Cell Therapies. Another important line of attack is to regrow our own cells, tissues, and even whole organs and introduce them into our bodies without surgery. One major benefit of this “therapeutic cloning” technique is that we will be able to create these new tissues and organs from versions of our cells that have also been made younger via the emerging field of rejuvenation medicine. For example, we will be able to create new heart cells from skin cells and introduce them into the system through the bloodstream. Over time, existing heart cells will be replaced with these new cells, and the result will be a rejuvenated “young” heart manufactured using a person’s own DNA. I discuss this approach to regrowing our bodies below.
Gene Chips. New therapies are only one way that the growing knowledge base of gene expression will dramatically impact our health. Since the 1990s microarrays, or chips no larger than a dime, have been used to study and compare expression patterns of thousands of genes at a time.23 The possible applications of the technology are so varied and the technological barriers have been reduced so greatly that huge databases are now devoted to the results from “doit-yourself gene watching.”24
Genetic profiling is now being used to:
Revolutionize the processes of drug screening and discovery. Microarrays can “not only confirm the mechanism of action of a compound” but “discriminate between compounds acting at different steps in the same metabolic pathway.”25
Improve cancer classifications. One study reported in Science demonstrated the feasibility of classifying some leukemias “solely on gene expression monitoring.” The authors also pointed to a case in which expression profiling resulted in the correction of a misdiagnosis.26
Identify the genes, cells, and pathways involved in a process, such as aging or tumorigenesis. For example, by correlating the presence of acute myeloblastic leukemia and increased expression of certain genes involved with programmed cell death, a study helped identify new therapeutic targets.27
Determine the effectiveness of an innovative therapy. One study recently reported in Bone looked at the effect of growth-hormone replacement on the expression of insulinlike growth factors (IGFs) and bone metabolism markers.28
Test the toxicity of compounds in food additives, cosmetics, and industrial products quickly and without using animals. Such tests can show, for example, the degree to which each gene has been turned on or off by a tested substance.29
Somatic Gene Therapy (gene therapy for nonreproductive cells). This is the holy grail of bioengineering, which will enable us to effectively change genes inside the nucleus by “infecting” it with new DNA, essentially creating new genes.30 The concept of controlling the genetic makeup of humans is often associated with the idea of influencing new generations in the form of “designer babies.” But the real promise of gene therapy is to actually change our adult genes.31 These can be designed to either block undesirable disease-encouraging genes or introduce new ones that slow down and even reverse aging processes.
Animal studies that began in the 1970s and 1980s have been responsible for producing a range of transgenic animals, such as cattle, chickens, rabbits, and sea urchins. The first attempts at human gene therapy were undertaken in 1990. The challenge is to transfer therapeutic DNA into target cells that will then be expressed at the right level and at the right time.
Consider the challenge involved in effecting a gene transfer. Viruses are often the vehicle of choice. Long ago viruses learned how to deliver their genetic material to human cells and, as a result, cause disease. Researchers now simply switch the material a virus unloads into cells by removing its genes and inserting therapeutic ones. Although the approach itself is relatively easy, the genes are too large to pass into many types of cells (such as brain cells). The process is also limited in the length of DNA it can carry, and it may cause an immune response. And precisely where the new DNA integrates into the cell’s DNA has been a largely uncontrollable process.32
Physical injection (microinjection) of DNA into cells is possible but prohibitively expensive. Exciting advances have recently been made, however, in other means of transfer. For example, liposomes—fatty spheres with a watery core—can be used as a “molecular Trojan horse” to deliver genes to brain cells, thereby opening the door to treatment of disorders such as Parkinson’s and epilepsy.33 Electric pulses can also be employed to deliver a range of molecules (including drug proteins, RNA, and DNA) to cells.34 Yet another option is to pack DNA into ultratiny “nanoballs” for maximum impact.35
The major hurdle that must be overcome for gene therapy to be applied in humans is proper positioning of a gene on a DNA strand and monitoring of the gene’s expression. One possible solution is to deliver an imaging reporter gene along with the therapeutic gene. The image signals would allow for close supervision of both placement and level of expression.36
Even faced with these obstacles gene therapy is starting to work in human applications. A team led by University of Glasgow research doctor Andrew H. Baker has successfully used adenoviruses to “infect” specific organs and even specific regions within organs. For example, the group was able to direct gene therapy precisely at the endothelial cells, which line the inside of blood vessels. Another approach is being developed by Celera Genomics, a company founded by Craig Venter (the head of the private effort to transcribe the human genome). Celera has already demonstrated the ability to create synthetic viruses from genetic information and plans to apply these biodesigned viruses to gene therapy.37
One of the companies I help to direct, United Therapeutics, has begun human trials of delivering DNA into cells through the novel mechanism of autologous (the patient’s own) stem cells, which are captured from a few vials of their blood. DNA that directs the growth of new pulmonary blood vessels is inserted into the stem cell genes, and the cells are reinjected into the patient. When the genetically engineered stem cells reach the tiny pulmonary blood vessels near the lung’s alveoli, they begin to express growth factors for new blood vessels. In animal studies this has safely reversed pulmonary hypertension, a fatal and presently incurable disease. Based on the success and safety of these studies, the Canadian government gave permission for human tests to commence in early 2005.
Reversing Degenerative Disease
Degenerative (progressive) diseases—heart disease, stroke, cancer, type 2 diabetes, liver disease, and kidney disease—account for about 90 percent of the deaths in our society. Our understanding of the principal components of degenerative disease and human aging is growing rapidly, and strategies have been identified to halt and even reverse each of these processes. In Fantastic Voyage, Grossman and I describe a wide range of therapies now in the testing pipeline that have already demonstrated significant results in attacking the key biochemical steps underlying the progress of such diseases.
Combating Heart Disease. As one of many examples, exciting research is being conducted with a synthetic form of HDL cholesterol called recombinant Apo-A-I Milano (AAIM). In animal trials AAIM was responsible for a rapid and dramatic regression of atherosclerotic plaque.38 In a phase 1 FDA trial, which included forty-seven human subjects, administering AAIM by intravenous infusion resulted in a significant reduction (an average 4.2 percent decrease) in plaque after just five weekly treatments. No other drug has ever shown the ability to reduce atherosclerosis this quickly.39
Another exciting drug for reversing atherosclerosis now in phase 3 FDA trials is Pfizer’s Torcetrapib.40 This drug boosts levels of HDL by blocking an enzyme that normally breaks it down. Pfizer is spending a record one billion dollars to test the drug and plans to combine it with its bestselling “statin” (cholesterol-lowering) drug, Lipitor.
Overcoming Cancer. Many strategies are being intensely pursued to overcome cancer. Particularly promising are cancer vaccines designed to stimulate the immune system to attack cancer cells. These vaccines could be used as a prophylaxis to prevent cancer, as a first-line treatment, or to mop up cancer cells after other treatments.41
&
nbsp; The first reported attempts to activate a patient’s immune response were undertaken more than one hundred years ago, with little success.42 More recent efforts focus on encouraging dendritic cells, the sentinels of the immune system, to trigger a normal immune response. Many forms of cancer have an opportunity to proliferate because they somehow do not trigger that response. Dendritic cells play a key role because they roam the body, collecting foreign peptides and cell fragments and delivering them to the lymph nodes, which in response produce an army of T cells primed to eliminate the flagged peptides.
Some researchers are altering cancer-cell genes to attract T cells, with the assumption that the stimulated T cells would then recognize other cancer cells they encounter.43 Others are experimenting with vaccines for exposing the dendritic cells to antigens, unique proteins found on the surfaces of cancer cells. One group used electrical pulses to fuse tumor and immune cells to create an “individualized vaccine.”44 One of the obstacles to developing effective vaccines is that currently we have not yet identified many of the cancer antigens we need to develop potent targeted vaccines.45
Blocking angiogenesis—the creation of new blood vessels—is another strategy. This process uses drugs to discourage blood-vessel development, which an emergent cancer needs to grow beyond a small size. Interest in angiogenesis has skyrocketed since 1997, when doctors at the Dana Farber Cancer Center in Boston reported that repeated cycles of endostatin, an angiogenesis inhibitor, had resulted in complete regression of tumors.46 There are now many antiangiogenic drugs in clinical trials, including avastin and atrasentan.47
A key issue for cancer as well as for aging concerns telomere “beads,” repeating sequences of DNA found at the end of chromosomes. Each time a cell reproduces, one bead drops off. Once a cell has reproduced to the point that all of its telomere beads have been expended, that cell is no longer able to divide and will die. If we could reverse this process, cells could survive indefinitely. Fortunately, recent research has found that only a single enzyme (telomerase) is needed to achieve this.48 The tricky part is to administer telomerase in such a way as not to cause cancer. Cancer cells possess a gene that produces telomerase, which effectively enables them to become immortal by reproducing indefinitely. A key cancer-fighting strategy, therefore, involves blocking the ability of cancer cells to generate telomerase. This may seem to contradict the idea of extending the telomeres in normal cells to combat this source of aging, but attacking the telomerase of the cancer cells in an emerging tumor could be done without necessarily compromising an orderly telomere-extending therapy for normal cells. However, to avoid complications, such therapies could be halted during a period of cancer therapy.
Reversing Aging
It is logical to assume that early in the evolution of our species (and precursors to our species) survival would not have been aided—indeed, it would have been compromised—by individuals living long past their child-rearing years. Recent research, however, supports the so-called grandma hypothesis, which suggests a countereffect. University of Michigan anthropologist Rachel Caspari and University of California at Riverside’s San-Hee Lee found evidence that the proportion of humans living to become grandparents (who in primitive societies were often as young as thirty) increased steadily over the past two million years, with a fivefold increase occurring in the Upper Paleolithic era (around thirty thousand years ago). This research has been cited to support the hypothesis that the survival of human societies was aided by grandmothers, who not only assisted in raising extended families but also passed on the accumulated wisdom of elders. Such effects may be a reasonable interpretation of the data, but the overall increase in longevity also reflects an ongoing trend toward longer life expectancy that continues to this day. Likewise, only a modest number of grandmas (and a few grandpas) would have been needed to account for the societal effects that proponents of this theory have claimed, so the hypothesis does not appreciably challenge the conclusion that genes that supported significant life extension were not selected for.
Aging is not a single process but involves a multiplicity of changes. De Grey describes seven key aging processes that encourage senescence, and he has identified strategies for reversing each one.
DNA Mutations.49 Generally mutations to nuclear DNA (the DNA in the chromosomes in the nucleus) result in a defective cell that’s quickly eliminated or a cell that simply doesn’t function optimally. The type of mutation that is of primary concern (as it leads to increased death rates) is one that affects orderly cellular reproduction, resulting in cancer. This means that if we can cure cancer using the strategies described above, nuclear mutations should largely be rendered harmless. De Grey’s proposed strategy for cancer is preemptive: it involves using gene therapy to remove from all our cells the genes that cancers need to turn on in order to maintain their telomeres when they divide. This will cause any potential cancer tumors to wither away before they grow large enough to cause harm. Strategies for deleting and suppressing genes are already available and are being rapidly improved.
Toxic Cells. Occasionally cells reach a state in which they’re not cancerous, but it would still be best for the body if they did not survive. Cell senescence is an example, as is having too many fat cells. In these cases, it is easier to kill these cells than to attempt to revert them to a healthy state. Methods are being developed to target “suicide genes” to such cells and also to tag these cells in a way that directs the immune system to destroy them.
Mitochrondrial Mutations. Another aging process is the accumulation of mutations in the thirteen genes in the mitochondria, the energy factories for the cell.50 These few genes are critical to the efficient functioning of our cells and undergo mutation at a higher rate than genes in the nucleus. Once we master somatic gene therapy, we could put multiple copies of these genes in the cell nucleus, thereby providing redundancy (backup) for such vital genetic information. The mechanism already exists in the cell to allow nucleus-encoded proteins to be imported into the mitochondria, so it is not necessary for these proteins to be produced in the mitochondria themselves. In fact, most of the proteins needed for mitochondrial function are already coded by the nuclear DNA. Researchers have already been successful in transferring mitochondrial genes into the nucleus in cell cultures.
Intracellular Aggregates. Toxins are produced both inside and outside cells. De Grey describes strategies using somatic gene therapy to introduce new genes that will break down what he calls “intracellular aggregates”—toxins within cells. Proteins have been identified that can destroy virtually any toxin, using bacteria that can digest and destroy dangerous materials ranging from TNT to dioxin.
A key strategy being pursued by various groups for combating toxic materials outside the cell, including misformed proteins and amyloid plaque (seen in Alzheimer’s disease and other degenerative conditions), is to create vaccines that act against their constituent molecules.51 Although this approach may result in the toxic material’s being ingested by immune system cells, we can then use the strategies for combating intracellular aggregates described above to dispose of it.
Extracellular Aggregates. AGEs (advanced glycation end-products) result from undesirable cross-linking of useful molecules as a side effect of excess sugar. These cross-links interfere with the normal functioning of proteins and are key contributors to the aging process. An experimental drug called ALT-711 (phenacyldimenthylthiazolium chloride) can dissolve these cross-links without damaging the original tissue.52 Other molecules with this capability have also been identified.
Cell Loss and Atrophy. Our body’s tissues have the means to replace worn-out cells, but this ability is limited in certain organs. For example, as we get older, the heart is unable to replace its cells at a sufficient rate, so it compensates by making surviving cells bigger using fibrous material. Over time this causes the heart to become less supple and responsive. A primary strategy here is to deploy therapeutic cloning of our own cells, as described below.
Progress
in combating all of these sources of aging is moving rapidly in animal models, and translation into human therapies will follow. Evidence from the genome project indicates that no more than a few hundred genes are involved in the aging process. By manipulating these genes, radical life extension has already been achieved in simpler animals. For example, by modifying genes in the C. elegans worm that control its insulin and sex-hormone levels, the lifespan of the test animals was expanded sixfold, to the equivalent of a five-hundred-year lifespan for a human.53
A hybrid scenario involving both bio- and nanotechnology contemplates turning biological cells into computers. These “enhanced intelligence” cells can then detect and destroy cancer cells and pathogens or even regrow human body parts. Princeton biochemist Ron Weiss has modified cells to incorporate a variety of logic functions that are used for basic computation.54 Boston University’s Timothy Gardner has developed a cellular logic switch, another basic building block for turning cells into computers.55 Scientists at the MIT Media Lab have developed ways to use wireless communication to send messages, including intricate sequences of instructions, to the computers inside modified cells.56 Weiss points out that “once you have the ability to program cells, you don’t have to be constrained by what the cells know how to do already. You can program them to do new things, in new patterns.”