Genomic Technologies Reviewed

Is a $1000 genome feasible?  Jay Shendure and colleagues break down this question into its components:

To resequence a genome, the sequencing error rate must be significantly lower than the amount of variation that is to be detected.  As human chromosomes differ at 1 in every 1,000 bases, an error rate of 1/100,000 bp is a reasonable goal. If the base accuracy of a RAW READ is 99.7% (on a par with state-of-the-art instruments), and assuming that errors are random and independent, then X3 coverage of each base will yield the desired error rate. However, to ensure a minimum X3 coverage of >95% of a diploid human genome, X6.5 coverage is required, or 40 billion raw bases. In this situation, the cost per base for an accurate US $1,000 genome must approach 40 million raw bases per US $1 — a 4–5-log improvement over current methods. Although they could potentially approach the cost of a US $2,000 computer, current integrated genomics devices typically cost US $50,000–500,000. If we assume that the capital/operating costs of our hypothetical instrument are similar to those of conventional electrophoretic sequencers, the bulk of improvements must derive from an increase in the rate of sequence acquisition per device from 24 bases per second (bp/s) to 450,000 bp/s. No assembly is required in resequencing a genome; sequencing reads need only be long enough to allow a given read to be matched to a unique location in an assembled reference genome, and then to determine whether and how that read differs from the reference. In a model in which bases are ordered at random, nearly all 20-bp reads would be expected to be unique (420 >>3109). However, as the mammalian genome falls short of being random, only 73% of 20-bp genomic reads can in fact be assigned to a single unique location. Achieving >95% uniqueness — a modest goal — will require reads of 60 bp.

Given these assumptions, a resequencing instrument that can deliver a US $1,000 human genome with reasonable coverage and accuracy will need to achieve 60-bp reads with 99.7% raw-base accuracy, acquiring data at a rate of 450,000 bp/s. Departures from this situation are almost certain, but will generally involve some trade-off — for example, dropping capital/operating costs by tenfold would enable an instrument with one-tenth of the throughput to achieve the same cost per base.

Read the whole article. 

Jay Shendure, Robi Mitra, Chris Varma, and George Church. Advanced Sequencing Technologies: Methods and Goals. Nature Reviews Genetics 5:335-344, 2004.  (I doubt the link to the article will be persistent.  Benevolently, the authors have posted preprint (pdf) at their recently updated Personal Genome Project website)

Finding the Fly in the Ointment: Pharmaco-Soda-nomics

Pharmacogenomics promises to help physicians tailor drug regimens to a patient’s genetic profile.  A recent event at Vanderbilt serves as a useful reminder that despite our best efforts to improve drug efficacy and to reduce the number and severity of toxic reactions to drugs with all kinds of fancy tools like pharmacogenomics, there is a swarm of flies threatening to muck up the ointment.  How about a citrus soda?

Glyn Moody on Googling the Genome

Glyn Moody, author of Digital Code of Life : How Bioinformatics is Revolutionizing Science, Medicine and Business has an article in the Guardian on the possibility of more or less googling your personal genome once the price of sequencing comes within range of the pocketbook.  One could even imagine a service similar to their "news alerts" where individuals are kept abreast of relevant advances in genomic medicine as they occur:

A bioinformatics program running on a PC could easily check our genomes for all genes associated with the autosomal recessive disorders that had been identified so far. Regular software updates downloaded from the internet - like those for anti-virus programs - would keep our search software abreast of the latest medical research.

Genetic testing will morph from a clinical to a computational procedure.  Even though the speed and efficiency of searching through the genome for blemishes might be as painless as running spell checker in a word processor, the disovery of misspellings might not be.  People will be faced with decisions about the types of constraints to place on genome searches.  While some might feel comfortable surfing their genome on their home computer others will undoubtedly want to foreordain, say, that search results include only treatable diseases. 

Moody also points out that privacy will be an issue: Who gets to google my genome besides me?  Employers?  Insurers?  Police?  Family members?      

Glyn Moody, Googling The Genome, The Guardian, April 15 2004.

(Thanks to Kristofer for the pointer)

NHGRI Requests One Cent Genotype

More evidence of the precipitous decline in the cost of sequencing and genotyping from a recent request for application (RFA): 

This RFA solicits applications for a cooperative agreement to augment the International HapMap Project by supporting the genotyping of approximately 2.25 million single nucleotide polymorphisms (SNPs) across the genome in 270 samples from four populations, at high quality and at a cost of about 1 cent per genotype…This RFA is being issued in response to recent technology improvements that have led to a large reduction in the cost of genotyping.  NHGRI estimates that it should now be possible to do large-scale genotyping for about one cent per genotype, which is considerably lower than the cost at the start of the HapMap Project [way back in October of 2002], and therefore to obtain more genotyping than had been planned initially.

You can read the whole RFA here.


Giving credit where it is due

The Dolan DNA Learning Center at Cold Spring Harbor is working with Clemson University to create a South Carolina DNA Learning Center.  From this news story:

"The mission of the Dolan DNA Learning Center is to prepare students and families to thrive in the gene age," said [David A.] Micklos, [executive director of the Dolan DNA Learning]. "We envision a day when all elementary students are exposed to principles of genetics and disease risk; when all high school students have the opportunity to do hands-on experiments with DNA; and when all families have access to genetic information they need to make informed health care choices. The center at Clemson will serve South Carolina, preparing students and families for the future."

Legislators should be added to this list of people that need to prepare for the future.  After a presentation at the Annual Meeting of Women in Biotechnology in late 2002, ethicist Arthur Caplan took a question from the audience about whether genetic testing would someday become routine during visits to the doctor.  Here is part of his response:    

"And molecular medicine will [get absorbed into the diagnostic culture] too. Someday if we don’t screw this up, I do believe you will go to the doctor’s office and get your molecular printout and be told that these drugs are bad for you, and those drugs are good for you, and this is a risk thing for you, and you should do this and that for your lifestyle change, and all that. And that’s great; I think that day is great. But I think it’s far off. People are not, we just mapped the genome. Most people don’t know where their genes are. Most people don’t want to eat genes. Most people think. I went and talked to a group of legislators about something and I asked them where their genes are, and about a quarter of them thought they were in their gonads. It’s partial credit. About a quarter of them thought they were in their brains. Which is very optimistic. And then, half of them knew they were kind of scattered around their bodies.


But I always laugh, I’m sorry to insult journalism here for a second, but you know all those pictures they show you of DNA on Time magazine? No o ne knows where that stuff is.  They have no idea. It’s like, and then we have this DNA thing and we replace it, and this is what genetic engineering is. We take the segment and we move it over here. And people are thinking, where is that? Where is that going on? I mean, is that like in my head or in my testicles or what are they talking about? I mean, they don’t know. So, a while for that to come. A while is what I would say. Not soon. The industry has to position itself for a lot of ignorance. A lot of fear, and some fear-mongering. There are critics of genetics out there all
over the place who want to use that to slow the industry down. For a variety of reasons."

It is important, as a society, to encourage some degree of scientific literacy.  For individuals eager to maximize personal well being, health literacy is an obstacle even for the educated.  These two indexes are of course interrelated. 

Here is the info for Caplan’s paper quoted above:
Arthur Caplan "Are We Ready for Mass Genetic Testing: Ethical and Social Hurdles" Annual Meeting of Women in Biotechnology. October 16, 2002. (Meeting transcript in pdf)

World Round-up: Ethical, Legal Aspects of Genetic Testing

United States:
The Third Annual International Bioethics Forum (April 22-23) is titled "Who Knows? Who Should Know? Welcome to the World of Genetic Testing." 

A European Commission Expert Group will present their 25 Recommendations on issues relating to genetic testing at a conference in Brussels on May 6th and 7th.

New Zealand:
University of Otago has been promised $2 million, says here, by the New Zealand Law Foundation to coordinate an international research team for studying the legal and ethical implications of genomic technologies.

Medical consumers want to read own medical records

Is there any interest in by medical consumers to read their own medical record?  EHR vendors take note, a recent survey of 4500 adults suggests that they do.  Of those that responded, 36% were "very interested" and 43% were "somewhat interested." 

Stockpile of Conference Presentations

Presentations from the recent Bio-IT World and Health-IT World conferences are now online. Lots of good stuff. Don’t miss this page containing the keynote addresses.

Biological Materials as Historical Artifacts

Does medical privacy last beyond the grave?  Historical artifacts that are biological materials, such as a lock of Beethoven’s hair or the blood of Lincoln–in the form of stains on bed sheets–can provide answers to historical questions: Were opiates included in the more than 75 medicines given to Beethoven on his deathbed?  Did Lincoln have Marfan syndrome?

This article describes the activities of a one interdisciplinary group organized by the Chicago Historical Society to look at these questions.

Glennda Chui, Rules Sought for Genetic Sleuths, Mercury News, April 9, 2004.

Continuous Health Monitoring: The Ring Sensor

This month’s MIT Technology Review has a brief mention of a "ring sensor" device being developed by Harry Asada and Phillip Shaltis.  Have a look at the prototype here.  A medical patient wears this ring and it monitors various vital signs such as heart rate, temp, and blood-oxygen concentration.  The device is also wireless enabled, so the data can be sent to another device such as your computer.  Couple this with a toilet that can perform a urinalysis, such as the Glycosuria Checker WELL-U II by Toto, and one can begin to see the front edge of continuous health monitoring.

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