Regenesis (35 page)

Other illnesses are caused by the difference of as little as a single base in an otherwise normal genetic structure. Sickle-cell anemia, the classic example, is the result of the substitution of just one letter of the HBB gene sequence that codes for normal hemoglobin. The HBB gene for normal hemoglobin includes the triplet GAG, which is the three-letter code for glutamic acid. In mutant hemoglobin, however, the triplet GTG, which codes for the amino acid valine, appears where GAG should be. The occurrence of the base T (thymine) instead of the proper base A (adenine), a difference of a single molecular structure on the gene, is enough to induce the malformation of the blood cells characteristic of sickle-cell anemia. For want of a nail good health is lost, here in the form of a severe, chronic, and generally incurable condition. (The variation of a single base from what's normal is known as a single nucleotide polymorphism, or SNP.)

As these examples show, we can now pinpoint, with literally atomic accuracy, the molecular basis of many human pathologies. For many such cases, we are reaching a major goal, in the reduction of health and disease states to their ultimate physical foundations in the human genome. The discovery of “dark matter” in the genome, material distinct from known genes that plays a causal role in some sicknesses, is of ongoing interest.

Thus the importance of the Human Genome Project as well as that of its latter-day descendant, the Personal Genome Project.

Our ability to trace states of disease and health to their atomic underpinnings is a manifestation of the fifth industrial revolution, which focused on atoms. This revolution originated in the discovery and applications of
strange quantum phenomena in physics and chemistry. In a single year (1905) a twenty-six-year-old patent clerk, unable to get a job in academia, published four papers (all in the same journal,
Annalen der Physik
). Any one of these papers could have earned him a Nobel Prize, and indeed the first one did do so. The topics were the photoelectric effect (in which light photons dislodge electrons, the outer components of atoms, from a solid or liquid surface), Brownian motion (in which small particles are buffeted by the thermal vibration of molecules), special relativity (which pertains to motion at nearly maximal speeds), and the mathematical relation between mass and energy. This last paper included what is without a doubt the most well-known equation of all time, E = mc
²
. It is famous both because of its brevity and for its Promethean recipe for the release of earth-shattering amounts of energy resulting from the splitting or fusion of small concentrations of atomic nuclei. Understanding these phenomena required measurements of matter interacting with light (atomic spectra) and other kinds of particle beam radiation.

The quantum revolution has made an enormous impact on chemistry and materials sciences. These effects can be roughly divided into nuclear and electronic phenomena. The radius of an atomic nucleus is about 100,000 times smaller than the radius of the surrounding electron cloud that defines most of the atom's chemical properties. Quantum-mechanical breakthroughs concerning electronic bonding have been fundamental to understanding the nature and strength of chemical reactions and interactions. Exploration of the nuclear realm enabled the introduction of radioisotopes, which have been crucial for many advances in biochemistry and medicine as well as the dating of ancient specimens, and in DNA sequencing. The use of stable isotopes and mass spectrometry extended such studies considerably. The diffraction of X rays from material objects ranging from simple salts to organelles like the ribosome, as well as information from the interactions of nuclear spins in nearby atoms in NMR, have provided a window into the world at atomic resolution, paving the way for precise molecular engineering.

The damaging biological effects of ionizing radiation were discovered by the American biologist Herman Joseph Mueller in 1926. Work done
by Mueller and others in the early days of studying X rays, as well as natural and artificial radioactivity, has helped us understand mutations that occur spontaneously due to cosmic radiation from our sun and many other celestial sources dating back to the dawn of time. These mutations occur despite the protective effects of the atmosphere (equivalent to about 10 meters of water) and the Van Allen belts, two regions of charged particles that partly surround the earth at heights of several thousand kilometers.

The unwelcome consequences of the atomic revolution include nuclear war and radiation sickness, the Chernobyl meltdown, and the possibility of worldwide nuclear holocaust. Negative aspects of chemistry include pollution, drug abuse, and the problems posed by semiconductors (a subject covered in my discussion of the sixth revolution), computer viruses, identity theft, privacy invasion, cyberwar, and bioterror.

The original Human Genome Project sequenced the 3 billion base pairs of the human genome at a cost of $3 billion, or at an average cost of one dollar per base pair. That was a milestone of science, but its significance was offset by two factors: its high cost and the fact that the genome that had actually been sequenced was not the DNA of any one individual but a composite genome of many DNA contributors. It was the sequence of a “blended” person, and so it had little value in practical, personal, or medical terms. It was the moon landing of molecular biology. (The genomes of two individual humans differ by an average of about 3 million positions, which is approximately 0.1 percent of the total. Most of these are single base changes or changes in tandem repeat lengths.)

Although the genomes of any two people are 99.9 percent identical, the genetic differences between them account for much of their physical uniqueness, including predisposition to illness and differential responses to drugs, medical treatments, and infectious disease agents, as well as their psychological individuality and personal tastes, preferences, talents and deficiencies.

Hitherto, medicine has operated largely on a one-size-fits-all approach, tailoring a cure to the disease rather than to the person who is suffering from it. For a long time this made sense: a disease, after all, is a specific thing and human beings are genetically almost carbon copies of each other, and so what alleviates a disease for one person ought to perform equally well for the next. But often enough it doesn't. A drug that helps one person may be toxic to another, may provoke an allergic reaction or have other adverse side effects, or may have no effect whatsoever. Such differential responses are often found with respect to antidepressant medications, for example, many of which can take two weeks or more to have an effect, if any. Discovering a genetic basis for these varying outcomes would allow doctors to prescribe drugs that worked most effectively for a given person. Indeed, such discoveries are now laying the groundwork for the new field of pharmacogenomics.

People also respond differently to the same disease agent. The bacterium
Staphylococcus aureus
, for instance, kills an average of 100,000 Americans per year, more than any other single microorganism. It is the leading cause of heart, skin, and soft tissue infections, and is a common cause of pneumonia. It is the top causal agent of nosocomial (hospital-acquired) infections. Nevertheless, some 30 percent of the population harbor the pathogen in their nasal passages but show no sign of infection. Evidently there are genetic factors at work that explain these dissimilar responses to the microbe. This finding has implications for the future of medicine. If a patient's genome sequence were part of his or her electronic medical record, and susceptibility to
Staph
infection was known in advance, then the subject could be treated with appropriate antibiotics before being admitted to a hospital where the infection might otherwise be acquired.

The original Human Genome Project was made possible by the then emerging niche technology of automated DNA sequencing machines. Ten years after the success of the HGP, improvements in that technology have brought down costs to levels at which commercial personal genomic services have become a reality, and one day a complete human genome sequence will be available for about $1,000. This will inaugurate the era of
new approaches to health and disease, an era of personalized genomic medicine.

As a teenager, I had the grand notion that we ought to sequence everybody—all 6 billion base pairs for all the 4 to 7 billion of us—and store the data in computers. This was a sort of “genomes for all” approach, to be pursued for predictive reasons alone. The idea was that if you knew the types of diseases or medical conditions you were predisposed to—adult-onset diabetes, let's say—then you could take appropriate countermeasures early in life. Given the cost of both sequencing technology and computers in those days, that plan was naive, to say the least.

But today, when the cost of computers and automated DNA sequencing technology continues to plummet, my plan is not so naive. Whereas the data storage capacity and processing speeds of computers has tended to follow Moore's Law over the past fifty years, with the number of transistors on integrated circuits doubling every year and a half, the cost-effectiveness of DNA sequencing has increased by about ten times per year over the last six years.
*
Such improvements are only likely to accelerate, and consequently the sequencing of whole populations at low cost soon will be possible.

I still think that, ideally, all who desire it should be able to have their genome sequenced, and for predictive reasons first and foremost. After all, there are already about two thousand known, actionable, and highly predictive genetic associations. Even though they may be rare, they are nevertheless predictable and actionable—conditions that you can do something about.

Another reason to sequence everybody is to create a database that shows correlations between genotype and phenotype—between a person's genome and the set of observable characteristics that result from the interaction of the person's genome with the environment. (As geneticists like to say, the genes may load the gun but the environment pulls the trigger.)
There are correlations not only between genes and diseases but between genes and observable traits such as eye color, hair color, facial features, cognitive abilities, eating habits, lifestyle, personal history and experiences, career choices, mental outlook, and lots of other things. The genomic database would be an immense toolbox for understanding the myriad ways in which genes and the environment interact to form the sum total of human individuality and variability.

This dataset would have to be fully open to researchers, to any investigator who wanted to use it for any purpose whatsoever, whether to generate hypotheses, run tests, establish or disprove correlations on any level, or anything else. That would mean open publication of the individual's genome and phenotype on the Internet, available for all the world to see. In effect it would be putting your life story, medical history, and genetic makeup on the web. It would be the Facebook of DNA.