Future Current

Dr. Michael West serves as President and Chief Scientific Officer of Advanced Cell Technology and is Adjunct Professor of Bioengineering at the University of California, Berkeley. He has extensive academic and business experience in age-related degenerative diseases, telomerase molecular biology and human embryonic stem cell research and development. He founded Geron Corporation of Menlo Park, California and from 1990 to 1998 he was a Director and Vice President, where he initiated and managed programs in telomerase diagnostics, oligonucleotide-based telomerase inhibition as anti-tumor therapy, and the cloning and use of telomerase in telomerase-mediated therapy wherein telomerase is utilized to immortalize human cells. At the 7th Alcor Conference he gave a presentation on the prospect of regenerative medicine.

The Prospect of Regenerative Medicine

Thank you very much. It’s a pleasure to be here, especially to see my old friends. It’s good to see you again. What I thought I would do is give you some background on this field and give you some sense of where regenerative medicine is going. You read about it a lot in newspapers. I think there is a lot of misinformation out there. I will try to dispel some myths. I thought I would also try to put it in the context that many of you are interested in. I’m a card-carrying gerontologist. This field called regenerative medicine, embryonic stem cell technology that you’ve heard so much about, actually comes from basic research in biology of aging. Let’s start at the beginning with the life cycle.

As I’ve studied aging my interest has been in cells, because we’re made up of them. When you look at the life cycle, what’s striking is this quote from Johannas Mueller that organic bodies, you and me, are perishable; “while life maintains the appearance of immortality in the constant succession of similar individuals, the individuals themselves pass away.” The species doesn’t. As a cell biologist I think that’s our first clue, at least that was my first clue as to the biology of aging. It’s not a new idea. If you turn to biology and folklore, there’s a whole body of ancient religion which many of the Western religions borrow heavily from. They’re called pagan religions. They were immortality myths. People often think of them as simple fertility rights, that people were trying to get a better crop. In fact, these were religious beliefs that recognized the mortal renewal of life.

Demeter is the female aspect of this. As some of you know, some of the older religions had both the male and the female component. Females kind of dropped off at some point. Here, Demeter on the left was associated with grain, Dionysus is on the right was associated with wine. They were symbols of the immortal renewal of life. People saw within that not just a crop, but a symbol for our lives. The ancient Greeks bifurcated this into immortal Zoe, which I’m showing here as this red continual thing that I will refer to subsequently as the germline. That’s the thing that perpetuates the species forever. Bios, from which we get the word “biography,” that’s the individual life that passes away. The gods were made of Zoe. That was an early recognition of this dichotomy, but also the ancient cultures hoped to learn from nature how to perform this amazing feat of the immortal renewal of life. How to perform immortality transfer from there to here, that was their whole archetypal story.

We come up now to the 19th century, we have the first really brilliant cell biologist August Weismann, a contemporary of Darwin. I can’t praise the man enough, a brilliant man. He looked at primitive multicellular animals that I’m showing you here from his book. On the left you can see a Volvox species here that when you break these cells apart, they’re truly an immortal cell, when you break these cells apart they can just grow a new Volvox. But here you notice a very similar species, Volvox minor, here on the right, that’s different in a fundamental respect. There were basically two kinds of cells, an outer sphere of cells that were called the somatic cells and cells that were inside were germline. When it broke open, these cells would make a new Volvox and these cells would die. They somehow were sacrificed for the benefit of their brother cells. Weismann made an interesting conclusion. His conclusion was that this was the origin of death. This was the first time in evolution where cells had as their destiny that they would die. They made a differentiation, they said I’ll be this dandelion fluff that helps protect and carry the germline to the next generation and then I’m going to die. Before that cells died, but they didn’t have to die. They had the potential to perpetuate and replicate forever. These somatic cells under this scenario leave dead ancestors behind.

Weismann suggested that with this immortal germline, generation after generation, there are changes that occur within the germ plasm, as he called it, that led to more and more complicated soma. These cells that were disposed of changed in more and more complex ways, differentiating into you and me. Darwin actually had a very different view. Weismann was right, Darwin was wrong. He made a prediction back then that death of you and me takes place because the worn-out tissue cannot forever renew itself and the capacity for increase by means of cell division is not everlasting. Meaning, the somatic cells would not have replicant immortality, unlike the germline, and that decision leads ultimately to aging and the demise of you and me. Obviously, he got it right and Darwin got it wrong.

What’s so significant here is that there was this salient, brilliant prediction and it was forgotten. The reason it was forgotten was, along came the chicken. People started studying embryonic chicken tissues. The chicken or the egg concept is that a chicken lays more eggs to make more chickens. What Weismann was proposing was that this was upside down. Chickens were eggs’ way of making more eggs. So, the soma was the transport vehicle. Maybe this was why Weismann’s book was pushed off the shelves. It wasn’t a popular idea, even back then. It certainly isn’t today. President Bush’s ethics commission referred to this as part of the dehumanization of man.

Again, now we have cell biology beginning to understand that there is an immortal lineage of cells in people forever and now we are into immortality transfer and more sophisticated cell biology. So this is a cell biology version of these ancient mystery religions. How do we take lessons from the immortal germline and transfer them into the soma for therapeutic purposes? Well, another problem for Weismann about a year or two before he died, Alexis Carell in New York took cells from a chicken, cultured them, and said Wiesmann was wrong. Alexis Carell’s lab in the Rockefeller Center, they did cell culture out in the open like this. It’s horrible to think that this is how they did surgery back then. Carell said the somatic cells proliferated and Weismann was wrong, so however we age it’s not because there is an intrinsic clock of aging in the somatic cells. That sent gerontology off into completely wrong areas of research for decades.

It actually turns out that Carell was wrong. Weismann was right. This was actually studied in some detail. There have been books written about it. In the 1960′s Leonard Hayflick came along and noticed that human somatic cells senesced, so if you looked at their growth curves this was an intrinsic property. Cells can however immortalize and get back the immortality they used to have in the germline. That was what I began working on in the mid-’70s, early ’80s. Taking cells from the skin, for instance, growing them to senescence and figure out what’s the clock, how does it work. They settled on a diagram, shown here, published by Howard Cooke, he showed that the ends of the DNA strands, the telomeres, were shortening in somatic cells. This was not just with cells in the dish, but in the blood cells of people as they aged. And that the germline didn’t shorten the ends of the chromosomes. There was a brilliant man, Alexei Olovnikov, who made a prediction, similar to Weismann, just a flash of insight. He was in Moscow, going back to the train station, and he suddenly saw it was the telomeres, the ends of the DNA strands were shortening in somatic cells, in cells in our body, but the germline had some way of keeping ends from shortening. So he proposed these shortening chromosomes were a clock of aging, sort of like a burning fuse. Here is actually how we know it does work: the germline retains telomeres through an enzyme called telomerase. It is an immortalizing enzyme and somatic cells generally lack it. The telomeres shorten and ultimately the cell dies.

This led to a company I started called Geron, where we tried to get this gene and transfer it into somatic cells to see if this could work. We cloned the two components of it. It’s a very unique enzyme. It takes the ends of the DNA strand to make these telomeric ends. It reminds me, by the way, of the Greek Fates who measure the fated length of human life as a string. One weaves it, one measures it against her measuring stick, and a third one cuts it to its fated length. These are the molecular components of that process. One day Leonard Hayflick was in our lab and donated a piece of his skin. We were joking that we were going to measure the real Hayflick limit. That was a thrill for me. I wrote about it in The Immortal Cell, to be the first to find in this gene clone (it cost $40 million) and drop it into Leonard Hayflick’s somatic cells. Man, that was fun.

That led us to the search for other ways we could extract lessons from the immortal germline. These primitive cells in the early embryo, when we cultured them in a dish, they are so primitive that they were still immortal. These are human embryonic stem cells, one of the lines blessed by President Bush. This is what the telomere length looks like. As I showed you in that diagram, it’s very long, typically 15,000 base pairs. But these telomeres will not shorten. A family of differing ages starting in the teens and going on through the 80s, they donated some blood to us. This is what the enzyme telomerase looks like. It builds a ladder of telomeres.

The remarkable thing about embryonic stem cells is that the first human cell ever cultured was from the immortal germline. You can grow them and share them with researchers. But the other thing, which most people don’t think about, is the aging aspect, that it’s an immortal cell. They think about the pluripotency of the cells. They can be turned into everything in the human body, and they do that in the dish. Another remarkable thing is they will try to build human tissues in the laboratory, either in the dish or after you have put them into animals, where they could grow in three dimensions. Here are some examples. This is a cross-section of the intestines. These amazingly complex things, these cells do this on their own. You don’t have to make them do this. They form tissues, as they are very primitive cells.

William Osler wrote an essay called “Science and Immortality” back about a hundred years ago about Weismann’s immortal germline cells, not knowing that these cells would someday exist. He referred to “this marvelous embryonic substance” as “eternally young, eternally productive, eternally forming new individuals to grow up and to perish, while it remains in the progeny always youthful, always increasing, always the same. Thousands upon thousands of generations which have arisen in the course of ages were its products, but it lives on in the youngest generations with the power of giving origin to coming millions. The individual organism is transient, but its embryonic substance, which produces the mortal tissues, preserves itself imperishable, everlasting, and constant.” That is a better description of embryonic stem cells than the germline, because of course the germline is changing.

Lastly, in 1997, along came Dolly, and many of us asked whether we could do one more trick with the germline: just take an aged somatic cell and put it back into the germline. Could the germline reset the clock of aging? After the initial work by Roslin some concluded no, Dolly was born prematurely old. That’s not true. There is absolutely no truth to that. Our reason for looking at it, of course, is that if you could make this cellular time machine work, we could potentially make tissues of any kind that are you. So that’s when we talk about therapeutic cloning. Our belief was that you could reset this clock of aging, so we studied that, first in cows.

Here you can see cells growing out to senescence. We took these senescent cells and did nuclear transfer cloning. We found that the clock of aging actually got over-reset. These cells had longer proliferative lifespans than they did originally. They were replicated in a mouse model by Teru Wakiyama. He cloned the clone, and then he cloned the clones of the clone. He showed that like us, telomeres get reset one notch longer, not shorter, every time they are cloned. Nuclear transfer does reset the clock of aging itself. So, in the human system, if you could reset cells back to the beginning of life, they could have the potential to form tissues of any kind that have their full lifespan back, even complex tissues, that are you. These cells would have new mitochondria, new batteries, so to speak. That’s pretty exciting for rejenerative medicine.

These are the first cloned human embryos that we published. No one to my knowledge has yet cloned human embryonic stem cells through nuclear transfer. We stopped this work because of it being difficult to perform in Massachusetts. This worked in many other animal species. In the years since that work, we’ve been working on making retinal pigment epithelium to treat age-related macular degeneration. It’s caused by the loss of these cells. We think this would be a very simple way of implementing embryonic stem cell technology to make new retinal pigment epithelium. We’re doing all the work to take these into the clinic. Here is some of our data from animal models.

Another cell type I’m excited about is called hemangioblasts. This is a cell that could be turned into blood and the vascular system. Our vascular cells are a big part of aging. We often say in gerontology, you’re as old as your arteries. These are circulated cells that can replumb the vascular system. Cloning your own cells that you had when you were born, I think is magical. And that’s entirely within our reach, since we have all these pieces put in place. They have clinical benefits including their ability to improve circulation. Here is a ligated femoral artery, and you can see there’s no blood flow in the lung, but when you inject these hemangioblasts, you can see a rapid restoration. There are many applications for these cells. You could go in millions of different directions. Part of the problem with embryonic stem cells is the breadth of cell types you can make.

What my group is working on right now is a technology called ACTCellerate. It’s kind of a high throughput technology trying to get at all the complexities of these cells. It’s often said there are 200 cell types in the human body. In reality, there are well over a thousand. Even within cell types, like skin cells, they all have their unique zip codes. Zebras have stripes because these skin cells are turning colors based on their so-called zip-codes. Homeobox genes and that sort of thing, signal to the cells where they are in the body and make all the complexities of the cell. Embryonic stem cells make all of these cells into a mixture in the dish and we’re working on some cell biology tricks to sort of sort the mail, and put in one pile precursors to the heart, and one pile, precursors to the liver, and that sort of thing. That’s where we’re at right now, struggling both with the opportunities and challenges of this field.

I will end my talk here where I began, really. Even today, as far as we’ve come as a society, we have a lot of technology, but we still face problems that faced mankind in the most ancient days. We face this abyss of suffering, disease and death. How can we substantively intervene in the problems facing mankind currently? My point is we find ourselves gravitating back to some of these ancient strategies. How can we learn from the immortality of the germline? The species renews itself indefinitely. You go to Africa and there are zebras and they are just like the zebras that were there a thousand years ago. They will still look that way a thousand years in the future. The immortal germline fights off free radical damage, x-rays, all these things, they brush it right off. When we take these old cells that are full of all these things that we say are gunk and gum up the machinery of aging, when we put it back into an egg cell, all those things were gone. Just vaporized.

So, there is a lot to learn about the germline, how it can maintain a species. I think we’re repeating some ancient myths. This is the myth of Isis and Osiris. Isis loved her husband and he was killed, as you know. What this depiction is showing is that Isis with her own two hands she found a way of taking mortal life, which has a beginning and an end, and connecting ends together as a symbol of infinity or immortality. This is their version of the infinity sign. She’s done this out of love for her husband Osiris, and so this ancient battle of love over death was part of these ancient myths and I think will be a part of our human destiny as well. Thank you.

This entry was posted on Sunday, October 14th, 2007 at 2:22 pm and is filed under Alcor, 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.