Regenesis (22 page)

AUG
AGGCUU
UUUGUG
UAG

then after recoding, the sequence would be:

AUG
CGGCUA
UUUGUG
UAA

(altered codons in black boxes), still making the same old MRLFV peptide, because the changed codons are synonymous with and perform the same function as the original ones. But if a tiny gene like the original one above were required for an incoming virus to be replicated, the virus would still be using the original five codons; and if the host had repurposed the original three, then the virus would find (much to its surprise!) that three of its precious codons (
AGG,CUU,UAG
) no longer worked.

We are in the midst of changing a dozen codons genome-wide in
E. coli
(in parentheses is the one-letter abbreviation for the amino acid or stop encoded, together with the number of times each is used in the small viral genome below): ACC (T, 24), AGA (R, 10), AGG (R, 6), AUA (I, 19), CCC (P, 10), CGG (R, 12), CUC (L, 27), CUU (L, 19), GCC (A, 20), GUC (V, 21), UAG (stop, 2), UCC (S, 20). This recoding strategy would affect 190 codons of the 1,147 total in the virus below. Most viruses use those twelve codons even more times in essential functions and “expect” a good host (or hostess) to provide the tRNA molecules that recognize them. But after our recoding, the essential viral RNA molecules stall on the ribosomes as soon as any of the missing tRNA molecules are needed, and the game is over.

Figure 5.4
is the full sequence of one of the smallest known viruses (MS2)—the first genome ever sequenced (in 1976 by Walter Fiers and team). It's related to the first genome subjected to Darwinian molecular evolution in the lab (Sol Spiegleman's monster Q-beta in 1965). The natural MS2 genome encodes four known proteins, which (in order along the genome, which is also essentially the mRNA) are: the
maturation protein
(one copy per virus) that holds onto a unique point in the RNA genome and guides it into the shell coating the virus and later into the host cell; the
major coat protein
(180 copies form the outer shell of the virus); a
lysis gene
used to help the baby viruses get out of the trashed cell host; and finally, the
gene for the polymerase
that makes copies of the genome. Interestingly, the lysis gene extensively overlaps the coat and replication proteins (underlined) so those base pairs are duplicated in parentheses in
Figure 5.4
. The protein coding regions are indicated by spaces between the triplet codons. The regions without spaces are not translated into proteins but are useful in regulation of timing and levels of the proteins.

Figure 5.4
The smallest viral genome? Think of the above as a detailed picture of a beautiful cathedral. You don't have to see or understand each stone, but you should get a feeling for the type of motifs that the architects used.

In
Figure 5.4
, the twelve codons that we are changing in the host (
E. coli
) of this virus are in uppercase and black-boxed. You can see how unlikely it is that this virus would get exactly these 190 changes all at once.

An essential condition here is that you must change the
E. coli
cell's genome while the virus isn't present in the cell. If you do it slowly while the virus is inside the cell, as in natural evolution, then the virus keeps pace step by step with every bacterial innovation in a kind of arms race. By doing this recoding “offline” we can introduce something that requires so many changes all at once in the virus that it can never get enough random mutations made simultaneously to accommodate the new state of the cell. Indeed, the changed cells should now be resistant to viruses that they have never seen before. In the best case for the virus, it would have a small genome (fewer chances to get one of the missing codons), a high mutation rate (to get rid of the newly impotent codons), and a large viral population (more ways to win). The smallest viruses that don't depend on other viruses are about 3,000 base pairs in length. Let's say (very generously) that would be 10 places in the 3,000 base pairs that need to change to deal with the new host code. I explained how high a mutation rate can go in
Chapter 3
, so let's pick an aggressively high rate of one error in 1,000 base pairs or about three errors per viral genome. That means 5 percent will have no mutations and 0.03 percent will have ten mutations or more. Of those with ten mutations, only one in 10,000 will be viable and of those, one in 10
²⁴
will have the correct ten changes in the genome. So a population of 10
²⁸
of that species of virus would be needed to find one that could handle the new host. But that is on the order of all virus particles of all types in the world today. The odds get worse fast for the virus if more than ten changes are needed, and exponentially worse with the number of required changes.

E. coli
has about 4,200 protein coding genes. Once we've been successful with
E. coli
and other industrial microbes, then we can tackle agricultural plants and animals that have some 20,000 protein genes—only five times that of
E. coli
. The changes would be introduced to the germ lines of the animals so that all of their progeny would also be resistant to all viruses. This is typically done by engineering pluripotent stem cells in culture and
then implanting them into blastocyst stage embryos (one in the later stages of cleavage).

If all of the above practical applications work out well, then the temptation to apply the same technique to humans, and to make ourselves multivirus resistant, will be quite strong. Initially this might be done on stem cells for adult therapies; for example, blood stem cells are routinely transplanted to cure blood diseases like cancer. If you could offer stem cells that are both cancer free and virus resistant, they might be more desirable than the same cells that are merely cancer free. Indeed, there will be a demand for those cells to be not just cancer free but cancer resistant too. That would require another set of genome changes almost as complex as those needed to produce viral resistance.

Possible unintended negative consequences of using this technique would also have to be taken into account; for example, nutritionally enslaving the changed cells so that they can't escape from the lab and beat all natural relatives (which are still virus-limited). But the potential payoff of multivirus resistance is so huge that this is a procedure that almost demands to be tried.

Multivirus resistance, if and when it's engineered into the human genome, does not necessarily make us immune to nonviral diseases such as those caused by parasites (e.g., malaria), bacteria (e.g., tuberculosis), or prions (e.g., mad cow disease). The pathogens that cause these diseases don't work by replicating themselves using human translation machinery of the human host cell. A speculative approach that could, in principle, provide protection from both viruses and cellular parasites is the mirror cell idea mentioned in
Chapters 1
and
3
. This would be much more challenging than making a simple mirror bacterial cell or making a viral-resistant human using code changes, but it's probably feasible. All of the tricks that pathogens use to evade the human immune system would fail in mirror humans since those tricks depend on specific chiral receptors. Furthermore, the enzymes they need to poke holes and digest the polymers of the
host (DNAses, RNAses, proteases, lipases, etc.) employ high chiral specificity and hence would be useless, and nearly all of the favorite foods needed to sustain those pathogens would be unavailable.

Finally, supposing that one day we have managed to conquer an impressive array of human maladies, including infectious disease of almost every kind, we might then turn our attention to a future era in which members of the human species might occupy an entirely new ecological niche . . . on another planet. Mars, for example.

One of the primary hazards of space travel is the threat of radiation damage. Even on earth, ultraviolet radiation causes skin cancers ranging from the relatively benign basal cell carcinoma to the relatively deadly malignant melanoma. And that's with the shielding effects of the earth's atmosphere already in place and working for us. Departing from that semiprotective buffer zone is to enter a realm that's especially hostile to human health.

Radiation in open space is of two types: electromagnetic radiation, which consists of massless photons, and high-speed particles that have mass, including atomic nuclei and electrons. Electromagnetic radiation travels at the speed of light, and the various types are distinguished by their wavelengths (the distance from one wave crest to the next) and frequencies (expressed in kilohertz, or kHz). The shorter the wavelength, the higher the frequency, and the greater the energy carried by the photon. X rays and gamma rays are the highest frequency forms of electromagnetic radiation and can do the greatest damage to human cells, tissues, and DNA. Gamma rays can penetrate the body and rip apart DNA molecules and damage sperm and egg cells as well as the reproductive organs. Gamma rays are used in medicine to kill cancer cells.

Gamma rays are a form of ionizing radiation—they carry enough energy to strip electrons from the atoms or molecules to which they are attached. They affect the body's chemistry in a way that can lead to serious health problems, including cancer, tumors, and DNA damage.

There's a lot of radiation in space, and people traveling to Mars would experience six months' worth of radiation every twenty-four hours. This means that a one-year outbound voyage would subject the traveler to a
dose of radiation equivalent to 180 years on the home planet. Clearly spacefarers are going to need radiation protection.

Lead shielding is one way to do it. Unfortunately, the amount of lead required might make the spacecraft too heavy to reach escape velocity. Fortunately, there are radiation-resistant animals. If we could find the genes responsible for their ability to resist radiation, then perhaps we could import those genes into our own genome and become radiation-resistant ourselves.

The all-time champion radiation-resistant organism is the extremely hardy bacterium
Deinococcus radiodurans
, a creature whose very name means “radiation-enduring.” It is listed in the
Guinness Book of World Records
as the world's toughest bacterium, and has been informally nicknamed “Conan the Bacterium.” It was discovered in 1956 by researchers conducting food sterilization experiments using high-dose gamma radiation, which it survived easily. This microbe can withstand a thousand times the gamma radiation that would kill a human being. Although its genome has been completely sequenced, bacteria are phylogenetically too distant from the human lineage for their genes to be easily usable.

But there is a backup radiation-resistant organism that happens to be an animal, the Bdelloid rotifer. This is a class of small invertebrates that live in freshwater pools, on the surfaces of mosses and lichens, and even in habitats that periodically dry up. To survive extended periods of desiccation, these animals have evolved the ability to repair portions of their DNA that gets damaged under these harsh conditions. In 2007, my Harvard colleagues Matthew Meselson and Eugene Gladyshev performed a series of experiments in which they subjected two species of these rotifers to high levels of ionizing radiation. They survived these megadoses well enough to repair their own double-strand DNA breaks and to produce viable offspring. (A human being would be killed by a hundredth of the radiation levels tolerated by the rotifers.) Note also the humble midge fly
Polypedilum vanderplanki
mentioned in
Chapter 3
and Epilogue.

If we could locate the genetic sequences that code for the rotifer's extraordinary DNA self-repair abilities, it would theoretically be possible to isolate and then import them into our own genome, with the result that
we too would have those same genomic talents and consequently increased resistance to ionizing radiation.