Many of you are probably fully aware of how immuno-oncology is changing cancer treatment. Ken Burns highlighted immunotherapy in his recent PBS series, “Cancer: The Emperor of All Maladies” (video link here). Forbes’ Matthew Herper, BBC and others have written extensively about it, too (here, here). More recently, Genome Magazine had a feature article on the history of immunotherapy (here). As the article states: “The promise of immunotherapy is startling in its simplicity: With a little help from cancer doctors, the patients will cure themselves.”
The key word here is “cure”. Cure!
The purpose of this blog is two-fold: (1) introduce geneticists and genomicists to cancer immunotherapy, if they have not thought about it before, and (2) highlight a recent Science publication by Elaine Mardis, Gerald Linette, and colleagues at WashU (here), with an accompanying News & Views article in Nature (here).
[Disclaimer: I am a Merck/MSD employee. The opinions I am expressing are my own and do not necessarily represent the position of my employer.]
Cancer immunotherapy is really cool! As a former practicing rheumatologist at Brigham and Women’s Hospital, I had thought about the role of neoantigens in autoimmunity for many years.…
I admit upfront that this is a self-serving blog, as it promotes a manuscript for which I was directly involved. But I do think it represents a very nice example of the role of human genetics for drug discovery. The concept, which I have discussed before (including my last blog), is that there is a four-step process for progressing from a human genetic discovery to a new target for a drug screen. A slide deck describing these steps and applying them to the findings from the PLoS One manuscript can be found here, which I hope is valuable for those interested in the topic of genetics and drug discovery.
[Disclaimer: I am a Merck/MSD employee. The opinions I am expressing are my own and do not necessarily represent the position of my employer. However, the PLoS One study was performed while I was still in academics at BWH/Harvard/Broad.]
Before I provide a summary of the study, I would like to highlight a few recent news stories that highlight that the world thinks this type of information is valuable. First, the state of California is investing US $3-million in a precision medicine project that links genetics and medical records to develop new therapies and diagnostics (here, here).…
There was an eruption in Iceland last week. No, this was not another volcanic eruption. Rather, there was a seismic release of human genetic data that provides a glimpse into the future of drug discovery. The studies were published in Nature Genetics (the issue’s Table of Contents can be found here), with insightful commentary from Carl Zimmer / New York Times (here), Matthew Herper / Forbes (here), and others (here, here).
[Disclaimer: I am a Merck/MSD employee. The opinions I am expressing are my own and do not necessarily represent the position of my employer.]
As I have commented before, human genetics represent a very powerful approach to identify new drug targets (see here, here). I have articulated a 4-step process (see slide #5 from this deck): (1) select a phenotype that is relevant for drug discovery; (2) identify a series of genetic variants (or “alleles”) that is associated with the phenotype; (3) assess the biological function of phenotype-associated alleles; and (4) determine if those same alleles are associated with other phenotypes that may be considered adverse drug events.
There is an important assumption about this model: genes with an “allelic series” will be identified from large-scale genetic studies, and these phenotype-associated alleles will serve as an estimate of function-phenotype dose-response curves.…
My overly simplistic vision of the way to transform drug discovery is to (1) pick targets based on causal human biology (e.g., experiments of nature, especially human genetics), (2) develop drugs that recapitulate the biology of the human experiments of nature (e.g., therapeutic inhibitors of proteins), (3) develop biomarkers that measure target modulation in humans, and (4) test therapeutic hypotheses in humans as safely and efficiently as possible.
Thus, one of my favorite themes is “causal human biology”. The word “causal” is key: it means that there is clear evidence between the cause-effect relationship of target perturbation in humans and a desired effect on human physiology. Human genetics represent one way to get at causal human biology, and in my last blog I highlighted recent examples outside of human genetics.
I am constantly scanning the literature to find examples that support or refute this model, as I predict that a discipline portfolio of projects based on causal human biology will be more successful than past efforts by the pharmaceutical industry.
This week I have selected two articles on genetics/genomics in drug discovery that provide further support of this model. [Disclaimer: the first study was funded by Merck, my employer.]
Oliver Sacks has terminal cancer. If you have not yet read his heart-warming Op-Ed piece in the New York Times and if you only have five-minutes to spare, then I suggest you read his essay rather than this blog about “experiments of nature” in drug discovery. In his essay, Dr. Sacks concludes with the poignant sentence: “Above all, I have been a sentient being, a thinking animal, on this beautiful planet, and that in itself has been an enormous privilege and adventure.”
So why do I blog, tweet, etc. given the potential risk? I enjoy the public exchange of ideas because, as Dr. Sacks write, that is the essence of our “sentient being”. I enjoy a network of inter-related ideas for which I can create unique connections.…
ICYMI – the New England Patriots won the Super Bowl. How they did it was remarkable, and improbable. To introduce this week’s articles on human genetics and drug discovery, I want to focus on the interception of Russell Wilson by Malcolm Butler. If the pass is on-target, Seahawks win. By now you know the story: the pass was off-target, and the Seahawks lost.
[A lot has been said about Pete Carroll’s play call (see FiveThirtyEight.com statistical analysis here), but that is irrelevant for this discussion.]
As in football, on-target vs off-target events are highly relevant in drug discovery. Think about what it takes to develop a drug, and how “drug accuracy” (like passing accuracy) can make-or-break a development program. First, you start with a target. Next, you develop a drug against that target. Then, you test the target in pre-clinical models to make sure it is doing what you think it should do. And finally, you take the drug into humans to see if it has an adequate therapeutic index (i.e., is safe and effective).
All along the way you assess whether the therapeutic molecule is selectively engaging and modulating the desired target, and not acting more promiscuously on other targets in the system.…
Imagine you live in Boston or New York. It is Monday January 26, 2015. You are watching headlines of an impending blizzard, trying to figure out the truth about the weather for the next day. You find that the National Weather Service has a cool online tool – experimental probabilistic snow forecast (see here). As described in Slate magazine (see here), this tool predicted a 67 percent chance of at least 18 inches in New York City.
Unfortunately, most people interpreted this data that there would be 18 inches of snow, not that there could be (with a certain probability) 18 inches of snow.
It was not until Mother Nature did her experiment that we saw the outcome: not much snow in the Big Apple, more than 2 feet of snow in Boston.
The analogy with human genetics is this: it is possible to forecast the functional consequences of deleterious mutations, but it is not until the experimental snow falls – molecular or cellular experiments revealing the functional consequences of mutations – that the functional consequences are actually known. And without knowing the functional consequences of mutations, it is difficult to determine the association of these mutations with human disease.…
I was very pleased to listen to your State of the Union address and learn of your interest in Precision Medicine. As I am sure you know, this has led to a number of commentaries about what this term actually means (here, here, here). I would like to provide yet another perspective, this time from someone who has practiced clinical medicine, led academic research teams and currently works in the pharmaceutical industry.
Let me start by acknowledging that I know very little about your plan, but that is because no plan has been announced. However, that inconvenient fact should not prevent me from forming a very strong opinion about what you should do. Similar behavior is observed in politics (which you know well) and sports radio (see for example “Deflate-gate”). So here it goes…
I want to clarify my definition of “precision medicine” (see here for my previous blog on how this is different from “personalized medicine”). In the simplest of terms, precision medicine refers to the ability to classify individuals into subpopulations based on a deep understanding of disease biology. Note that this is different than what clinicians normally practice, which is to classify patients based on signs and symptoms (which can be measured by clinicians as part of routine clinical appointments).…
Recently I was asked by the American Society of Human Genetics (ASHG) to provide my perspective on career and professional development in genetics (see here). At about the same time, I read the book “How Google Works”, by Google Executive Chairman and ex-CEO Eric Schmidt and former SVP of Products Jonathan Rosenberg. A very creative slide deck accompanies the book, which is definitely worth a few minutes of your time (here).
Both got me thinking about opportunities in the pharmaceutical industry for genetic graduate students. Here are a few thoughts based on the outline from the Google slide deck.
What is different now?
In human genetics, large-scale genotyping and sequencing is unlocking the inherited basis of most complex and rare traits in the ideal model organism, humans. This is very different than it was just a few years ago. But there is more: this is happening at a scale that will not likely stop until most humans on the planet have their genome sequenced. Like the “Internet of things”, there will soon be a “Genomes of things”, in which our genomes will be connected to all sorts of data – electronic health records, wearable technology, portable blood monitoring, etc.…
Welcome to our first blog of 2015 on genetics/genomics for drug discovery. After a nice vacation in sunny Arizona flying drones (here), I am back soliciting ideas from our Merck Genetic & Pharmacogenomics (GpGx) team. This week’s pick riffs off the events at J.P.Morgan 2015, where there were a number of interesting deals made by pharmaceutical companies and genetic companies (see here, here, here).
With all of this interest in human genetics, it raises the question about how genetics can be used to develop new drugs. The first step is to go from “genes to screens”. That is, the first step is to progress from a human genetic variant associated with a clinical trait of interest to an actual drug screen. This week’s article, published in Nature Chemical Biology, describes one example (see here, here).
Summary of the manuscript: Deleterious mutations in the ABHD12 gene cause a rare neuroinflammatory-neurodegenerative disorder named polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract (PHARC, see here). A similar phenotype is observed in ABHD12-deficient mice. ABHD12 is an enzyme degrading lysophosphatidylserine (lyso-PS), a signaling lipid known to regulate macrophage activation. The Nature Chemical Biology study by Kamat and colleagues describes the chemical proteomic identification of a related enzyme, ABHD16A, which synthesizes the terminal step leading to lyso-PS generation.…
I got a drone for Christmas. The first thing my wife asked me was, “Why do you need a drone?” I did not have a great answer, other than to say it would be fun to take aerial videos. My sister teased me, as did my kids, nieces and nephew (Sam Sutherland). They said I was obsessed; they said I was acting like a little kid. My neighbors were worried – “no more nude sunbathing” was awkwardly expressed by more than one.
The new recreational drones represent pretty cool technology. Just a few years ago, the technology was not available to stabilize and control the flying of drones…at least not at an affordable cost. Now, GPS satellites and gyro sensors can do just that. Until recently, the range on remote controlled drones was relatively limited. Now, wireless communication allows for first-person viewing and long-distance control at long-range (up to 500 meters from my Phantom DJI FC40 drone). And until recently, the cameras attached to drones were not of sufficient quality to record high-definition images. Now, simple microchips installed in HD cameras with stabilizing functions allow for professional-grade photography (e.g., GoPro).
And with these drones, there is a new perspective on old things.…
This week’s theme is genes to function for drug screens…with a macabre theme of zombies! As more genes are discovered through GWAS and large-scale sequencing in humans, there is a pressing need to understand function. There are at least two steps: (1) fine-mapping the most likely causal genes and causal variants; and (2) functional interrogation of causal genes and causal variants to move towards a better understanding of causal human biology for drug screens (“from genes to screens”).
Genome-editing represents one very powerful tool, and the latest article from the laboratory of Feng Zhang at the Broad Institute takes genome-editing to a new level (see Genetic Engineering & Biotechnology News commentary here). They engineer the dead!
Since its introduction in late 2012, the CRISPR-Cas9 gene-editing technology has revolutionized the ways scientists can apply to interrogate gene functions. Using a catalytically inactive Cas9 protein (dead Cas9, dCas9) tethered to an engineered single-guide RNA (sgRNA) molecule, the authors demonstrated the ability to conduct robust gain-of-function genetic screens through programmable, targeted gene activation.
Earlier this year, the laboratories of Stanley Qi, Jonathan Weissman and others \ reported the use of dCas9 conjugated with a transcriptional activator for gene activation (see Cell paper here).…
Welcome to this second blog post on genetics/genomics for drug discovery! So far, we are 2 for 2. That is, this is the second week in a row where we have reviewed the literature for interesting journal articles and written a blog on why the study is relevant for drug discovery. I say “we”, because this week I asked for input from our Merck Genetic & Pharmacogenomics (GpGx) team. We received a number of interesting submissions from GpGx team members, as summarized at the end of the blog.
This week’s article uses antisense as therapeutic proof-of-concept in humans for a genetic target…again! This story is reminiscent of last week’s post on APOC3 (see here).
Summary of the manuscript: While patients with congenital Factor XI deficiency have a reduced risk of venous thromboembolism (VTE), it is unknown whether therapeutic modulation of Factor XI will prevent venous thromboembolism without increasing the risk of bleeding. In this open-label, parallel-group study, 300 patients who were undergoing elective primary unilateral total knee arthroplasty were randomly assigned to receive one of two doses of FXI-ASO (200 mg or 300 mg) or 40 mg of enoxaparin once daily.…
There are an increasing number of very interesting published studies around genetics / genomics and drug discovery. Just last week, there were a series of articles in Nature on predictors of response to anti-PD1 therapy. (Disclaimer: I work for Merck, which markets an anti-PD1 drug.) In this new blog series, I try and pick at least one paper that highlights some of the key principles of genetics/genomics and drug discovery. This is week #1…hopefully I will be able to do this routinely!
This week, I have selected an article in NEJM by Gaudet et al: Targeting APOC3 in the Familial Chylomicronemia Syndrome. As described in the introduction: “The familial chylomicronemia syndrome is a rare autosomal recessive disease characterized by the buildup in the blood of fat particles called chylomicrons (chylomicronemia), severe hypertriglyceridemia, and the caused by mutations in the gene encoding LPL or, less frequently, by mutations in genes encoding other proteins necessary for LPL function. Patients with this syndrome have plasma triglyceride levels ranging from 10 to 100 times the normal value (1500 to 15,000 mg per deciliter [17 to 170 mmol per liter]), eruptive xanthomas, arthralgias, neurologic symptoms, lipemia retinalis, and hepatosplenomega without pancreatitis, that interfere with normal life and result in frequent hospitalizations.”
Separately, a human genetic study, published in NEJM by Sekar Kathiresan and colleagues (see here), found that loss-of-function (LOF) mutations in APOC3 result in very low levels of plasma triglycerides and a dramatically reduced risk of myocardial infarction.…
At the Harvard-Partners Personalized Medicine Conference last week I participated in a panel discussion on complex traits. When asked about where personalized medicine for complex traits will be in the future, I answered that I envision two major categories for personalized therapies.
(1)Development of drugs based on genetic targets will lead to personalized medicine; and
(2)Large effect size variants will be detected in clinical trials or in post-approval studies and will lead to personalized medicine.
This answer, I said, was based in part on current categories of FDA pharmacogenetic labels and in part on how I see new drug discovery occurring in the future. But did the current FDA labels really support this view?
The answer is “yes”. In reviewing the 158 FDA labels (Excel spreadsheet here), my crude analysis found that 31% of labels fall into the “genetic target” category (most from oncology – 26% of total) and 65% fall into the “large effect” category (most from drug metabolism [42% of total], HLA or G6PD [15% of total]).
A subtle but important point is that I predict that category #2 (PGx markers for non-oncology “genetic targets”) will grow in the future. In other words, development of non-oncology drugs will riff-off the success of drugs developed based on somatic cell genetics in oncology. …
I have come across three reports in the last few days that help me think about the question: How many genomes is enough? My conclusion – we need a lot! Here are some thoughts and objective data that support this conclusion.
(1) Clinical sequencing for rare disease – JAMA reported compelling evidence that exome sequencing identified a molecular diagnosis for patients (Editorial here). One study investigated 2000 consecutive patients who had exome sequencing at one academic medical center over 2 years (here). Another study investigated 814 consecutive pediatric patients over 2.5 years (here). Both groups report that ~25% of patients were “solved” by exome sequencing. All patients had a rare clinical presentation that strongly suggested a genetic etiology.
(2) Inactivating NPC1L1 mutations protect from coronary heart diease – NEJM reported an exome sequencing study in ~22,000 case-control samples to search for coronary heart disease (CHD) genes, with follow-up of a specific inactivating mutation (p.Arg406X in the gene NPC1L1) in ~91,000 case-control samples (here). The data suggest that naturally occurring mutations that disrupt NPC1L1 function are associated with reduced LDL cholesterol levels and reduced risk of CHD. The statistics were not overwhelming despite the large sample size (P=0.008, OR=0.47). …
So, you have a target and want to start a drug discovery program, do ya? How would you do it?
When I was at Brigham and Women’s Hospital, Harvard Medical School and the Broad Institute, I presented an idea from an early GWAS of rheumatoid arthritis (RA, see here) to Ed Scolnick (former president of Merck Research Labs, now founding director of the Stanely Center at the Broad Institute, see here). In this study, we found evidence that a non-coding variant at the CD40 gene locus increased risk of RA. The first questions he asked: How does the genetic mutation alter CD40 function? Is it gain-of-function or loss-of-function? What assay would you use for a high-throughput small molecule screen to recapitulate the genetic finding?
I was caught off-guard. Sadly, I had never really thought about all of the details. At the time, I knew enough as a clinician, biologist and a geneticist to appreciate that CD40 was an attractive drug target for RA. However, I was quite naïve to the steps required to take a target into a drug screen. That simple conversation led to several years worth of work, which ultimately led to a proof-of-concept phenotypic screen published in PLoS Genetics five years later (see here).…
In my previous blog series I talked about why genetics is important in drug discovery: human genetics takes you to a target, informs on mechanism of action (MOA) for therapeutic perturbation, provides guidance for pre-clinical assays of target engagement, and facilitates indication selection for clinical trials.
Here, I provide an overview of a new blog series on how genetics influences decision-making during drug discovery. The key principle: human genetics establishes a disciplined mindset and a firm foundation – anchoring points – for advancing targets through the complicated process of drug discovery. [For those less familiar with drug discovery, the end of this blog provides a brief primer on the stages of drug discovery.]
I highlight three areas: establishing a balanced portfolio, identifying targets with novel MOA, and creating a framework for objective decision-making. In subsequent posts, I will focus primarily on how human genetics informs on the latter (decision-making), with blogs pertaining to designing assays for screens and target engagement, utilizing pre-clinical animal models, predicting on-target adverse drug events, and selecting indications for clinical trials.
1. Establish a balanced portfolio
Whether in academic research, a small biotech company (see here) or a large pharmaceutical company (such as Merck, where I work), a balanced portfolio of projects is very important.…
In this post I will build on previous blogs (here, here, here) about genetics for target ID and validation (TIDVAL). Here, I argue that new targets with unambiguous promotable advantage will emerge from studies that focus on genetic pathways rather than single genes.
This is not meant to contradict my previous post about the importance of genetic studies of single genes to identify new targets. However, there are important assumptions about the single gene “allelic series” approach that remain unknown, which ultimately may limit its application. In particular, how many genes exist in the human genome have a series of disease-associated alleles? There are enough examples today to keep biopharma busy. Moreover, I am quite confident that with deep sequencing in extremely large sample sizes (>100,000 patients) such genes will be discovered (see PNAS article by Eric Lander here). Given the explosion of efforts such as Genomics England, Sequencing Initiative Suomi (SISu) in Finland, Geisinger Health Systems, and Accelerating Medicines Partnership, I am sure that more detailed genotype-phenotype maps will be generated in the near future.
[Note: Sisu is a Finnish word meaning determination, bravery, and resilience; it is about taking action against the odds and displaying courage and resoluteness in the face of adversity. …
A key learning from my time in academia was the value of collaborations. Much of my most enjoyable and productive research was conducted in collaboration with fellow scientists across the globe.
I am pleased to report that industry is no different. After one year working for Merck, I have found that in addition to collaborations across the company ties with external scientific experts focused on advancing programs of interest are actively encouraged.
It is heartening to see how some recent progress in several notable drug development programs is leading to increased excitement around the application of human genetics in identifying human drug targets. As I have previously noted, human genetics can also provide insights to identifying pathways enriched for approved drugs (see Nature article here), which indicates that novel pathways may provide an important foundation for novel drug discovery programs. Indeed, the use of pathway-based approaches, including phenotypic screens, can provide a powerful way to make complex genetic pathways actionable for drug discovery.
Today, I am excited to note that Merck has launched a Merck Innovation Network (MINt) Request for Proposals to identify collaborations with academic scientists to evaluate genetic targets or genetic pathways for their potential to become drug discovery programs. …