January 27, 2012

Genetic testing during pregnancy, before pregnancy, or before dating?

Last week, I discussed genetic tests that aim to detect disorders in a foetus during pregnancy. This week, I look at pre-pregnancy or carrier tests. These tests are taken by couples that are considering having a baby, but are worried about the genetic disorders that they may pass on, possibly because there is a history of genetic disease in the family. The couple can then base their decision on how to go ahead with family planning on the test results.

There is an overlap between what pre-pregnancy tests do and the services offered by more traditional genetic counselors and clinical geneticists. In fact, most companies market their preconception tests via genetic clinics, rather than directly to consumers. Whether direct-to-consumer genetic tests should be legal at all is still being debated in many countries.

Two companies that develop sequencing-based preconception tests are Good Start Genetics and Ambry. Counsyl, another company in the sector, uses array-based technology. The number of disorders that can currently be detected with pre-pregnancy tests is higher than what is possible with non-invasive prenatal diagnosis. Whilst Sequenom's prenatal test returns information about a single disorder (trisomy 21), Good Start's test diagnoses 22 disorders, Counsyl's over 100, and Ambry's 90. But even once the providers of prenatal tests catch up, there is still the question if it makes sense to screen for less severe conditions. Do parents really want to know that their baby boy will suffer from pattern baldness once he grows up? The number of conditions that can be diagnosed is likely to be different from the number of conditions that are actionable.

But why stop at genetic counselling for couples? The start-up Gmatch plans to offer genotyping to the customers of an online dating website who want their future partner not only to be compatible socially, but to be a perfect genetic match as well.

Next week, I'll look at the third way besides prenatal and pre-pregancy diagnosis: Pre-implantation diagnosis.

January 21, 2012

How large a market for prenatal diagnosis by sequencing?

Prenatal diagnosis is one of the most interesting clinical applications of sequencing. The idea behind prenatal diagnosis is that potential disorders that a foetus may have are detected before birth, so that the parents can decide what to do about it. A widespread and ancient technology is ultrasound. An alternative method involves sampling of the amniotic fluid surrounding the foetus with a large needle (amniocentesis), which causes a miscarriage in 1% of cases. More recently genetic screening technologies, including sequencing, have entered the market.

The most prominent company offering prenatal diagnosis by screening is Sequenom. This week, Sequenom announced a public offering of shares valued in excess of $50m. The aim is to finance further expansion of its business, including sales of its MaterniT21 prenatal test.

The principle behind the MaterniT21 test is that some of the DNA in a pregnant woman's blood is of foetal origin. By sequencing that DNA, it is in principle possible to reconstruct most of the genotype of the foetus, and to detect most genetic disorders from the 10th week of pregnancy onwards- earlier than with equivalent tests.

Sequenom's MaterniT21 test currently only returns information on whether there is an third copy of chromosome 21, which causes Down syndrome. If the test returns a positive result, the parents can then decide which actions to take, which could include termination of the pregnancy.

Sequenom is reported to charge $2,700 per test to insurance companies, which is likely to be the cost to them many times over. Therefore there should be plenty of room for prices to come down once there is more competition. That there will be more competition is likely. In the United States, Verinata, which raised $47m in autumn 2011, and TrovaGene are also working on technology based on sequencing foetal DNA from the mother's blood. In Germany, LifeCodexx is developing a similar test, licencing technology from Sequenom.

Even at lower prices, which will probably be paid for by insurers anyway, the big question is how many couples are willing to purchase a test. Of 4.1 million births each year in the US, 750,000 (18%) are judged to be at a high risk of Down syndrome or other chromosomal abnormalities, either because the mother is over 35 years old or because there is a history of such disorders in the family.

It is likely that in the future the tests of Sequenom and its competitors will include other disorders such as cystic fibrosis, muscular dystrophy, anaemia, neuropsychiatric conditions like autism, and beta-thalassaemia. This could widen their appeal to parents that are not in the 18% currently judged as high risk. If prices come down sufficiently, I don't see a reason why sequencing-based tests for pregnant women could not be as prevalent as ultrasound is today.

At 4.1 million births in the US alone each year, and even if the price of tests decreases to a fraction of what they are now, it could well be a multi-billion dollar market.

Time to buy some of those new Sequenom shares?

January 13, 2012

Who's driving innovation?

I used to think that progress in science drives technical innovation. With sequencing it is the other way around: The sequencing companies provide new technology (a recent example being the Ion Proton sequencer), and the scientists gratefully use it to produce new knowledge, or at least new data.

In other words, the companies that develop sequencing technology are at the top of the innovation pyramid. Illumina, Life Technologies, Pacific Biosciences, Complete Genomics and Oxford Nanopore produce the innovations that keep the sequencing market growing.

At the next level are the organisations that use sequencing technology directly. These come in two flavours. One is academia, dominated by large sequencing centres such as the BGI, the Broad Institute, the Sanger Institute or the Joint Genome Institute. The other is clinical sequencing companies such as Sequenom, Ambry Genetics, LifeCodexx or Good Start Genetics.

At the third level are companies that provide services or products that are accessory to sequencing technologies. Again, there are two types: There are bioinformatics companies such as DNAnexus, Personalis, GenomeQuest or Accelerys, and sample preparation and supplies companies such as Agilent, Fluidigm or Roche Nimblegen.

Whilst this structure with sequencing companies at the top of the pyramid in my opinion nicely characterises the current marketplace, it will be interesting to see how it develops in the future. Are there any trends that indicate that sequencing companies may lose the initiative?

January 6, 2012

What does the history of computing teach us about the future of sequencing?

"I think there is a world market for maybe five computers", goes an infamous quote from the early days of computing, often attributed to IBM CEO Thomas J. Watson. That turned out to be wrong, and today pretty much everyone carries a programmable computer in the format of a smartphone in their pocket and has at least one more at home.
Genome sequencing is an emerging technology that has a number of similarities to computing. For example, exponential growth in performance. In computing, the computing power that can be bought for a fixed amount of money doubles every 18 months or so (Moore's law). In DNA sequencing, the number of bases that can be sequenced for a fixed amount of money doubles at an even faster pace.

Another similarity is the occurrence of disruptive innovation in both fields. Initially, computers called mainframes filled whole rooms. Later years saw them being replaced by minicomputers and even later by PCs, which would be smaller, cheaper, and easier to use. A similar trend can be observed for DNA sequencing. A possible comparison is:

Mainframe computer - e.g. Illumina HiSeq, PacBio
Minicomputers - e.g. IonTorrent, Illumina MiSeq
PCs - Possibly third generation sequencers

It's possible to continue this game, predicting that eventually there'll be sequencers that are equivalent in size to laptops or smartphones, and that everyone will carry one in their pocket.

Of course this is possible, but just because it happened with computers does not mean that the same thing will happen with sequencers. The reason is that there are important differences between the two technologies. One is that whilst even in the early days of computing IBM sold computers to a diverse bunch of companies, DNA sequencers go to a more restricted set of customers in the life sciences. That may change, but currently it's not obvious how an accountancy firm or a apparel retailer would benefit from sequencing technology. I'm not claiming that this couldn't happen, but I don't see why it should be more likely just because it also happened in the computer industry.

After having thought about the issue, I'm sceptical that the computing market can teach us anything concrete about the sequencing market. Except maybe not to indulge in bold predictions.