August 01, 2005
New Tool Speeds Up DNA Sequencing By 100 Times

DNA sequencing keeps getting faster and cheaper.

454 Life Sciences Corporation, a majority-owned subsidiary of CuraGen Corporation , today announced the publication of a new genome sequencing technique 100 times faster than previous technologies. This is the first new technology for genome sequencing to be developed and commercialized since Sanger-based DNA sequencing. 454's proprietary technology is described in the paper "Genome sequencing in microfabricated high-density picoliter reactors," in the July 31, 2005, online issue of Nature, with the print edition of the paper to follow later in the year. The technique was demonstrated by repeatedly sequencing the bacterial genome Mycoplasma genitalium in four hours, with up to and exceeding 99.99% accuracy. With a 100-fold increase in throughput over current sequencing technology, 454 Life Sciences' instrument system opens up new uses for sequencing, including personalized medicine and diagnostics, oncology research, understanding third world diseases, and providing fast responses to bioterrorism threats and diagnostics.

"It is clear that sequencing technology needs to continue to become smaller, faster and less expensive in order to fulfill the promise of personalized medicine," said Francis S. Collins, M.D., Ph.D., Director of the National Human Genome Research Institute. "We are excited that our support of sequencing technology development is yielding results and we look forward to the applications of such innovative technologies in biomedical research and, ultimately, the clinic."

In May 2004, the NHGRI awarded a grant to 454 Life Sciences to help fund the scale-up of 454 Life Sciences' technique toward the sequencing of larger genomes, starting with bacterial genomes, and to develop the Company's ultraminiaturized technology as a method to sequence routinely individual human genomes. The scalable, highly parallel system described in this article sequenced 25 million base pairs, at 99% or better accuracy, in a single four hour run. The researchers illustrated the technique by sequencing the genome of the Mycoplasma genitalium bacterium.

"Much like the personal computer opened up computing to a larger audience, this work will enable the widespread use of sequencing in a number of fields, and ultimately place machines in your doctor's office," stated Jonathan Rothberg, Ph.D., senior author and 454 Life Sciences' Founder and Chairman of the Board of Directors. "This sequencing technique, leveraging the power of microfabrication, is 100 times faster than standard sequencing methods at the start of its development cycle. We expect, as with computers, for it to get more powerful and cheaper each year, as we continue to advance and miniaturize the technology."

To repeat a frequent FuturePundit theme: Biotechnology is going to advance at the rate of computer technology because biotechnology is shifting toward the use of very small scale devices. The current cost of human DNA sequencing is in the tens of millions of dollars per person. But that high cost won't last for much longer.

The half million dollar sequencing machine uses 1.6 million tiny reaction wells in parallel.

The novel sequencing technique, designed by Jonathan M. Rothberg of 454 Life Sciences Corp. in Branford, Conn., and his colleagues, uses tiny fiber-optic reaction vessels that measure just 55 micrometers deep and 50 micrometers across--a slide containing 1.6 million wells takes up just 60 square millimeters.

The 25 million base pairs that this machine sequenced in 4 hours should be compared to the approximately 3 billion base pairs in the human genome. If the machine's ability to process 25 million base pairs in 4 hours scales up to larger genomes then the human genome would take 480 hours or 20 days on this machine. But there are additional challenges in sequencing a large genome such as breaking it down into doable pieces. Also, the genome has to be read several times to correct for errors.

This article has details on the process used by this sequencing instrument.

The 454 approach involves shearing the starting material DNA using a nebulizer. Rothberg explains: “[We] nebulize the DNA into little fragments, shake it in oil and water, so each DNA fragment goes into a separate water droplet. So instead of bacteria, we separate the DNA into drops. Then we do PCR, so every drop has 10 million copies. Then we put in a bead, drive the DNA to the bead, so instead of the cloning and robots, one person can prepare any genome.”

The DNA-covered beads are loaded into the microscopic hexagonal wells of a fiber-optic slide, which contains about 1.6 million wells. In 454’s benchtop instrument, chemicals and reagents flow over the beads in the wells. Solutions containing each nucleotide are applied in a repetitive cycle, in the order T-C-A-G. Excess reagent is washed away using a nuclease, before a fresh solution is applied. This cycle is repeated dozens of times.

The researchers see their techology following a similar pattern to the development of integrated circuits which have sped up at the rate predicted by Intel co-founder Gordon Moore with his famous Moore's Law.

“Future increases in throughput, and a concomitant reduction in cost per base, may come from the continued miniaturization of the fibre-optic reactors, allowing more sequence to be produced per unit area – a scaling characteristic similar to that which enabled the prediction of significant improvements in the integrated circuit at the start of its development cycle.”

Future iterations of their design will increase the level of parallelization while at the same time keeping costs the same per instrument or even lowering costs per instrument. So these folks have an approach that will drive down DNA sequencing costs by orders of magnitude.

Rothberg expects individual DNA sequencing for medical purposes once DNA sequencing costs fall to $20,000.

Jonathan Rothberg, board chairman of 454 Life Sciences, said the company was already able to decode DNA 400 units at a time in test machines. It was working toward sequencing a human genome for $100,000, and if costs could be further reduced to $20,000 the sequencing of individual genomes would be medically worthwhile, Dr. Rothberg said.

Another very important application of cheap DNA sequencing technology which is rarely mentioned is in social sciences. Cheap DNA sequencing will allow controlling for genetic influences on behavior in social science experiments. Most existing social science research results will be discredited by experiments that control for genetic influences. The excessive assumption of environmental influences on human behaviors and abilities will be discredited. This will lead to the disproof of key assumptions underlying beliefs of factions on both the political Left and the political Right.

Share |      Randall Parker, 2005 August 01 10:14 AM  Biotech Advance Rates


Comments
Anonymous said at August 1, 2005 10:24 AM:

[This will lead to the disproof of key assumptions underlying beliefs of factions on both the political Left and the political Right.]
That is, of course, assuming that political factors don't prevent this techonology from even being considered in practice. You'd be surprised how fiercly some people hold on to their beleifs. Evidence has nothing to do with it.

Ivan said at August 1, 2005 10:53 AM:

No, Randall, it will lead to the disproof of SOME key assumptions underlying beliefs of SOME factions on both the political Left and the political right. Others will be reinforced by what the research shows us.

The research should allow us to draw a brighter line between genetic effects and environmental effects. It does not mean that there are NO environmental effects. I'm sure that's what you really meant. Thanks.

Randall Parker said at August 1, 2005 11:21 AM:

Ivan,

By not saying all assumptions or all factions I think I implied "some".

For example, while I consider myself as being on the political Right I do not consider myself a member of one of the Right's factions that are going to suffer much undermining of beliefs due to genetic discoveries. I'd place myself among the evolutionary conservatives. Is there a corresponding group of evolutionary liberals? If so, their ranks are even smaller than the ranks of the evolutionary conservatives.

Yes, of course there are environmental effects.

But even many of the non-genetic effects are not environmental - at least not social environmental. Some of the non-genetic effects are just plain noise. Brownian motion and other sources of noise make epigenetic state different. Development alters. Some small number of social scientists are now speaking of "non-shared" environmental influences. But I think social scientists as a whole still have a long way to go to recognize how small the role is for SES and other shared environmental factors.

BTW, In the long run I've predicted that children will become more genetically determined.

jim moore said at August 1, 2005 12:49 PM:

I would like to make a couple of points.

1.) More than any other animal, humans are effected by their social / cultural environments. Only a few other animals can express what could be considered to be a cultural heritage.
2.) Humans have a very long childhood and a comparatively slow rate of development, both of which tend to maximize the possibility of social influence.
3.) The social system has been the prime actor in “natural selection” for humans and proto-humans for millions of years. By this I mean that individual’s status in the group is the prime determinant of their reproductive success. (If the other apes kick you out of the group you don’t reproduce)
4.) Our current cultural system is developing a very deep understanding of the genetic system. We are learning how to insert and delete genes and how to selectively activate genes.

This makes me think that who (what?) children become will increasingly be less determined by the genes that they receive from their parents and more determined by social and cultural factors.

(Just to be clear I think that the genes you inherit are very important but the influence that social factors can have is increasing with time.)

Sam said at August 1, 2005 8:05 PM:

Jim Moore,

Totally agree. Many people like to place blame on bad genes and bad blood, when really it is clear from simple observation that the dominant influences on people is the environment in which they grow up and live.

apocalypse said at August 1, 2005 8:50 PM:

"This makes me think that who (what?) children become will increasingly be less determined by the genes that they receive from their parents and more determined by social and cultural factors."

I personally differ, and agree more with Randall, with advanced gm things can get ALOT more determined. Say you make your child more/less outspoken/extrover/introvert/shy the number of friends they'd have and how much time they'd spend inside the house could be significantly influenced. What of those genetic buffers that prevent physical abuse from causing abnormal development? Some parents may like to keep extremely strict physical discipline(I personally don't agree) and still get normal development.

In other animals we've seen how elaborate behavior can even be coded into the genes(don't recall right now the species, may've been some species of bird.). There's also imprinting/sex-drive/aggressiveness-non-aggressiveness/iq/etc, things like jealousy and dislike of individuals as partners, whom one's shared an extreme amount of one's childhood with, obviously have been significant genetic component. Say a parent who favors polyamory, they may simply go to great lengths to impede the mechanisms behind jealousy, and also to allow simultaneous romantic affection towards multiple partners, so that their child may more likely end up with their same style. The pheromone system could also be re-strengthened to the lvl of our ancestors, allowing when combined with other mods, for significantly determined sexual-orientations.

You also have abilities, blindness/deafness or lack of such. Physique, attractiveness, charm, etc, etc... All of these can highly influence behavior. You can have a high IQ supah attractive, charming, graceful individual who's highly resistant to environmental stress(say school bullying, bad diet, etc), and highly outspoken/extrovert and very passive, with little sex drive. Or an extremely ugly introvert obese highly aggressive person with low iq. You could even, as said, make someone deaf/blind/etc, say you give someone no sex drive at all ever, that'll certainly significantly modify behavior.

I mean I can already imagine a future M-J going about messing with things, and causing very very nasty combos(very submissive, normal development with resistance to abuse, permanent imprinting but rather than imprinting as parent imprinting as a romantic partner, high sexual drive, some bonobo'ish genes, etc, etc, etc...), this would be something society would abhor.

Say we find obedience can be highly affected by genes(not sure if this' already been looked into) even if its only in some individuals. We've all seen char.s in movies/books/tv-shows/etc who worship their parents as Gods, and strongly desire to follow their every command to the letter, what if that sort of behavior is do to a significant genetic component? This sort of thing could most certainly allow for extreme forms of determinism where it the case. Only thing I see that could keep more determined behavior from being the case would be laws, and even so there's always gonna be black markets, and parents willing to do so.

Brett said at August 2, 2005 9:02 AM:

apocalypse:
Take your gm modified extrovert kid with his buffers against abuse, beat him with a stick every time he opens his mouth. How long does he remain an extrovert? Everybody likes to think he or she has the best genes lurking in his/her gonads. Call it the "Lake Wobeggon"(sp?) fallacy. Probably, you're about average. That's ok, so am I. I strongly believe that "breeding" is overrated in humans. There is also a whole other argument about whether you are so fully in control of the environment that your child will be raised in as a farmer is over his stock and crops. And how much practice do you have controlling for environment with children so that "blood can tell"? Way too many factors for me.

LPG said at August 2, 2005 9:09 AM:

Mayilyn Monroe was very beautiful in both an objective and subjective manner. She obviously had it. She is still with us as an icon to this day. Something about her appeals to all levels of apes. She is equally attractive and sought after by both men and women. She is emulated and impersonated by both sexes. Oh guess what? Her mother was insane and spent most of her life in a mental institution. Marilyn commited accidental or (not that it matters) deliberate suicide. She had a psyciatric, although incompetent, nurse looking after her and she still came to a bad end. What does that tell you about genetic influence? Of course if she hadn't met the Kennedys, who obviously have some sort of gene that causes death in women; she might have survived past her mother, but was already on her way to permanant institutionalisation. She ended up being an institutuion one way or the other.

apocalypse said at August 2, 2005 1:00 PM:

"Take your gm modified extrovert kid with his buffers against abuse, beat him with a stick every time he opens his mouth. How long does he remain an extrovert? Everybody likes to think he or she has the best genes lurking in his/her gonads. Call it the "Lake Wobeggon"(sp?) fallacy. Probably, you're about average. That's ok, so am I. I strongly believe that "breeding" is overrated in humans. There is also a whole other argument about whether you are so fully in control of the environment that your child will be raised in as a farmer is over his stock and crops. And how much practice do you have controlling for environment with children so that "blood can tell"? Way too many factors for me."

You could also knock the ability to feel physical pain as sometimes occurs on some children, though this does bring forth serious side-effects(bitting of tongue, self-cutting, self-injuring behavior at least at early ages.).

The dmg caused by exposure to certain toxins can be diminished by introducing resistance to the effects of such. Physical dmg to the point of brain dmg, could probably be prevented from being permanent given extensive regen abilities. You could probably make it so metabolism suspends itself(cryptobiosis) if the environmental influence(say absence of nutrients, presence of toxins) does not allow the coded dev, in such a case one'd have to kill or go to extensive measures to hack/trick the coded traits from developing.

We've seen how addicted people react, how even after all that social influence simple chem.s that affect their mind can override the complex behavior of an adult, altering goals, mental state, conduct the whole enchilada. This is but a simple drug, what power lies in altering the very structures that enable the mind itself? Anger, Happiness, Sadness, Jealousy, the emotions and the facial expressions they entail seem to have at their root substantial genetic components. There are individuals that when struct/physically injured repeatedly will strike back, or develop internal hate, others will dev. abnormally even up to the point of dev. mental illness, yet still there are other's who'd grow submissive and loving of he who'd done so. This is even seen in grown up adults, even after decades of social influence, with partners who love and protect their abuser and even seek such BDSM.

When you look deep down, and think about it, things like sexuality are basically pointless taken the interests of a highly dev. mind... yet despite it being so, such behavior remains central to the lives of many, to society/culture, to our moral codes of conduct. If you had the knowhow you'd probably be able to posit behavior such as "licking each others thumbs or even some vigorous hand shake" as uber important too, of utmost moral importance causing the mere image of a thumb to be highly erotic, while those of other parts of the body not being so(probably'd have to increase the sensitivity of nerves around such, and make such activities highly pleasurable to aid it being so).

If you could somehow maintain those traits through the generations and allow for a society to dev. independent from the present one, you'd probably see the ridiculousness of the behavior that'd be taken. Everyone using gloves all the time(may even go about naked-by our standards- in many indoor environments.), Religions espousing the importance of wearing gloves and not shaking-hands/licking-thumbs till marriage. Parents telling their kids "don't let anyone see your hand without your gloves, and don't let anyone touch you there". Hand-shaking/thumb-licking would be a sin, immoral, and a crime under some circumstances in the eyes of the mayority. People'd go to great lengths to get images and videos of people hand-shacking/licking-thumbs vigorously, and it'd be a central aspect of their lives, culture/society, and moral code. I can imagine many saying: "Oh, so you shacked-his-hand/licked-his-thumb!!! You unfaithful whore I'm leaving you!!!"... this be but a crude example to show how powerful and overriding a coded behavior can be, even if deep down it's a simple activity which'd should not've such overwhelming influence, such is the case even in our society.

Randall Parker said at August 2, 2005 2:22 PM:

Brett,

If you have to repeatedly beat someone with a stick to get them to stop acting in an extroverted fashion then this suggests extroversion is very innate. In fact, extroversion and introversion have a large genetic component.

Introversion and extraversion has also been the subject of innumerable studies that have indicated a large genetic component. In 1956 Eysenck, for example, in a study of identical and paternal twins, found that identical twins resembled each other more closely than fraternal twins in extraversion and introversion. He summarized the evidence for the heritability of personality in "The Biological Basis of Personality" (1967). Scarr (1969), studying the results of ten twin studies including Eysenck's and her own found moderate to high genetic contributions to social introversion -extraversion, and Horn, Plomin and Rosenman (1976) found that talking to strangers, which is a good indicator of introversion -extraversion, was the strongest of all the traits in which identical twins were more concordant than fraternal twins.

Differing levels of fear of the unfamiliar is very obviously hard-wired. An extreme example this is seen with sufferers of Williams Syndrome who lack fear of strangers. The deletions on chromosome 7 that cause Williams Syndrome cause abnormalities of the amygdala in the brain.

Researchers at the National Institute of Mental Health (NIMH), part of the National Institutes of Health, have discovered a genetically controlled brain mechanism responsible for social behavior in humans--one of the most important but least understood aspects of human nature. The findings are reported in Nature Neuroscience, published online on July 10, 2005.

The study compared the brains of healthy volunteers to those with a genetic abnormality, Williams Syndrome, a rare disorder that causes unique changes in social behavior. This comparison enabled the researchers to both define a brain circuit for social function in the healthy human brain, and identify the specific way in which it was affected by genetic changes in Williams Syndrome.

People with Williams Syndrome who are missing about 21 genes on chromosome seven are highly social and empathetic, even in situations that would elicit fear and anxiety in healthy people. They will eagerly, and often impulsively, engage in social interactions, even with strangers. However, they experience increased anxiety that is non-social, such as fear of spiders or heights (phobias) and worry excessively.

Look at highly aggressive criminals. The worst of them have to be stuck in isolation cells and handled by many guards whenever their cell is opened.

Or look at people with obsessive compulsive disorders. Or look at people who suffer depression or anxiety attacks. Do you think you can beat them out of their behaviors? I don't think so.

Some political views are learned. But as Dr. John Hibbing of the University of Nebraska, Dr. John R. Alford of Rice University and Dr. Carolyn L. Funk of Virginia Commonwealth have recently demonstrated, other political views are highly inherited.

The researchers then compared dizygotic or fraternal twins, who, like any biological siblings, share 50 percent of their genes, with monozygotic, or identical, twins, who share 100 percent of their genes.

Calculating how often identical twins agree on an issue and subtracting the rate at which fraternal twins agree on the same item provides a rough measure of genes' influence on that attitude. A shared family environment for twins reared together is assumed.

On school prayer, for example, the identical twins' opinions correlated at a rate of 0.66, a measure of how often they agreed. The correlation rate for fraternal twins was 0.46. This translated into a 41 percent contribution from inheritance.

As found in previous studies, attitudes about issues like school prayer, property taxes and the draft were among the most influenced by inheritance, the researchers found. Others like modern art and divorce were less so. And in the twins' overall score, derived from 28 questions, genes accounted for 53 percent of the differences.

But after correcting for the tendency of politically like-minded men and women to marry each other, the researchers also found that the twins' self-identification as Republican or Democrat was far more dependent on environmental factors like upbringing and life experience than was their social orientation, which the researchers call ideology. Inheritance accounted for 14 percent of the difference in party, the researchers found.

You Blank Slaters ought to read up on more twins research. Your intuitions about the malleability of human nature are not supported by the empirical evidence.

AA2 said at August 2, 2005 2:43 PM:

I find it sort of funny that the 'leftwing' sociologists look at people as a totally blank slate. AND many religious types on the 'rightwing' look at people as having total free will. Both discounting genetic influence in behavior.

I would think sociologists of all people who are studying these things professionally should know better. I have a feeling that political correctness dictates that they keep silent about the strong genetic correlations. If you go back and look at the research in the 20's and 30's where our social sciences were pretty developed, yet political correctness had not set in, there is a ton of very interesting research. Even into the 50's you see some of it, although not as radical.

Probably after where some of that research led, to the excesses of the 30's and 40's, there was a strong gut reaction against probing deeply into it.

Jim said at August 2, 2005 3:31 PM:

i think more direct cause-and-effect social experiments relating particular genes with particular physi-biological mechanisms will usher in an entirely new wave of bio-medical engineering. it will put old, correlation-type studies (like twin studies) to shame and in some cases completely undo previous conclusions and assumptions. furthermore, the information will be much more useful for engineering solutions to problems.

a similar analogy is well underway in materials science. for millenia man has understood that the addition of carbon to iron produced a strengthening effect that was far from linear across wide composition ranges, and in some cases it has an embrittling effect. only through the understanding of the smorgasborg of carbide particles that are precipitated in the steel at varying temperatures and a number of other mechanistic effects can the steel composition and heat treatment be optimized to achieve a given set of properties.

Randall Parker said at August 2, 2005 5:29 PM:

AA2,

I do not think social science really contributed to the development of Nazi ideology. In fact, since psychometric tests showed Jews were smarter than non-Jewish Germans the Nazis suppressed IQ tests. The Nazis are better thought of as tribal or at least pre-modern. The idea of wiping out whole peoples is something that Genghis Khan or the early Roman Empire builders would have understood.

The intellectual war against psychometrics research and human differences research was waged for ideological reasons. The promoters of the Blank Slate wanted everyone to view humans as blank slates in order to get them to accept social enginering for various utopian (though ultimately dystopian) purposes. Look at Lysenkoism in the Soviet Union under Stalin. The communists hated Darwinian evolution by natural selection. It was ideolgically very inconvenient. So they put ideology ahead of scientific truth. Russian biologists who were Darwinists ended up in Siberian concentration camps.

You are right that some right wing factions want to deny genetic influences on behavior. But the vast bulk of the enforcers of the taboos and thought police are Lefties. The academy is 90+% leftist in faculties. So the Right has little input into the suppression of research and the marginalization of those who point out inconvenient facts. Also, the major media outlets are of course staffed overwhelmingly with leftward leaning folks.

The irony here is that Leftists point at fundamentalist Christians who deny natural selection as the cause of species. But Leftists deny the consequences of natural selection on human behavior. I call these Leftists "neo-Cartesian dualists" since their position amounts to a claim that the approximately 6,000 genes which code for the nervous system in humans have been exempt from the forces of natural selection in all the environments humans moved into in the last 50,000 years or so. To believe what they believe one essentially has to imagine that God held out his hand about 50,000 years ago and claimed that henceforth natural selection would no longer operate on the genes that code for the nervous system.

Charles Darwin was the greatest scientific mind of the last couple of hundred years and yet his ideas are still widely resisted even by people who claim to accept natural selection. I can remember clearly when I was in late grade school (probably 13) deciding that I was going to believe things that made me uncomfortable or unhappy or disturbed if I thought those ideas were true. I only wish more people would make that decision. I'm tired of all the lies.

James Bowery said at August 3, 2005 6:50 AM:

I don't think its rational to compare political/religious groups without looking at how much violence they do, not to random humans, but to the truth. Virtually everyone believes in violence against humans is justified under the "rigth" circumstances. Almost all who deny it are hypocrites. The only rational basis for comparing these groups is on the basis of how rational their imputations are given the data at any point in time. Their "dogmas" or "morals" or "ethics" or... are really just clusters of working hypotheses imputed to varying degrees from the known data -- and the reality of our existence is we know so little.

On this basis it might be said that the "racists" were more irrational in the early part of the 20th century but after WW II it has clear that the "anti-racists" were more irraltional. This goes pretty much hand in hand with how much state power a particular religious group has at their disposal to enforce their imputations on others.

Remember, Lewontin wrote his fallacy over 30 years ago and there really was _no excuse_ for such a gross and fundamental error to come from a Harvard authority let alone have his conclusion form the basis of understanding of human genetic diversity among the elite of the most powerful nation on Earth. Lewontin's fallacy was outright intellectual buggery at the highest levels of civilization and proves beyond a reasonable doubt in my mind that any civilization that doesn't have the right of territorial secession as the foundation of all other rights should be targeted for destruction by any means necessary.

Charles Murray's accounting system in "On Human Accomplishment" didn't have negative numbers. Negative numbers were invented by the Arabs specifically for accounting purposes for a very good reason. Murray should retract his chapter on Jews.

AA2 said at August 3, 2005 7:45 PM:

I also came to a point about the same age as you where I decided that I was going to just look for the truth, even if it was uncomfortable. I imagine it is uncomfortable to many leftist academics to have their whole worldview threatened, and people have an amazing way of deluding themselves. Just change the facts when they run counter to their ideology.

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