CHAPTER FIVE.

GNR.

Three Overlapping Revolutions

There are few things of which the present generation is more justly proud than the wonderful improvements which are daily taking place in all sorts of mechanical appliances....But what would happen if technology continued to evolve so much more rapidly than the animal and vegetable kingdoms? Would it displace us in the supremacy of earth? Just as the vegetable kingdom was slowly developed from the mineral, and as in like manner the animal supervened upon the vegetable, so now in these last few ages an entirely new kingdom has sprung up, of which we as yet have only seen what will one day be considered the antediluvian prototypes of the race....We are daily giving [machines] greater power and supplying by all sorts of ingenious contrivances that self-regulating, self-acting power which will be to them what intellect has been to the human race.-SAMUEL BUTLER, 1863 (FOUR YEARS AFTER PUBLICATION OF DARWIN'S THE ORIGIN OF SPECIES THE ORIGIN OF SPECIES Who will be man's successor? To which the answer is: We are ourselves creating our own successors. Man will become to the machine what the horse and the dog are to man; the conclusion being that machines are, or are becoming, animate.-SAMUEL BUTLER, 1863 LETTER, "DARWIN AMONG THE MACHINES"1

The first half of the twenty-first century will be characterized by three overlapping revolutions-in Genetics, Nanotechnology, and Robotics. These will usher in what I referred to earlier as Epoch Five, the beginning of the Singularity. We are in the early stages of the "G" revolution today. By understanding the information processes underlying life, we are starting to learn to reprogram our biology to achieve the virtual elimination of disease, dramatic expansion of human potential, and radical life extension. Hans Moravec points out, however, that no matter how successfully we fine-tune our DNA-based biology, humans will remain "second-cla.s.s robots," meaning that biology will never be able to match what we will be able to engineer once we fully understand biology's principles of operation.2 The "N" revolution will enable us to redesign and rebuild-molecule by molecule-our bodies and brains and the world with which we interact, going far beyond the limitations of biology. The most powerful impending revolution is "R": human-level robots with their intelligence derived from our own but redesigned to far exceed human capabilities. R represents the most significant transformation, because intelligence is the most powerful "force" in the universe. Intelligence, if sufficiently advanced, is, well, smart enough to antic.i.p.ate and overcome any obstacles that stand in its path.

While each revolution will solve the problems from earlier transformations, it will also introduce new perils. G will overcome the age-old difficulties of disease and aging but establish the potential for new bioengineered viral threats. Once N is fully developed we will be able to apply it to protect ourselves from all biological hazards, but it will create the possibility of its own self-replicating dangers, which will be far more powerful than anything biological. We can protect ourselves from these hazards with fully developed R, but what will protect us from pathological intelligence that exceeds our own? I do have a strategy for dealing with these issues, which I discuss at the end of chapter 8. In this chapter, however, we will examine how the Singularity will unfold through these three overlapping revolutions: G, N, and R.

Genetics: The Intersection of Information and Biology

It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.-JAMES WATSON AND FRANCIS CRICK3 After three billion years of evolution, we have before us the instruction set that carries each of us from the one-cell egg through adulthood to the grave.-DR. ROBERT WATERSON, INTERNATIONAL HUMAN GENOME SEQUENCE CONSORTIUM4

Underlying all of the wonders of life and misery of disease are information processes, essentially software programs, that are surprisingly compact. The entire human genome is a sequential binary code containing only about eight hundred million bytes of information. As I mentioned earlier, when its ma.s.sive redundancies are removed using conventional compression techniques, we are left with only thirty to one hundred million bytes, equivalent to the size of an average contemporary software program.5 This code is supported by a set of biochemical machines that translate these linear (one-dimensional) sequences of DNA "letters" into strings of simple building blocks called amino acids, which are in turn folded into three-dimensional proteins, which make up all living creatures from bacteria to humans. (Viruses occupy a niche in between living and nonliving matter but are also composed of fragments of DNA or RNA.) This machinery is essentially a self-replicating nanoscale replicator that builds the elaborate hierarchy of structures and increasingly complex systems that a living creature comprises. This code is supported by a set of biochemical machines that translate these linear (one-dimensional) sequences of DNA "letters" into strings of simple building blocks called amino acids, which are in turn folded into three-dimensional proteins, which make up all living creatures from bacteria to humans. (Viruses occupy a niche in between living and nonliving matter but are also composed of fragments of DNA or RNA.) This machinery is essentially a self-replicating nanoscale replicator that builds the elaborate hierarchy of structures and increasingly complex systems that a living creature comprises.

Life's Computer

In the very early stages of evolution information was encoded in the structures of increasingly complex organic molecules based on carbon. After billions of years biology evolved its own computer for storing and manipulating digital data based on the DNA molecule. The chemical structure of the DNA molecule was first described by J. D. Watson and F. H. C. Crick in 1953 as a double helix consisting of a pair of strands of polynucleotides.6 We finished transcribing the genetic code at the beginning of this century. We are now beginning to understand the detailed chemistry of the communication and control processes by which DNA commands reproduction through such other complex molecules and cellular structures as messenger RNA (mRNA), transfer RNA (tRNA), and ribosomes. We finished transcribing the genetic code at the beginning of this century. We are now beginning to understand the detailed chemistry of the communication and control processes by which DNA commands reproduction through such other complex molecules and cellular structures as messenger RNA (mRNA), transfer RNA (tRNA), and ribosomes.

At the level of information storage the mechanism is surprisingly simple. Supported by a twisting sugar-phosphate backbone, the DNA molecule contains up to several million rungs, each of which is coded with one letter drawn from a four-letter alphabet; each rung is thus coding two bits of data in a one-dimensional digital code. The alphabet consists of the four base pairs: adenine-thymine, thymine-adenine, cytosine-guanine, and guanine-cytosine.

Special enzymes can copy the information on each rung by splitting each base pair and a.s.sembling two identical DNA molecules by rematching the broken base pairs. Other enzymes actually check the validity of the copy by checking the integrity of the base-pair matching. With these copying and validation steps, this chemical data-processing system makes only about one error in ten billion base-pair combinations.7 Further redundancy and error-correction codes are built into the digital data itself, so meaningful mutations resulting from base-pair replication errors are rare. Most of the errors resulting from the one-in-ten-billion error rate will results in the equivalent of a "parity" error, which can be detected and corrected by other levels of the system, including matching against the corresponding chromosome, which can prevent the incorrect bit from causing any significant damage. Further redundancy and error-correction codes are built into the digital data itself, so meaningful mutations resulting from base-pair replication errors are rare. Most of the errors resulting from the one-in-ten-billion error rate will results in the equivalent of a "parity" error, which can be detected and corrected by other levels of the system, including matching against the corresponding chromosome, which can prevent the incorrect bit from causing any significant damage.8Recent research has shown that the genetic mechanism detects such errors in transcription of the male Y chromosome by matching each Y chromosome gene against a copy on the same chromosome.9 Once in a long while a transcription error will result in a beneficial change that evolution will come to favor. Once in a long while a transcription error will result in a beneficial change that evolution will come to favor.

In a process technically called translation, another series of chemicals put this elaborate digital program into action by building proteins. It is the protein chains that give each cell its structure, behavior, and intelligence. Special enzymes unwind a region of DNA for building a particular protein. A strand of mRNA is created by copying the exposed sequence of bases. The mRNA essentially has a copy of a portion of the DNA letter sequence. The mRNA travels out of the nucleus and into the cell body. The mRNA code are then read by a ribosome molecule, which represents the central molecular player in the drama of biological reproduction. One portion of the ribosome acts like a tape-recorder head, "reading" the sequence of data encoded in the mRNA base sequence. The "letters" (bases) are grouped into words of three letters called codons, with one codon for each of the twenty possible amino acids, the basic building blocks of protein. A ribosome reads the codons from the mRNA and then, using tRNA, a.s.sembles a protein chain one amino acid at a time.

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The notable final step in this process is the folding of the one-dimensional chain of amino acid "beads" into a three-dimensional protein. Simulating this process has not yet been feasible because of the enormous complexity of the interacting forces from all the atoms involved. Supercomputers scheduled to come online around the time of the publication of this book (2005) are expected to have the computational capacity to simulate protein folding, as well as the interaction of one three-dimensional protein with another.

Protein folding, along with cell division, is one of nature's remarkable and intricate dances in the creation and re-creation of life. Specialized "chaperone" molecules protect and guide the amine-acid strands as they a.s.sume their precise three-dimensional protein configurations. As many as one third of formed protein molecules are folded improperly. These disfigured proteins must immediately be destroyed or they will rapidly acc.u.mulate, disrupting cellular functions on many levels.

Under normal circ.u.mstances, as soon as a misfolded protein is formed, it is tagged by a carrier molecule, ubiquitin, and escorted to a specialized proteosome, where it is broken back down into its component amino acids for recycling into new (correctly folded) proteins. As cells age, however, they produce less of the energy needed for optimal function of this mechanism. Acc.u.mulation of these misformed proteins aggregate into particles called protofibrils, which are though to underlie disease processes leading to Alzheimer's disease and other afflictions.10 The ability to simulate the three-dimensional waltz of atomic-level interactions will greatly accelerate our knowledge of how DNA sequences control life and disease. We will then be in a position to rapidly simulate drugs that intervene in any of the steps in this process, thereby hastening drug development and the creation of highly targeted drugs that minimize unwanted side effects.

It is the job of the a.s.sembled proteins to carry out the functions of the cell, and by extension the organism. A molecule of hemoglobin, for example, which has the job of carrying oxygen from the lungs to body tissues, is created five hundred trillion times each second in the human body. With more than five hundred amino acids in each molecule of hemoglobin, that comes to 1.5 i 1019 (fifteen billion billion) "read" operations every minute by the ribosomes just for the manufacture of hemoglobin. (fifteen billion billion) "read" operations every minute by the ribosomes just for the manufacture of hemoglobin.

In some ways the biochemical mechanism of life is remarkably complex and intricate. In other ways it is remarkably simple. Only four base pairs provide the digital storage for all of the complexity of human life and all other life as we know it. The ribosomes build protein chains by grouping together triplets of base pairs to select sequences from only twenty amino acids. The amine acids themselves are relatively simple, consisting of a carbon atom with its four bonds linked to one hydrogen atom, one amino (-NH2) group, one carboxylic acid (-COOH) group, and one organic group that is different for each amino acid. The organic group for alanine, for example, has only four atoms (CH3-) for a total of thirteen atoms. One of the more complex amino acids, arginine (which plays a vital role in the health of the endothelial cells in our arteries) has only seventeen atoms in its organic group for a total of twenty-six atoms. These twenty simple molecular fragments are the building blocks of al life.

The protein chains then control everything else: the structure of bone cells, the ability of muscle cells to flex and act in concert with other muscle cells, all of the complex biochemical interactions that take place in the bloodstream, and, of course, the structure and functioning of the brain.11

Designer Baby Boomers

Sufficient information already exists today to slow down disease and aging processes to the point that baby boomers like myself can remain in good health until the full blossoming of the biotechnology revolution, which will itself be a bridge to the nanotechnology revolution (see Resources and Contact Information, p. 489). In Fantastic Voyage: Live Long Enough to Live Forever, which I coauth.o.r.ed with Terry Grossman, M.D., a leading longevity expert, we discuss these three bridges to radical life extension (today's knowledge, biotechnology, and nanotechnology).12 I wrote there: "Whereas some of my contemporaries may be satisfied to embrace aging gracefully as part of the cycle of life, that is not my view. It may be 'natural,' but I don't see anything positive in losing my mental agility, sensory acuity, physical limberness, s.e.xual desire, or any other human ability. I view disease and death at any age as a calamity, as problems to be overcome." I wrote there: "Whereas some of my contemporaries may be satisfied to embrace aging gracefully as part of the cycle of life, that is not my view. It may be 'natural,' but I don't see anything positive in losing my mental agility, sensory acuity, physical limberness, s.e.xual desire, or any other human ability. I view disease and death at any age as a calamity, as problems to be overcome."

Bridge one involves aggressively applying the knowledge we now possess to dramatically slow down aging and reverse the most important disease processes, such as heart disease, cancer, type 2 diabetes, and stroke. You can, in effect, reprogram your biochemistry, for we have the knowledge today, if aggressively applied, to overcome our genetic heritage in the vast majority of cases. "It's mostly in your genes" is only true if you take the usual pa.s.sive att.i.tude toward health and aging.

My own story is instructive. More than twenty years ago I was diagnosed with type 2 diabetes. The conventional treatment made my condition worse, so I approached this health challenge from my perspective as an inventor. I immersed myself in the scientific literature and came up with a unique program that successfully reversed my diabetes. In 1993 I wrote a health book (The 10% Solution for a Healthy Life) about this experience, and I continue today to be free of any indication or complication of this disease.13 In addition, when I was twenty-two, my father died of heart disease at the age of fifty-eight, and I have inherited his genes predisposing me to this illness. Twenty years ago, despite following the public guidelines of the American Heart a.s.sociation, my cholesterol was in the high 200s (it should be well below 180), my HDL (high-density lipoprotein, the "good" cholesterol) below 30 (it should be above 50), and my h.o.m.ocysteine (a measure of the health of a biochemical process called methylation) was an unhealthy 11 (it should be below 7.5). By following a longevity program that Grossman and I developed, my current cholesterol level is 130, my HDL is 55, my h.o.m.ocysteine is 6.2, my C-reactive protein (a measure of inflammation in the body) is a very healthy 0.01, and all of my other indexes (for heart disease, diabetes, and other conditions) are at ideal levels.14 When I was forty, my biological age was around thirty-eight. Although I am now fifty-six, a comprehensive test of my biological aging (measuring various sensory sensitivities, lung capacity, reaction times, memory, and related tests) conducted at Grossman's longevity clinic measured my biological age at forty. 15 15 Although there is not yet a consensus on how to measure biological age, my scores on these tests matched population norms for this age. So, according to this set of tests, I have not aged very much in the last sixteen years, which is confirmed by the many blood tests I take, as well as the way I feel. Although there is not yet a consensus on how to measure biological age, my scores on these tests matched population norms for this age. So, according to this set of tests, I have not aged very much in the last sixteen years, which is confirmed by the many blood tests I take, as well as the way I feel.

These results are not accidental; I have been very aggressive about reprogramming my biochemistry. I take 250 supplements (pills) a day and receive a half-dozen intravenous therapies each week (basically nutritional supplements delivered directly into my bloodstream, thereby bypa.s.sing my GI tract). As a result, the metabolic reactions in my body are completely different than they would otherwise be.16 Approaching this as an engineer, I measure dozens of levels of nutrients (such as vitamins, minerals, and fats), hormones, and metabolic by-products in my blood and other body samples (such as hair and saliva). Overall, my levels are where I want them to be, although I continually fine-tune my program based on the research that I conduct with Grossman. Approaching this as an engineer, I measure dozens of levels of nutrients (such as vitamins, minerals, and fats), hormones, and metabolic by-products in my blood and other body samples (such as hair and saliva). Overall, my levels are where I want them to be, although I continually fine-tune my program based on the research that I conduct with Grossman.17 Although my program may seem extreme, it is actually conservative-and optimal (based on my current knowledge). Grossman and I have extensively researched each of the several hundred therapies that I use for safety and efficacy. I stay away from ideas that are unproven or appear to be risky (the use of human-growth hormone, for example). Although my program may seem extreme, it is actually conservative-and optimal (based on my current knowledge). Grossman and I have extensively researched each of the several hundred therapies that I use for safety and efficacy. I stay away from ideas that are unproven or appear to be risky (the use of human-growth hormone, for example).

We consider the process of reversing and overcoming the dangerous progression of disease as a war. As in any war it is important to mobilize all the means of intelligence and weaponry that can be harnessed, throwing everything we have at the enemy. For this reason we advocate that key dangers-such as heart disease, cancer, diabetes, stroke, and aging-be attacked on multiple fronts. For example, our strategy for preventing heart disease is to adopt ten different heart-disease-prevention therapies that attack each of the known risk factors.

By adopting such multip.r.o.nged strategies for each disease process and each aging process, even baby boomers like myself can remain in good health until the full blossoming of the biotechnology revolution (which we call "bridge two"), which is already in its early stages and will reach its peak in the second decade of this century.

Biotechnology will provide the means to actually change your genes: not just designer babies will be feasible but designer baby boomers. We'll also be able to rejuvenate all of your body's tissues and organs by transforming your skin cells into youthful versions of every other cell type. Already, new drug development is precisely targeting key steps in the process of atherosclerosis (the cause of heart disease), cancerous tumor formation, and the metabolic processes underlying each major disease and aging process.

Can We Really Live Forever? An energetic and insightful advocate of stopping the aging process by changing the information processes underlying biology is Aubrey de Grey, a scientist in the department of genetics at Cambridge University. De Grey uses the metaphor of maintaining a house. How long does a house last? The answer obviously depends on how well you take care of it. If you do nothing, the roof will spring a leak before long, water and the elements will invade, and eventually the house will disintegrate. But if you proactively take care of the structure, repair all damage, confront all dangers, and rebuild or renovate parts from time to time using new materials and technologies, the life of the house can essentially be extended without limit. An energetic and insightful advocate of stopping the aging process by changing the information processes underlying biology is Aubrey de Grey, a scientist in the department of genetics at Cambridge University. De Grey uses the metaphor of maintaining a house. How long does a house last? The answer obviously depends on how well you take care of it. If you do nothing, the roof will spring a leak before long, water and the elements will invade, and eventually the house will disintegrate. But if you proactively take care of the structure, repair all damage, confront all dangers, and rebuild or renovate parts from time to time using new materials and technologies, the life of the house can essentially be extended without limit.

The same holds true for our bodies and brains. The only difference is that, while we fully understand the methods underlying the maintenance of a house, we do not yet fully understand all of the biological principles of life. But with our rapidly increasing comprehension of the biochemical processes and pathways of biology, we are quickly gaining that knowledge. We are beginning to understand aging, not as a single inexorable progression but as a group of related processes. Strategies are emerging for fully reversing each of these aging progressions, using different combinations of biotechnology techniques.

De Grey describes his goal as "engineered negligible senescence"-stopping the body and brain from becoming more frail and disease-p.r.o.ne as it grows older.18 As he explains, "All the core knowledge needed to develop As he explains, "All the core knowledge needed to develop engineered negligible senescence engineered negligible senescence is already in our possession-it mainly just needs to be pieced together." is already in our possession-it mainly just needs to be pieced together."19 De Grey believes we'll demonstrate "robustly rejuvenated" mice-mice that are functionally younger than before being treated and with the life extension to prove it-within ten years, and he points out that this achievement will have a dramatic effect on public opinion. Demonstrating that we can reverse the aging process in an animal that shares 99 percent of our genes will profoundly challenge the common wisdom that aging and death are inevitable. Once robust rejuvenation is confirmed in an animal, there will be enormous compet.i.tive pressure to translate these results into human therapies, which should appear five to ten years later. De Grey believes we'll demonstrate "robustly rejuvenated" mice-mice that are functionally younger than before being treated and with the life extension to prove it-within ten years, and he points out that this achievement will have a dramatic effect on public opinion. Demonstrating that we can reverse the aging process in an animal that shares 99 percent of our genes will profoundly challenge the common wisdom that aging and death are inevitable. Once robust rejuvenation is confirmed in an animal, there will be enormous compet.i.tive pressure to translate these results into human therapies, which should appear five to ten years later.

The diverse field of biotechnology is fueled by our accelerating progress in reverse engineering the information processes underlying biology and by a growing a.r.s.enal of tools that can modify these processes. For example, drug discovery was once a matter of finding substances that produced some beneficial result without excessive side effects. This process was similar to early humans' tool discovery, which was limited to simply finding rocks and other natural implements that could be used for helpful purposes. Today we are learning the precise biochemical pathways that underlie both disease and aging processes and are able to design drugs to carry out precise missions at the molecular level. The scope and scale of these efforts are vast.

Another powerful approach is to start with biology's information backbone: the genome. With recently developed gene technologies we're on the verge of being able to control how genes express themselves. Gene expression is the process by which specific cellular components (specifically RNA and the ribosomes) produce proteins according to a specific genetic blueprint. While every human cell has the full complement of the body's genes, a specific cell, such as a skin cell or a pancreatic islet cell, gets its characteristics from only the small fraction of genetic information relevant to that particular cell type.20 The therapeutic control of this process can take place outside the cell nucleus, so it is easier to implement than therapies that require access inside it. The therapeutic control of this process can take place outside the cell nucleus, so it is easier to implement than therapies that require access inside it.

Gene expression is controlled by peptides (molecules made up of sequences of up to one hundred amino acids) and short RNA strands. We are now beginning to learn how these processes work.21 Many new therapies now in development and testing are based on manipulating them either to turn off the expression of disease-causing genes or to turn on desirable genes that may otherwise not be expressed in a particular type of cell. Many new therapies now in development and testing are based on manipulating them either to turn off the expression of disease-causing genes or to turn on desirable genes that may otherwise not be expressed in a particular type of cell.

RNAi (RNA Interference). A powerful new tool called RNA interference (RNAi) is capable of turning off specific genes by blocking their mRNA, thus preventing them from creating proteins. Since viral diseases, cancer, and many other diseases use gene expression at some crucial point in their life cycle, this promises to be a breakthrough technology. Researchers construct short, double-stranded DNA segments that match and lock onto portions of the RNA that are transcribed from a targeted gene. With their ability to create proteins blocked, the gene is effectively silenced. In many genetic diseases only one copy of a given gene is defective. Since we get two copies of each gene, one from each parent, blocking the disease-causing gene leaves one healthy gene to make the necessary protein. If both genes are defective, RNAi could silence them both, but then a healthy gene would have to be inserted. A powerful new tool called RNA interference (RNAi) is capable of turning off specific genes by blocking their mRNA, thus preventing them from creating proteins. Since viral diseases, cancer, and many other diseases use gene expression at some crucial point in their life cycle, this promises to be a breakthrough technology. Researchers construct short, double-stranded DNA segments that match and lock onto portions of the RNA that are transcribed from a targeted gene. With their ability to create proteins blocked, the gene is effectively silenced. In many genetic diseases only one copy of a given gene is defective. Since we get two copies of each gene, one from each parent, blocking the disease-causing gene leaves one healthy gene to make the necessary protein. If both genes are defective, RNAi could silence them both, but then a healthy gene would have to be inserted.22

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. 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. 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 "do-it-yourself gene watching." 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 "do-it-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." 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."25Improve cancer cla.s.sifications. One study reported in Science demonstrated the feasibility of cla.s.sifying 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. One study reported in Science demonstrated the feasibility of cla.s.sifying 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.26Identify 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. 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.27Determine 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. 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.28Test 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. 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. (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 a.s.sociated 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. The concept of controlling the genetic makeup of humans is often a.s.sociated 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. 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 pa.s.s 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. 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 "nan.o.b.a.l.l.s" for maximum impact. Yet another option is to pack DNA into ultratiny "nan.o.b.a.l.l.s" 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 princ.i.p.al 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 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. 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. 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 best-selling "statin" (cholesterol-lowering) drug, Lipitor. 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 best-selling "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. 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 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 playa 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. 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 playa 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 a.s.sumption 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." 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. 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. 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. 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 a.s.sume 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 a.s.sisted in raising extended families but also pa.s.sed on the acc.u.mulated 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. 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. 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. 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 acc.u.mulation of mutations in the thirteen genes in the mitochondria, the energy factories for the cell. Another aging process is the acc.u.mulation 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. 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. 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 const.i.tuent 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. 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.