeful one — macular degeneration. This is the leading cause of blindness, due to the aging of our retina. These cells have now been made in a form that is appropriate to begin human clinical trials. You can see pictures of the cells on the lower right. When they become lost or dysfunctional in the back of the retina, they cause this cascade of pathology that is a leading cause of blindness in the elderly. The eye is a good place to start, I think. It is at least one of the top targets for how we hope these cells will eventually be used in medicine.

To summarize, I would argue that President Bush’s restrictions on these kinds of cells really angered a lot of people, because this was medicine and it should not be politics. It caused the voters of California to vote to fund the work themselves. Similarly, I think the whole scientific community is being engaged by this new technology. This new initiative will allow all those researchers to get together to try to delve into the complexity and the commensurate opportunity that these cells give us.

These are actually the ultimate young cell — an immortal cell — and able to make cells of any kind. The implications I think are obvious in medicine. These early embryonic cells have impressive plasticity, meaning they are used to building the human body, so they are very good at regenerating the human body. With the new technologies that we have now, finally we can have a very pure product that will be safe to use in humans. Ultimately, with these new technologies we now have the capability to take control of the human life cycle.

Woody Allen once said, on the immortality of the germline, some people would like to have immortality through their children, I would prefer to have immortality by not dying. That is really what we think we have here. We have captured the central mechanisms of immortality in the human species, and we can now manipulate it. At minimum, we hope we will be able to make some inroads in how we age. Thank you very much.

This entry was posted on Monday, July 21st, 2008 at 3:21 pm and is filed under SENS, Life Extension. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.