Watch Out, Darwin

“Darwin Turns 200” read the January 2009 headlines.  The birthday fireworks included a series of fascinating articles published by  Science News; a commemorative edition of National Geographic with the suggestive title “What Darwin Didn’t Know,” and a related web site with an interactive Flash app showing a 50-million-year-old wolf-like Pakicetus morphing into amphibian-like Ambulocetus, morphing into dolphin-like Dorudon.

Had Darwin lived to be 200, his jaw would have dropped to learn that indeed you can mess with mother nature. Technology now exists to make multiplex alterations to genetic material so that changes to bacteria that normally take several months can be completed in days.  Evolution on fast forward.

Twenty-two-year-old Cambridge graduate Charles Darwin was many years away from publishing his paradigm-shifting book, The Origin of Species, when His Majesty’s Ship Beagle was anchored near Bahia Blanca – a settlement at the opening of a bay not far from Buenos Aires –- on its epic journey towards the now famous Galapagos Islands in 1832.  Darwin’s observations and discovery of the role of natural selection in evolution on this voyage led to his famous and highly controversial statement in later life that, “All the organic beings which have ever lived on this earth have descended from one primordial form.”  Heresy, of course, at the time.

There are a lot of things that Darwin didn’t — and couldn’t — know then about the mechanisms of evolution.  It took a team of young researchers in the 1950s, including Francis Crick and James Watson – to elaborate the structure of chemist Linus Pauling’s alpha helix using X-ray crystallography and molecular model building. And so they decoded the language of life, — the double helix Deoxyribonucleic acid (DNA) and a simple four-letter chemical code.  With this discovery, the fossil evidence of the “descent of species” that Charles Darwin initially observed in armadillos, rheas, and ground sloths while surveying the South American coastline — and later in the now famous Galapagos finches — became a matter of reading encoded strands of DNA like a book. 

Genetic sequencing of DNA is now big business.  George Church, Professor of Genetics at Harvard Medical School and Director of the Center for Computational Genetics developed the first direct genomic sequencing method. This led to automation and software used for the first commercial genome sequence, a pathogen called Helicobacter, a genus of bacteria possessing a characteristic helix shape (ah, there’s that helix again).  This nasty little guy is associated with peptic ulcers, chronic gastritis, duodenitis, and stomach cancer.  Other bacterial genomic sequences are more benign and potentially very beneficial.  With more effective genomic sequencing, this will mean better bacteria for the production of drugs, nutrients, and biofuels.

Biological evolution as observed in the fossil record spans millions of years.   Machine evolution, arguably the progeny of biological evolution in the form of ever more sophisticated human-generated computational devices and associated AI software, has spanned maybe a hundred a fifty years since the landmark design of Charles Babbage’s Difference Engine (the first mechanical “computer” that was never actually built but was designed during Darwin’s lifetime).  Now, with Church’s genetic sequencing technology, biological evolution can occur in days. 

This, in fact, is what Church and his team of researchers are now able to demonstrate.  Called multiplex-automated genomic engineering (MAGE), up to 50 changes to a bacterial genome can be made nearly simultaneously to accelerate development of bacterial cells.  "What once took months now takes days," says Stephen del Cardayré, vice president of research and development at LS9, a biofuels company based in South San Francisco of which Church is a founder.

Using MAGE, researchers generate 50 short strands of DNA, each containing a sequence similar to a gene or gene regulatory sequence in the target genome, but one that has been updated in some way, incorporating a change that might “make an enzyme more efficient, or boost production of a particular protein.”

The DNA is mixed into a vial of bacteria, which is then put into a special machine in Church’s lab. The mixture is subjected to “a precisely choreographed routine of temperature and chemical cycles that encourage the bacterial cells to take up the foreign DNA, swapping it into their genomes in place of the native piece it resembles.”  Single-stranded pieces of DNA most likely "fake out the cell’s DNA replication machinery, sneaking in and filling a gap”, says Church. Each successive generation of the rapidly reproducing bacteria absorbs more and more of the foreign DNA, “ultimately producing a population that has all the desired genetic changes.”

In one experiment, the DNA strands targeted genes known to be involved in lycopene production.   Lycopene is a red, fat-soluble pigment found in certain plants and microorganisms and is a powerful antioxidant.  Church’s team was able to monitor multiple tubes of engineered bacteria for production of the bright-red compound.  Amazingly, in just three days they had generated a genetic strain that could produce five times more lycopene.  The results, to be published by Harvard University. show that “The best lycopene producer had 24 genetic changes — four that completed blocked production of the gene’s protein, and 20 that resulted in small or large changes in the expression of that gene.”

Speeding up the evolution of a bacteria to produce an antioxidant or biofuel sounds pretty promising.  But what about the production of a pathogenic bacteria like Helicobacter?  Messing with mother nature is not without its critics, and the field of bioengineering ethics is still fairly immature.  Bill Joy’s well-known article, “Why the Future Doesn’t Need Us,” offers a warning about the possible extreme consequences of tinkering with evolution through bioengineering.   In the SciFi novel, The White Plague by Frank Herbert, a molecular biologist is driven insane by the senseless murder of his family and seeks revenge by constructing and disseminating a new and highly contagious plague “that kills widely but selectively.”  Joy writes, “While there are many important issues here, my own major concern with genetic engineering is narrower: that it gives the power – whether militarily, accidentally, or in a deliberate terrorist act – to create a White Plague.”

Hmmm… so a possible trade off in the development of a biofuel –- one that might help solve the world’s energy crisis –- is the risk of a runaway sped-up evolutionary process that results in a doomsday scenario like a White Plague?  Hypothetical, yes, but what would Darwin say?  He might have trouble blowing out his 200 candles.