Regenesis (37 page)

A volunteer for the Personal Genome Project donates saliva, blood, and a bit of skin. This allows checking for accuracy and for somatic mutations, epigenetic changes, and microbial components. (“Epigenetic” refers to the ways in which influences outside of strict DNA nucleotide sequences—for example, environmental factors—can modify gene expression.) The skin samples provide fibroblast cells that could be reprogrammed into synthetic yet personalized pluripotent stem cells that could be further reprogrammed into a variety of cell types—probably into all natural body cell types as well as many novel cell types and tissues of medical value. Their value includes personal tests for drug toxicity and efficacy, testing
for inherited disorders in advance of their appearance, and generating perfectly histocompatible tissues for organ transplants without the need for immunosuppressant drugs. It makes gene therapy possible without the use of viral vectors (which caused cancer in some previous gene therapy trials). Two tipping-point events that the world barely noticed while they happened in 2007 (but were covered by Pulitzer Prize-winning articles recently) were the stem cell treatments of little Nic Volker and Timothy Ray Brown.

Nic Volker was a child living in Madison, Wisconsin, who had started having gastrointestinal problems just before his second birthday. Physicians at Children's Hospital in Milwaukee failed to come up with a definitive diagnosis, but nonetheless performed more than one hundred intestinal surgeries before Nic was four years old, without ever solving the problem.

“Normally with medicine we can get these problems under control,” said Dr. Alan Mayer, a gastroenterologist. “But with Nic we never really did. And the disease continued to progress. It was so severe, my intuition told me this had to be due to a genetic mutation.”

Mayer enlisted the help of genomics experts Howard Jacob and Elizabeth Worthey and had Nic's genome sequenced. Within four months, Jacob identified the gene that was responsible for Nic's condition, a rare disease for which a bone marrow transplant was the treatment of choice. This was done in July 2010, using stem cells from the cord blood of a matched, healthy donor, and the boy was cured.

“So what we really did was we replaced his immune system that was defective with a different immune system that lacked that defect,” Mayer explained. Nic is fine today, a testament to the power of genomic medicine.

Forty-two-year-old Timothy Ray Brown lived in Berlin, Germany, and suffered from both leukemia and AIDS. Gero Hütter, a hematologist at Berlin's Charité Hospital, found a blood stem cell donor who was not only matched for Brown's tissue type but also had a rare double deletion of the CCR5 gene, which happens to be the host cell receptor for the HIV-1 virus. As a result of that transplant Brown has been free of both leukemia and AIDS (and without anti-HIV drugs) for the last four years. In a sense, he was the world's first person to be cured of AIDS.

Nic Volker's case was a turning point because now many parents concerned about developmental delays or other medical mysteries in their child will insist that their children be given the kind of genomic examination that Nic got. Brown's case is significant because his genome therapy made use of a rare genotype (the double deletion of the CCR5 gene, which is carried by only about 1 percent of humans). In principle, many of us might want to have this rare genome, just as we might want a vaccine to prevent AIDS, even if we aren't planning on engaging in risky sexual behavior. Sangamo BioSciences, a California biopharmaceutical company, has in the works a clinical trial of a method to change a patient's own stem cell genomes precisely and efficiently to inactivate both copies of CCR5. The results of the trial are promising so far. These stem cell transplants might some day be extended to include resistance to all viruses (see
Chapter 5
).

The pace of personal genomics' impact on health is accelerating as this book goes to print. The Noah and Alexis Beery twins misdiagnosis of cerebral palsy nearly thirteen years ago was corrected when their genome sequence revealed a mutated gene related to brain serotonin and dopamine production and fixed by dietary supplements (like 5-hydroxy tryptophan). The drug Ivacaftor (aka Kalydeco) was approved in three months by the FDA, a speed record we all hope will become typical. It is specific for a single base change in the gene responsible for cystic fibrosis. In the face of steady progress, we still hear echoes of cautionary notes that genetics diagnostics will generally be uninformative, but need to also note that most (nongenetic) diagnostics, like pulse rate and blood chemistry at your annual medical exam, will also not tell us anything new. But often enough these tests do have high predictability and actionability, so we all should check. Genetics seems to be similar.

The prospect of improved health through personal genomics raises the question of what the limits are to such improvements, and whether it makes sense to envision exceptionally long-lived human beings and even potentially immortal human components. Thoughts of immortality go back to the early Neolithic era, when humans began to think deeply about
death, mortality, and everlasting life. The ancient heroes—pharaohs and kings—took every means available to ensure their own vestigial future persistence through the ages. They had themselves enshrined in legends, songs, poems, constellation names; they had their remains preserved in vast pyramids, in larger-than-life statues, and so on. Why?

Part of the reason may lie in the fact that we live so long already, on average. Our species is distinctive in our ability to remember and to predict future events based on past experience. (Granted, some animal species also do this, at least on a primitive level.) Before the invention of writing (and to a large extent even afterward), reliable prediction-making required the embodiment of these memories in a living person. People well past their reproductive years could add value to their tribe by remembering what to do when a rare phenomenon approached—a drought, locusts, war, and so on. In modern times, our training is even more extended, including postdoctoral or on-the-job training well into our sixties (or even longer). Unlike computers whose full memories can be moved to a new model, human memories and skills are much harder to transfer. Most modern diseases are caused by aging. Many researchers even argue that, with nations becoming wealthier and exposure to infectious agents and toxins dropping, aging will become the underlying cause of most diseases. Yet many people remain quite active beyond the age of one hundred. We have much to learn from these natural human long-lived specimens, and this is a clear opportunity for synthetic biology since the cure is probably not a drug but rather a redo of our genome. We can search the best of the biosphere for ideas.

As we have seen, species run the gamut when it comes to longevity. Mayflies live up to their insect order name. Among
Ephemeroptera
(Greek for “ephemeral wing”) the adults live, dance, and mate for thirty minutes (after having lived for months as larvae). Gastrotrichs, a type of microscopic aquatic invertebrate, live out their entire life cycle in three days.

At the other extreme is the bowhead whale
(Balaenamysticetus;
see
Chapter 3
), which grows to 150 tons, second only to the blue whale, by feeding in the fertile but chilly Arctic. Estimates of individual bowhead whale longevity have ranged up to 210 years, judging from the age of ancient
spear heads lodged in their flesh as well as the rate of mirror-flipping of amino acids in their eye lenses. The oldest fish of all, a koi, was a female scarlet specimen named Hanako (born c. 1751), which died at the age of 226 years on a memorable date: 7/7/77. Two radiated tortoises have set the land record: one named Tu Malila lived to 188 years (until 1965), and another, Adwaita, lived for possibly 256 years (dying in 2006). The ocean bivalve mollusk,
Arcticaislandica
(also known as the quahog, or the hardshell clam), can live up to 405 years, albeit in nearly freezing water where the rate of chemical changes, metabolism, and hence ensuing oxidative damage is very low. (As is, for that matter, the roster of hard-shell clam accomplishments.)

Trees, which are even more limited in their mobility and accomplishments than mollusks, can nevertheless live to the grand old age of 4,860 to 5,000 years. Indeed, the world record for oldest nonclonal organism is held by a bristlecone pine named Prometheus, which lived for literally centuries near Wheeler Peak in eastern Nevada. It was killed in 1964 by grad student Donald Currey, who was unfortunately bent on determining the tree's age by counting tree rings. By Currey's count, Prometheus was at least 4,862 years old when felled, and probably older than 5,000 years. (Wordsworth's famous line “We murder to dissect” was never so apt!)

But it is possible to go beyond old age. At least one researcher, Daniel Martinez, reported in 1998 that the hydra is one of the few animals that does not undergo senescence at all and is therefore biologically immortal. (In 2010 another researcher, Preston Estep, disputed Martinez's claim.)

Astonishingly,
Turritopsisnutricula
, a jellyfish, can actually
get younger
. It has the fountain of youth gift of returning from its sexually mature (medusa) state back to a younger (polyp) state. An entire population of such organisms can do this synchronously and swiftly—although it is difficult to observe in the wild. Still, in virtue of its unique ability to return to an earlier stage of life,
Turritopsisnutricula
have managed to escape biological death through aging (although members of the species succumb to predation, accident, and disease).

What this bizarre menagerie of extremely long-lived, possibly immortal organisms is leading up to is the fact that, arguably, human cells (if not
people) can be immortal too. This is suggested by the case of Henrietta Lacks, an African American woman who died of cervical cancer on October 4, 1951, at Johns Hopkins Hospital in Baltimore, at the age of 31. For cancer research purposes cell samples had been taken from her cervix. They were code-named HeLa cells, after the first two letters of her first and last names.

Then the cells took on a life of their own. Hopkins researcher George Gey found that HeLa cells could be kept alive and grown in lab glassware. The cells replicated, grew, and proliferated so wildly and uncontrollably that they often took over and wiped out any other cell lines they happened to come into contact with. Indeed, HeLa cells are still alive today, all around the world, many decades after they were removed from the cancerous tumor of Henrietta Lacks.

On the other hand, HeLa cells are so biologically aberrant that they have seventy to eighty-six chromosomes (which works out to an average of 82, amid the midst of chaos of chromosome breakage, joining, deletion, and duplication), rather than the usual forty-six, in twenty-three pairs (which in contrast to the indeterminacy of HeLa cell chromosomes is an exquisitely precise number). Furthermore, HeLa cells are far from being able to produce normal human tissues.

The human cells that are both immortal and capable of making humans immortal, or at least longer-lived, are germ cells. Some large multicellular creatures (many plants, for example) do not have an opposition between germ line cells and somatic cells. But for many animals, including humans, the germ line is the only part of us that naturally survives us in our offspring. (Germ line cells are the body's reproductive cells, or gametes; the rest of the body's cells are somatic cells.) Indeed, germ line cells are the all-time champions of cellular survival. We can trace their DNA back through billions, possibly trillions of binary divisions. In 99.999+ percent of those past divisions, only one of the cellular siblings survived, or if both survived then eventually all of the offspring of one died and only our ancestor survived the bloodbath.

Is cloning a possible route to immortality? Over twenty species of animal have been cloned, including carp, mice, sheep, rhesus monkeys, gaurs
(wild oxen), cattle, cats, dogs, rats, mules, horses, water buffalo, and camels. Some of these clonings are routine procedures with a clear agricultural benefit. Cloning is sometimes viewed as dangerous, but many new technologies go through a phase in which they are actually unsafe, or at least perceived as unsafe, and the technology is banned at least locally. This is often followed by a phase in which the public demands the technology. For example, railroads. (Or for that matter, automobiles, early examples of which were detested by some because they scared the horses.)

A similar progression may be occurring with regard to cloning. In the United Kingdom the Human Reproductive Cloning Act 2001 explicitly prohibited reproductive cloning. But then the Human Fertilisation and Embryology Act of 2008 repealed the 2001 Cloning Act, and allowed cloning and experiments on hybrid human-animal embryos. In the United States there are no federal laws that ban cloning, but some states do have such laws. The main argument against cloning is that the difficulties observed in cloning other animals makes it likely that there would be many failures in the creation of a living human clone and hence many disabled children. One can imagine at least two possible outcomes of the current ambivalence toward cloning. One is to increase the effectiveness of agricultural cloning until its success rate is very high. This would likely be followed by greater societal acceptance of the practice. The second possibility is to establish a line of tissues for individuals derived from their induced pluripotent stem cells. This would blur the line between stem cell therapy (routine for bone marrow transplants) and therapeutic cloning.