Friday, May 21, 2010

Synthetic Life, First Edition

Ham Smith and Craig Venter, together with their coworkers, have made what is certainly the first ever living organism put together by a chemically synthesized genome.

The ingredients of the genome came from four bottles of chemicals, containing the equivalents of adenine (A), thymine (T), guanine (G) and cytosine (C), and a computer-stored information of the entire "tape" of the entire DNA sequence of Mycoplasma mycoides, a microorganism. (You can hear a podcast of Venter describing their work by clicking this link)

They chemically synthesized fragments of the genome in test tube, then used the "awesome power of yeast genetics" to stitch the fragments into a "complete" genome (with certain "water marks" and mutations created for specific purposes of identification and/or engineering) in baker's yeast (a totally different organism). Then the synthetic genome was introduced into a second microbe, Mycoplasma capricolum (as related to Mycoplsma mycoides as mouse is to humans) in various stages, debugged until the newly introduced synthetic genome took over the host cell and simultaneously the host genome was jettisoned.

What they now have is a completely new synthetic cell because most of the chemical building blocks of the new cell is now replaced by new molecules whose synthesis is directed by the synthesized genome.

This is a landmark technology achievement. It will also be touted as a landmark philosophical, psychological, ethical and moral watershed moment.

There is no doubt that it is a high moment in biotechnology. The scientific cleverness and engineering sophistication that went into this is of the finest order (I am still reading the pre-print and already much impressed).

However, its philosophical and extra-scientific implications are less than what some will surely claim.

There is no paradigm shift here: the concept has been consistent with scientific potentials of the day at least since 1991.

In fact, the crucial idea--that a host cell can be made to house a completely different genome and somehow be changed to the properties of the guest genome--was thinkable since a 1990 publication by Ron Davis in which his lab introduced full yeast genome into mouse cells, and I wrote a proposal to NSF, and got funded to introduce whole Arabidopsis chromosomes into yeast cells in stages by cell fusion (but did not succeed beyond the early stages due to technical reasons).

The fact that you can take over a host cell's "shell" ultimately by a new genome IS a challenging proposition which is first demonstrated by the present publication, and this is its most surprising novelty (beyond the technical tour-de-force).

None of it would likely persuade a sophisticated"believer" that man now can create life from fully inanimate objects (man cannot yet do so, because they needed living yeast cells and Mycoplsma capricolum cells, and M. mycoides genome information).

However, I can imagine now a fully synthetic life form being created some time in the future, where no previously living organism's "body part" materials will be used--in this direction recent work in Jack Szostak's laboratory in Harvard Medical School will be crucial. That synthetic organism will still have to use the "information" encoded in an already living organism's genome.

Perhaps the synthetic genome could use a mosaic of information from multiple organisms' genomes, and thus create a completely synthetic species. This would have to solve the issues of compatibility of gene regulation--a very difficult technical and theoretical problem. It will be a great achievement is successful.

Nevertheless, I still cannot imagine a completely synthetic organism in which both the genome (the software) and the "shell" (the hardware) are synthetic and did not exist before. Possible on paper, but not in reality. When that happens, man will have created life.

(If you click on the title, you should be directed to an editorial on the paper. IF you cannot access it, write in the comment and I will see what I can do)

Sunday, May 16, 2010


If ever there were
perfectly good 1.5 hour
lost to giddiness,
it was last night; feel-good nevertheless.
Babies suckling,
Babies crying,
Babies laughing,
Babies thumping
floor, babies thumping
themselves, babies thumping
each other, babies thumping
giddy cats; babies galore,
Babies with tinker toys,
Babies with nothin' more
than themselves: little boys,
And girls, and goats,
And mooing cows...

The lesson: never believe again
Women of childbearing age
Declaring: Surely you'll enjoy, I presage,
documentary notwithstandin'....

The hero of the movie, if there's one,
Was the heroic rooster, who done
The cute baby on bed peacefully a-snore,
Posed for the camera hidden behind door!!

(Tickets for two--$22)

Tuesday, May 11, 2010

The Hungry Tide

The Hungry Tide: A Novel The Hungry Tide: A Novel by Amitav Ghosh

My rating: 4 of 5 stars
Amitav Ghosh, the author of The Circle of Reason and The Shadow Lines, weaves a complex fabric with some of the fundamentals of the deepest corners of our mind: the animistic instinct, the urge to discover, and the magnetism of finding one's roots. All this woven against a primitive landscape of water and silt, time set against tidal surges and mangrove forest, a flat land low against a stormy sky in the Bengal delta, a place that Ghosh brings alive with the apparent deftness of long familiarity. The plot is brilliant--a young woman smitten with the bug of a naturalist's passion is looking for the elusive fresh water porpoise in the riverine Sunderbans, an uneducated fisherman youth, his youthful wife and the locals with convoluted past in the backdrop of 1970s Bengal, create a drama that is wholly compelling yet mysteriously magical. Ghosh draws with broad swaths of a charcoal, as it were, constructing a dark world of primitive elements that probe deeply into our human self with the ease and flourish of a master craftsman. Magic is in the air and water, in the sky and in dolphin's breath. The story attains a crescendo in the form of a huge storm that changes not merely the landscape. A book written with deft craftsmanship and intimate knowledge. Read it.

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Saturday, May 8, 2010

A Sea of Poppies

A Sea of Poppies Sea of Poppies by Amitav Ghosh

My rating: 2 of 5 stars
Apparently the first of a trilogy, Sea of Poppies has a meritorious plot. Beginning in the poppy plantations of north eastern India in 1830s, the novel explores pre-mutiny India under the East India Company rule, and follows its protagonists into a ship crossing the 'black waters' on its voyage to the Mauritius islands. Ghosh has done his homework well; his description of opium plantations is credible and so is his depiction of the landed gentry of precolonial Bengal and its contrast with its unsophisticated but wily new masters. Geography of 1830s Calcutta is fascinating to read. Where the book falls flat is in its overly dramatic, bollywood script of a story line, in its mix of authentic period pieces of linguistic constructs with lamentably modern colloquialisms given to post-bollywood mannerisms (and tollywood Bengali of 1980s) that ring hollow to the cognizant ear. Attempting to be Rushdiesque, Ghosh has fallen prey to the Bollywood film script genre (if that exists!). I bet someone in Bombay would be calling Ghosh's agent by this time. It would be a spicy flick; a sad loss, given that Ghosh had a plot as strong as any of his previous novels.

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Tuesday, May 4, 2010

I should've been an economist

Had I read Asimov’s The Foundation series when I was in high school, or had I met an economist who was not a banker or a financial advisor but an economic theorist, I most likely would have chosen economics as a career option.

As it turned out, back in high school I thought economics is a boring field of stiff accountants, where you learn how to balance books and make investments. Since I equated money with vulgar incentives, a man-made device meant for corrupting the mind, I avoided all contact with economics though some contact with money was pleasurable. I knew no better until my late 30s, when I chanced upon Amartya Sen’s articles in the Scientific American.

Having always had that love for neat theories with the power of explaining large things, I gravitated towards biology because I thought the complexity of biology is ripe for theory. I was mistaken. In biology nearly anything goes. Evolution finds one solution among many. There are very few general principles.

Surely there are some principles. Evolution by natural selection on rare spontaneous variants is a powerful principle. Then the idea of information as an organizing principle is another. Coding theory. Mendel’s laws and Hardy-Weinberg equilibrium. Haldane’s rule. But these can be counted on one’s digits.

This general lack of theories gave biology its charms too. Just when I think of myself as so clever having figured out something, there comes the unexpected surprise. During my own career there were many such surprises. Splicing; RNA enzymes; PCR (dang! I should’ve thought ‘bout it!!); combinatorial design; miRNA. Perhaps the prion fold as a “bit-flipping” memory molecule is just over the horizon; hope it turns out to be true.

Biotechnology has profited from these unexpected insights in due courses, and more will surely come. It is even more surprising how staid most research in successful biotech companies usually is, and, paradoxically, how invigorating research can be in many unsuccessful biotech companies. This happens so much so that some say, for a biotech company to succeed one doesn’t need good science. One only needs simple, practical solutions and managed development.

Nothing can be further than the truth. The truth is that one never knows what would succeed. So the initial investment, at least in terms of time, must be long and tolerant of blind alleys—merely because there are very few theories in biology—there is only chance and surprise—there are few principled risk factor calculators, unlike in hedge fund investment. When one doesn’t know what will work, the best that one can do is to nurture the creative energy of the scientists. Less the management, more the nurture, the better. Scientists in powerful positions in biotech know this well. Managers in powerful position rarely appreciate this. Venture capital fund managers are even less tolerant. The balance between the next quarter’s books and the creative energy of science is a tough one to achieve; tough to tolerate the latter in the absence of a theory.

Nothin’ beats the austere satisfaction of constructing a purely algebraic formalism of a paradox, resolving it by logic, and finding its application to a thing as complicated as the voting behavior of people; as Arrow’s impossibility theorem shows, for example. Imagine an ‘impossibility theorem for a peptide drug for HIV-AIDs treatment’!

I should’ve been an economist.