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BOOK REVIEW |
Institute for Behavioral Genetics University of Colorado at Boulder Boulder, Colorado 80309
Ageless Quest: One Scientist's Search for Genes That Prolong Youth, by Lenny Guarente. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2002, 154 pp., $19.95 (cloth).
Merchants of Immortality: Chasing the Dream of Human Life Extension, by Stephen S. Hall. Houghton Mifflin Company, Boston, 2003, 439 pp., $25.00 (cloth).
The quest for immortality has been with humankind since our first ancestor prepared his beloved for the afterlife, some tens of thousands of years ago, well before the start of recorded history. Initially, religion offered the only solace for mortality and an essential aspect of many religions is spiritual (and even physical) immortality. However, the search for immortality (as Woody Allen quips "by not dying") has also been a dream represented throughout recorded history. There have been numerous attempts at "biomedical" interventions to rejuvenate and extend life. Many of these attempts were legitimate, representing scientific attempts to prolong life and/or rejuvenate certain organs. At the other extreme, many represented charlatanism with little or nothing scientific at all to demonstrate the efficacy of their "snake oil" products and services.
Most current interventions for life extension that are in the marketplace have no proven validity for human life extension (Olshansky, Hayflick, & Carnes, 2002). However, there are numerous interventions that have shown efficacy in animal trials, particularly dietary restriction (DR), typically meaning restriction to 60% of an ad libitum (unrestricted) diet. However, DR is too tough for almost any human to adhere to and so many companies are searching for "dietary mimetics," that is, dietary supplements that can mimic the effects of DR without the deprivation (Pollock, 2003). Two other attacks on aging have utilized model systems: either the finite ability of human tissue culture cells to replicate in laboratory culture (Hayflick & Moorhead, 1961) or the identification of genetic alterations leading to extended longevity (Johnson & Wood, 1982), especially, the identification of single-gene mutants that show life extension (Friedman & Johnson, 1988; Hekimi & Guarente, 2003). These two approaches are those described, respectively, in Stephen S. Hall's Merchants of Immortality: Chasing the Dream of Human Life Extension and in Lenny Guarente's, Ageless Quest: One Scientist's Search for Genes That Prolong Youth. In these approaches one first discovers the rate-limiting process using genetics or another intervention, and then one establishes this process as a target in a search for a small molecule (a drug) that will work to block the function of the protein thus identified.
Hayflick, Cellular Senescence, and Michael West
A leading contemporary scientist, Cynthia Kenyon, notes in Hall's volume, "‘it's a very very powerful human desire, I think, not to get old. And you really feel that in a big way when you study aging'" (p. 11). A few dozen, mostly small, "biotech" companies are pursuing the dream, if not of eternal youth, at least of prolonged functional life span. Hall gives us a glimpse of the fight to prolong life beyond its "normal" limits, organized around an account of one man's search for this goal, the companies that he has founded, and the political intrigue engendered by that search. Hall also addresses some of the bigger issues involved in searching for life-extension drugs, and he manages to do all of this with a heady, interesting prose style that makes much of the book into a page-turner!
The major protagonist of the book is Michael West. We meet West (the founder of the Geron Corporation) as a 37-year-old third-year medical student, growing tired of medicine, volunteering to work in the lab of Woody Wright and Jerry Shay at the University of Texas Southwestern Medical School. West had already had quite a scientific odyssey, passing through the labs of biogerontologists Sam Goldstein and Jim Smith. The Wright/Shay lab had long focused on aging in human cells, often referred to as "cellular senescence," a phenomenon that forms a major subplot of the book (Shay & Wright, 2000).
Cellular senescence had been discovered by Leonard Hayflick, who, as a young cell biologist at the Wistar Institute in Philadelphia, found that he could not keep human cell lines growing indefinitely in culture (Hayflick & Moorhead, 1961). Instead, his cells grew only for about 50 doublings. This inability of human cells to sustain growth is often referred to as "the Hayflick Limit." Hayflick carefully replicated his results and became firmly convinced that his findings were not due to "toxic growth media." As Hall quotes Hayflick, "‘I was by no means the first person to discover that cultured normal cells don't live forever. That had been discovered before I was even born! But nobody ever realized that it was probably a normal state of affairs, and not attributable to failure to understand how to culture’" (p. 26). The Hayflick Limit directly challenged one of the best-established "myths" of cell biology—that cells could grow indefinitely in culture. In a well-documented example of self-correction in experimental science, Hall gives us many details of how Hayflick's findings prevailed. Hayflick Limits have been established for numerous human cell lines and for uncounted numbers of other species and cells. However, Hayflick did more than merely report that early dogma was wrong. He went on to speculate that this phenomenon "‘may bear directly upon problems of aging, or more precisely, senescence’" (quoted in Hall, p. 27). This account of Hayflick's discovery, essentially a prologue to Hall's book, moves us into the rest of the story.
The End of the Chromosome Is Special
DNA is the carrier of the genetic information in human cells (and almost everywhere else). DNA is a long, incredibly thin, piece of genetic twine. The total length of the DNA in a human cell is about 2 meters. Each of the 46 chromosomes in a normal human cell contains one long piece of DNA. Humans cells have figured out how to maintain all of this DNA and package it into an incredibly tight little ball so that it can be contained in the tiny nucleus, only a few microns in diameter. There is another challenge in maintaining DNA, however, and that is called the "end-replication dilemma." The ends of chromosomes (termed telomeres—meaning "end bodies") are special, so special that Nobel Laureates have studied their structure. (If these structures turn out to hold at least a hint of how to postpone senescence, if not the secret of mortality, Nobel Prizes will certainly be awarded for their discovery.)
Cal Harley, Bruce Futcher, and Carol Greider (1990) reported in the prestigious journal Nature that as cells approach the Hayflick Limit, the DNA in the telomere becomes shorter and shorter. The immediate hypothesis is that the inability of cells to continue replication is associated with the shortening of the telomeres of these cells. This short telomere DNA offered a mechanical explanation for cellular senescence. This mechanism grabbed the imagination of Mike West, whom Hall quotes as saying, "‘The whole thing really sounded like telomeres and it started to smell right’" (p. 71). West soon corralled a group of "angel investors" around the Houston area to put up $250,000 and West was off, searching for a thousand times that amount of "venture financing." This quarter of a billion dollars is about what is needed to bring a drug to market, given the huge cost of the essential research and development, and clinical trials.
Biotech, Venture Capitalists, and Geron
Biotech, and indeed most of novel technology in all fields, is driven by investments from venture capitalists (VCs). Many billions of dollars a year are invested by VCs, who are seeking very high rates of return (one fund that I am familiar with advertised 50% annual returns—at least before the stock market crash of 2000). VCs expect these returns to occur fairly rapidly. And there's the rub. For a VC, a 3-year investment is "long-term." I doubt if any biotech company ever founded, certainly not one doing fundamental research, ever returned a profit within this time period. There are other ways to return profits to the VCs, however, and among these is the ability to go public (to issue publicly traded stock). West, or at least his VC backers, realized that the promise of life extension was so engaging that it might be possible to bring a company public based only on the promise of eventual success—again a commonly used strategy in biotech. However, without long-term profitability of the company, this can become merely a pyramid scheme.
In biotech, there are only two business plans that yield long-term profitability: (a) selling drugs to consumers, or (b) selling products and services to those who sell these drugs. Human life extension is a heady goal but without doubt it is almost impossible to demonstrate on a time scale consistent with the expectations of the VC investors. Hall repeatedly illustrates how the management of Geron comes to this realization and decides to refocus the company and its patents on telomere-related mechanisms as anti-cancer possibilities. Indeed, the Hayflick Limit has long been interpreted to be an anti-cancer mechanism. It seems likely, if not probable, that the first documented human life-extension drug will be verified through epidemiological studies of "off-label" use of a drug with a different primary use. In any event, this shift in focus to the anti-cancer arena marks the beginning of the end for Mike West's involvements in Geron.
Are Human Embryonic Stem Cells The Holy Grail?
Hall follows West through other concepts and other companies, most notably Advanced Cell Technology (ACT), a company based in Worcester, Massachusetts. The last half of the book deals with another type of human cell: embryonic stem cells. West, Geron, and ACT all become involved with this type of research, but now the game is transformed. George W. Bush is elected president of the United States, and he limits the use of these cells for research. Hall argues that Bush's opposition to these cells and "therapeutic cloning" is based on political, not moral. grounds and further states: "The long-term promise of stem cell therapy is everything it has been cracked up to be: the potential clinical impact is staggering, on a par with the therapeutic importance of antibiotics or vaccines" (p. 340).
But how comprehensive is Steven Hall's view of the field of longevity extension? How realistic are the views expressed in the book concerning the probability of success? How many alternatives to the stem cell approach championed within Merchants of Immortality are there? Stephen Hall is a great writer and has done an immense amount of good scholarly research but nevertheless falls short in addressing these questions.
Hall largely ignores the development of drugs targeting proteins made by individual genes. He argues that there is little likelihood of success to be seen in targeting individual genes: "there are good biological reasons to argue that single-gene changes are not going to dramatically change longevity expectations any time soon, if ever" (p. 342). Perhaps Hall assumes that gene therapy (a very unproven and so far pretty unsuccessful prospect) is the chosen method. However, this is not the case. Pharmacological approaches would be ideal. Drugs are perfect for attaching to and blocking the action of a protein. Indeed, such interventions have already been demonstrated in model systems like the little nematode, C. elegans, that I like to work on (Babar et al., 1999; Melov et al., 2000). Whether such approaches can work in humans is years, if not decades, away from being demonstrated.
Merchants of Immortality is excellently indexed and very well documented. It contains 56 pages of citations and an extensive list of references. It is written for the educated lay audience but the cognoscenti will also profit from reading the book. Moreover, the cast of characters depicted in Hall's book could be used to teach a fairly comprehensive course on the biology of aging.
Genetic Approaches to Life Extension
Lenny Guarente takes an autobiographical approach in Ageless Quest. I liked this book a lot! (I have learned not to review a book I don't like.) Lenny's book is short and conveys a charm and the excitement that is at the essence of why we do science. Most importantly for me, it captures the spirit of those of us who work on the biology of aging—or perhaps more appropriately "anti-aging" research. Dr. Guarente is remarkably forthright, providing details of his scientific career from preschool to the present. He conveys aspects of his company and its founding that are normally not available (and definitely were not available to me 5 years ago when I was holding forth to Lenny, on a lovely Tuscan night, as to how my company, GenoPlex—not mentioned in the book—was planning to develop anti-aging drugs). Little did I know that Lenny's company, Elixir Pharmaceuticals, would soon be pursuing very similar approaches.
We read about the young Lenny growing up in Revere, Massachusetts. We follow him to a Jesuit High School and then to MIT (a route I followed as well; but there the trails diverge). Lenny describes in some detail his time at Massachusetts General Hospital in Boston and moves into high gear when he arrives at his postdoctoral and assistant professor years at Harvard and MIT. This part of the book provides good insight into the way things work in the fast-track biology departments in which much of the best aging research is currently being pursued. Dr. Guarente's description of forming Elixir Pharmaceuticals (we had toyed with the name Elixir at GenoPlex but rejected it because of negative connotations) is both entertaining and instructive. I wish I had listened more to the sage advice of scientific advisors like Larry Gold who gave me similar cautions, when we were founding GenoPlex on way too little funding.
Lenny's current research, his company, and much else in Lenny's life focus on life extension. We hear in great detail how Lenny chose yeast—S. cerevisiae—as a model and how he was seduced by his students into embarking on aging research. S. cerevisiae is almost perfect for aging research, as has been shown by several other yeast geneticists (most notably, Michal Jazwinski who, curiously, is not even mentioned in the otherwise gracious acknowledgements of other people's work). We hear Guarente's thoughts that aging is something best to be studied after one has tenure. (I did not learn this lesson in my own academic career [see Johnson, 2002]). Another eminent researcher and a co-founder of Elixir, Cynthia Kenyon, once told me the same thing in that she found my research very exciting and when she was tenured she planned on coming into the field, which she did in 1993 (Kenyon et al., 1993). Until recently, research into the biology of aging has been tainted by the perception that the field is not very good; Lenny, Cynthia, and others, many of whom are mentioned in Ageless Quest, have done a lot to change that perception.
SIR Genes and Life Extension
Lenny's yeast research initially focused on one gene that had been called SIR4. In the days before DNA sequencing, one could spend several years in finding one gene and it had taken years to understand the function of SIR4. Lenny discovered the involvement of SIR4 by using what geneticists call a selection screen: mutated yeast was left for weeks under adverse conditions and the few survivors were found to be long-lived (Kennedy et al., 1995). Similarly, in the nematode worm (C. elegans) with which I work, a mutant strain that survived the power outage and subsequent high laboratory temperatures that killed all non-mutant worms when Hurricane Andrew hit Miami in 1994 led to the discovery of the age-2 longevity mutant.
Of course most genes encode the instructions that a cell can use to synthesize a protein, and so did SIR4. Much of the book is devoted to details of Lenny's attempts to understand how genes like SIR4 function and the book describes the arduous routes by which these functions have been elucidated. Lenny seems to have done his homework early and clearly adapted the evolutionary point of view. He observes, "Under conditions of sufficiency, aging plays out passively according to the evolutionary theory. ... However, under conditions of scarcity, a regulated program of survival is kicked into gear that ... slows aging and delays reproduction" (p. 82). I believe that this fundamental concept is the basis of many other ways of retarding aging, including dietary restriction and hormesis; we have termed this the "stress-response hypothesis" (Johnson et al., 1996). Indeed, the great deal of work from many labs—especially those of Cynthia Kenyon and Gary Ruvkun—on longevity genes in the worm has revealed that these genes specify not only an elaborate series of morphological changes, but also alter many biochemical processes allowing the worms to enter what my friend and colleague Chris Link calls "a hunker down" mode of survival, perhaps even utilizing an alternative metabolic pathway, leading to lower production of free radicals. (For detailed technical background, see Guarente & Kenyon, 2000, and Rea & Johnson, 2003).
It may seem astounding but there is an increasingly large body of genetic knowledge showing that this pathway has been evolutionarily conserved. This means that the common ancestor of nematodes, yeast, mice, and humans (which lived 600 million years ago) had a mechanism for slowing its rate of aging in response to hard times. This genetic mechanism has been so important that each of these four species has retained the mechanism. In mice, when the function of a gene called "IGF-1 Receptor" is reduced 50% (Holzenberger et al., 2003), the life of the mouse is extended by about 30%.
SIR2 rapidly became the focus of Lenny's aging research with the finding that titration of SIR2 activity is directly associated with yeast longevity; an extra copy of SIR2 leads to longer life. SIR2 is evolutionarily highly conserved and when overexpressed, it lengthens life in nematode worms as well (Tissenbaum & Guarente, 2001)—a finding Lenny showed me while at Woods Hole, where he ran the course on the molecular genetics of aging, sponsored by the Ellison Foundation. This finding is influencing a new generation of aging researchers in ways that we are yet to discover. Lenny's department chair responds with the same enthusiasm as mine did at the University of California, Irvine—"Great, just what the world needs: long-lived worms." Lenny conveys the excitement, competitiveness, and serendipity with which he and his group discovered that SIR2 is a histone deacetylase and proposes a model of energy sensing by SIR2, which relies on the bioavailability of NAD, a vitamin necessary for its action.
Founding a Company
So how should one found a company to develop applications of such findings? The answer starts with the same old adage of how one gets federal research funding: "First have a good idea." There the tack differs completely. As the NASDAQ fallout of 2000–2002 showed, one must also have a business plan—a way to make money. It is most important to get enough funding to survive, while the science matures. Part of the answer is to bring in big names. Guarente, Kenyon, and Ruvkun are all geneticists, who fulfill this criterion and who are at renowned coastal universities (now I see why those jobs are so prized) who can convince investors that this is good science (even though the investors may not understand it). But one must also have an "exit strategy"—a way to sell the company or at least one's shares for a profit. All too often the exit strategy for startups is little more than a pyramid scheme wherein the early investors make big returns by selling their interests to later investors who must sell their interests to later investors, and so forth. Such exit strategies were responsible for the rapid fall of the NASDAQ a few years ago when the dot.com bubble burst. But they need not underlie investments made into anti-aging companies if these companies can bring drugs to market rapidly enough.
Both of these books describe the beginnings of legitimate scientific work into developing drugs and other therapies that could be used to slow aging and extend healthy life. I think we can all look forward to many more fascinating books in this vein as more and more companies populate this field (for an overview of companies engaged in anti-aging research, see Pollock, 2003).
References
This article has been cited by other articles:
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  T. E. Johnson Genes, Phenes, and Dreams of Immortality: The 2003 Kleemeier Award Lecture J. Gerontol. A Biol. Sci. Med. Sci., June 1, 2005; 60(6): 680 - 687. [Abstract] [Full Text] [PDF]
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 T. Wetle FOUNTAINS OF YOUTH OR FOUNTAINS OF HEALTH? SEARCHING FOR THE FUTURE OF AGING RESEARCH Gerontologist, December 1, 2004; 44(6): 844 - 847. [Full Text] [PDF]
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