Tuesday, 16 September 2014

Is genomics past its peak?

In his excellent blog, Robert Plenge recently asked how far along the hype cycle we are with regards to applying genomics to drug discovery.

The absolute number of genomics papers published in 2014 is likely to be higher than in any previous year. But when normalising by the total number of biomedical papers listed on Pubmed, a search engine for biomedical publications, it seems like we may be past the Peak of Inflated Expectations. The proportion of papers that contain genomics in their title or abstract has peaked in 2012.


I found the number of publications each year by searching for genomics on Pubmed. The number of papers for 2014 is an extrapolation based on the number of papers to date.


Monday, 18 August 2014

Should every drug have to pass a clinical trial?

If a pharmaceutical company wants to sell a drug, it first has to prove that it works and is safe by doing a double-blind controlled trial. Everything else is quackery.

At least that is what I used to think, but now I am not so sure any more. A major reason for my new-found uncertainty has been Peter W. Huber's book The Cure in the Code. Huber is a senior fellow of the Manhattan Institute, a free market think tank. Whilst his book is political, it raises points that should transcend the political divide. His central aim is to show that the top-down drug licensing process, as it is currently implemented in the United States and other developed countries, is not in the long-term interest of patients.

Consider the rare diseases that we study at the Sanger Institute, where I am a postdoc. In many cases, they are caused by a single mutation disrupting a single gene. Because the mutation is rare, not enough people have the disease to make it profitable for anyone to invest in developing a drug.

Nevertheless, sometimes doctors are able to repurpose a drug that has originally been developed for a different disease. For example, if the causal mutation disrupts a gene in a particular biochemical pathway, the doctor may know of a drug that upregulates the expression of another gene in the same pathway, therefore compensating for the mutated gene. That is great when there is a drug that can be repurposed, which in most cases there is not.


This issue is not limited to rare disorders. Complex diseases such as autism or diabetes have a large genetic component, but rather than a single causal variant there are tens or even hundreds. Each patient has a different combination of variants, and it is therefore unlikely that there will be a single drug that works for everyone. This makes a personalised medicine approach necessary, where the drugs that are prescribed are adjusted based on the patient's genotype. As with rare diseases, this means that patients with less common genotypes may lose out because there are not enough of them to warrant the development of a new drug, and because no drug that has been licensed for another disease is likely to help.

The higher the level of proof that is required before a drug can be sold, the lower the number of drugs that pass this threshold will be. Always requiring the highest level of proof may seem like the safest option, but is not necessarily in the public's interest if it means that many drugs will ultimately be unavailable. There is legislation such as the US Orphan drug act and a number of accelerated approval rules, but they only partly address the problem. There are still plenty of examples of drugs that may work in a subset of patients, or that may in the future be repurposed, but that are killed off in the licencing process and are therefore not available to anyone.

What is to be done? Creating legislation that allows the use of any compound whatsoever for the purpose of treating people with rare diseases or rare genetic variants could be one option. Of course, such a laissez-faire approach to drug licencing would be controversial and could encourage unscrupulous practices.

Right now, it is unclear to me what the balance between the two extremes of complete permissiveness and complete top-down control of drug licensing should be, but I doubt it is the status quo. I would welcome any views readers of this post may have.

Sunday, 3 August 2014

How important is health care system quality?

A few weeks ago, I came across an article comparing the health care systems of eleven developed countries. This made me wonder how much health care system quality impacts physical wellbeing, for which I used life expectancy as a proxy. I was expecting a strong correlation between the two, but in fact health care system quality doesn't seem to be that important.

Healthcare system ranking (from best to worst) and life expectancy of eleven Western countries. The correlation (r) is -0.32 (solid line), or 0.06 when excluding the United States as an outlier (dotted line). In either case, the 95% confidence interval of the correlation spans zero, meaning that the data does not support any relationship between the two variables
Health warning: Do not overinterpret such a small dataset. This is me messing around with a few numbers I found on the internet. I am not a health economist.

Saturday, 31 May 2014

When are we going to get a 3rd generation sequencer?

Two years ago, there were at least a dozen companies trying to develop DNA sequencing technology to rival incumbents like Illumina, Life Technologies, Roche/454, PacBio, and Complete Genomics (the latter offers sequencing as a service). What has changed since?

Despite numerous optimistic announcements by start-ups (for example, here and here and here and here and here) and investments totaling more than $400 million, there hasn't yet been any great breakthrough. The only exception is Oxford Nanopore, whose MinION sequencers seems to be close to ready for prime time.

The table below lists companies that have said they are developing sequencing technology and that have received funding according to the online database Crunchbase, which tracks that sort of thing:

Company
Funding
Status
$211.7m
Active
$58.8m
Active
$45.5m
Active
$35.0m
Active
$22.5m
Active
$20.9m
Active
$10.4m
Acquired by Roche
$5.0m
Active
$2.4m
Active
$1.5m
Active
Total
$413.7m


Even though that's a long list, it is not complete. Companies whose funding situation or current status are unclear and who have therefore not made it onto the list are Noblegen, Base 4 Innovation , Electron Optica, the Beijing Institute of Genomics (BIG), Electronic Biosciences, Qiagen's Intelligent Bio-systems, Reveo, and MobiousBiosytems. Doubtlessly, some of those have quietly exited the race.

Let's summarise: There are a lot of companies trying to develop the sequencer of the future, and at least some of them have received generous funding. Most have been active for at least two years, but we haven't seen any results yet, at least in the form of a sequencing machine we can buy. Clearly, 3rd generation sequencing is a though nut to crack.

I'd like to thank Keith Robison for pointing out omissions in an earlier version of this post, which I've now fixed.

Thursday, 3 April 2014

How useful is genomics for drug discovery?

In a previous post, I discussed a number of large sequencing projects, including by the governments of Saudi Arabia and the United Kingdom, which are sequencing the genomes of 100,000 of their citizens each.

I also lamented that these projects are exclusively government-funded, and that big pharma and biotechnology companies don't appear to consider large-scale sequencing a viable approach to drug discovery. Well, actually some of them do.

Three recent developments stand out: 

Regeneron, a large biopharmarmaceutical company, has teamed up with Geisinger Health Systems, a local American healthcare network, to sequence 100,000 exomes at an estimated cost of $100 million. Geisinger has detailed electronic health records of its patients, which will help with the interpretation of the data.


Amgen, another large biopharma company, announced that it would partner with the Broad Institute, one of the world's biggest genomics research institutes, to discover new drug targets. Prior to that, Amgen had acquired DeCode Genetics, which despite producing first-class science had been struggling.

And finally, the pharmaceutical giant GSK, together with two European genomics research centres, the EBI and the Sanger Institute (where I'm based), launched the Centre for Therapeutic Target Validation (CTTV), which will validate drug targets using a genomic approach.

Overall, it seems that pharmaceutical and biotech companies indeed have an increasing appetite for applying genomics to drug discovery. The question remains how successful this approach will be, and how much of an advantage it confers to the companies that invest in it.

Sunday, 9 March 2014

Why so many huge sequencing projects?

In the United Kingdom, a project to sequence 100,000 whole genomes is under way. Saudi Arabia has started another 100,000 genome sequencing project. And a few days ago, bioentrepreneur Craig Venter announced a new company called Human Longevity, which is going to initially sequence 40,000 genomes, followed by hundreds of thousands later. Most likely, additional projects on a similar scale will be kicked off over the next months and years.

All this sequencing is not going to be cheap. For example, the British government has put aside £100 million (around $170 million) for its project. How can these costs be justified to taxpayers and investors?


One reason for government-funded projects like the one in Saudi Arabia and the UK is that they are going to directly benefit the sequenced patients. The other and probably more significant reason is that the resulting data will impact the development of new cures.

Genetic variants protecting against common diseases such as Alzheimer's and diabetes have already been discovered. Any drug that mimics the effect of those variants would be likely to also protect against the disease whilst at the same time being safe. The caveat is that rare protective variants can only be detected by studies involving tens or hundreds of thousands of people. Hence the need for sequencing-megaprojects.

Given the potential impact on drug discovery, it may seem puzzling that the initiative comes from governments and startups, rather than from established pharmaceutical companies, whose core competency is, after all, drug discovery.This is probably due to both the relatively conservative nature of most pharmaceutical companies, as well as the so far unproven nature of the approach.

Sunday, 26 January 2014

How happy are 23andMe customers?

In October last year, I joined several of my colleagues at the Sanger Institute to order a bunch of direct-to-consumer genetic testing kits from 23andMe. The reason for the batch order was the associated discount. The total cost per person turned out to be around $130, of which $80 were for the kit and $50 for shipping from California to England.

Most of us received our data earlier this month, and I thought that it could be interesting to learn what my colleagues, all of whom probably know more about genetics than the average person, thought of their experience. This is why I asked them to fill in a small survey. Here are the results.

Results of a survey of 16 23andMe users at the the Wellcome Trust Sanger Institute. Click on the figure to enlarge it.

The results are largely self-explanatory. In the following, I am elaborating on a few points that may not be obvious.

Everyone thought that the test was worth what they had paid for it, and 7 out of 16 changed their diet, exercise or lifestyle habits as a result. Respondents generally thought that 23andMe did a good job in presenting the data.

We ordered in October 2013, before the FDA told 23andMe to stop providing health-related results, which meant that we were able to get ours. There are dozens, if not hundreds, of diseases the test returned information on. For the most severe ones, such as Alzheimer's, users had to click through a series of questions affirming that they really want to see their results. This is due to the potentially severe impact of these variants. For example, those who have two copies of a specific APOE gene variant are around ten times more likely develop Alzheimer's. 13 out of 16 respondents chose to see their data on these potentially high-impact variants.

Generally, people thought the health section of their test was interesting. The same cannot be said about the ancestry section, which provides information about genetic origins of the user's family. This result is likely to cause concern for 23andMe, as they have been asked by the FDA to stop providing health information and as a result are now concentrating on ancestry information. A majority (11 out of 16) users thought that 23andMe should not be regulated by regulatory authorities like the FDA.

Do you have any thoughts on the survey or on 23andMe? Please feel free to share them below.