About Hannes Smarason

Hannes Smarason is CEO of NextCODE Health, a genomics leader. He is the former CEO of the FL Group (formerly Icelandair) and Chief Business Officer of deCODE Genetics, an Iceland-based genomics company.

WuXi NextCODE at ASHG17: Part IV of our “Genomes for Breakfast” Series Features Rare Disease Findings from Boston Children’s Hospital and deCODE genetics

hannes-smarson-ashg17-boston-iceland

Presenters from Boston Children’s Hospital and Iceland’s deCODE genetics detailed the impact of sequence-based diagnosis of rare disease at WuXi NextCODE’s “Genomes for Breakfast” series at ASHG17.

My last post described work on rare diseases at Children’s Hospital of Fudan University (CHFU) in China, but at our recent “Genomes for Breakfast” series at ASHG17, we also heard about the impact of sequence-based diagnosis of rare disease from colleagues in Boston and Iceland.

From our longstanding partners at Boston Children’s Hospital (BCH), we heard a detailed discussion of how sequencing hundreds of people across numerous families, and the analysis of all that data together, was accelerating our understanding of one disease: nemaline myopathy. That was presented by Alan Beggs of BCH’s Division of Genetics and Genomics, and the Manton Center for Orphan Disease Research at BCH/Harvard Medical School.

A myopathy is a disorder affecting the skeletal muscles. Typical symptoms of congenital myopathies include early onset of hypotonia and weakness, which reflect distinctive pathologic changes in the muscle fibers. There are multiple subtypes of myopathy. Nemaline myopathy is the most common subtype. It can cause painful contortions (arthrogrypothis), make patients dependent on ventilators and wheelchairs or, in less acute forms, lead to mild weakness that can still impair mobility.

One of the biggest challenges in understanding these myopathies is that they are heterogeneous in every way—clinically, pathologically, and genetically. There are multiple genes associated with different subtypes, and they are sometimes shared but can also be completely distinct. Scientists have also found multiple patterns of inheritance even for a single gene.

To try to shed light on this genetic puzzle, Beggs and colleagues have been looking in detail at the particular mutations found in certain patients and mapping those against their symptoms and inheritance patterns. Recently, the researchers sequenced 857 patients with several subtypes, including just over 300 with nemaline myopathy. The BCH researchers are using a variety of sequencing approaches, including exome analysis, RNA sequencing, and whole-genome sequencing (WGS). This is necessary, they have found, because there are unusual variants that are difficult to identify with traditional tools.

Using this array of sequencing technologies and WuXi NextCODE’s clinical interpretation and case-control research tools, they were able to identify specific genetic variants that have already been associated with certain subtypes, identify new variants, and start to predict the clinical impact of each mutation or constellation of mutations. These tools are able to instantly draw upon a wealth of data from BCH, WuXi NextCODE’s knowledge base, and public databases.

The picture that emerges is complex: a large set of variants that sometimes overlap across multiple subtypes, but sometimes are just strongly associated with a single subtype. The NEB gene is of particular interest because it is so strongly associated with nemaline myopathy and quite a bit is known about its biology. Based on these studies, Beggs and his colleagues have also suggested a more accurate approach to diagnosing nemaline myopathy. All of these are steps that benefit patients and their care, and they provide the first step toward developing new and more effective ways of treating these conditions.

The third country represented at our second breakfast was Iceland. Patrick Sulem, who leads the clinical team at deCODE genetics in Reykjavik, presented. Like our collaborators in Shanghai and Boston, but armed with a truly unique set of resources and expertise, the deCODE scientists have made significant strides in better diagnosing rare diseases in children.

The deCODE database is unique in many ways and powered to uncover rare disease-causing variants. It includes the directly sequenced whole genomes of nearly 50,000 Icelanders and 10,000 others; imputed whole genome data on some 400,000 Icelanders; and SNP data from nearly a million people around the world. This gives deCODE allelic frequency data of unrivaled detail. As we have shown, this data can be helpful in diagnosing disease around the world—but when used in Iceland itself, it can point straight to pathogenic mutations and provide a map to wherever they lie in the population.

These strengths are based on some advantages of the population approach, some that others would like to replicate, others that are tough to match. Iceland’s population participates in genetics studies at a higher rate than that of any other country; Iceland has a long, strong tradition of preserving ancestry records and so has a nearly complete national genealogy for the modern era; and a national health system with a centralized record system. These ingredients have given deCODE the right data to find important variants in diseases that have baffled others. (For more details, read my post on Kari Stefansson’s headlining talk for our breakfast series.)

Based on deCODE’s work, it is now evident that whole-genome sequencing (WGS) can greatly improve diagnosis and clinical management of infants and children with hard-to-diagnose diseases. Like their peers at BCH and CHFU, researchers in Iceland have been able to use genomic screenings not just for better diagnoses—giving parents at least the comfort of knowing what’s wrong—but also, in some cases, they have been able to offer better guidance for the children’s treatment.

One such case was the result of the early application of our technology, before NextCODE had spun out of deCODE. It involved two sisters who had undergone a diagnostic odyssey of several years. With whole-genome sequence data from them and their parents, and with the ability to filter allelic frequency data in the context of different modes of inheritance, we were able to identify the culprit variant—a previously unknown variant causing Brown Vialetto Van Laere syndrome—in a matter of minutes. Because the variant was disrupting a riboflavin transporter gene, the diagnosis immediately suggested riboflavin therapy, a course of treatment that halted the progression of their disease.

Finally, it is important to note that the identification of rare disease variants is a promising avenue for feeding drug discovery—not just for the rare conditions themselves, but also potentially for much more common conditions, of which rare diseases can be extreme versions. Solving rare disease is a challenge for us all—indeed, it is a common challenge in the truest sense. The more diagnostics we do, the bigger our databases all over the world, and with the informatics and tools to mine all this data, the more benefits we can deliver to people around the world.

email

WuXi NextCODE at ASHG17: Our Partnership with Fudan Children’s Hospital—Pioneering Rare Disease Diagnostics in China and Building Toward the Country’s Biggest Rare Disease Database

WuXi NextCODE and Fudan Children’s Hospital

In just one year, Fudan Children’s Hospital and WuXi NextCODE have diagnosed 11,000 pediatric patients in China and created a program that rivals the largest labs in the U.S.

Children’s Hospital of Fudan University (CHFU) in Shanghai is widely considered China’s top pediatric hospital. The doctors there see almost 2.5 million patients annually.

One short year ago, WuXi NextCODE and Fudan launched sequence-based rare disease

testing at CHFU using WuXi NextCODE’s RareCODE test and backed by our knowledgebase and the collective expertise of both organizations. In this first year, an astonishing 11,000 patients received sophisticated genomic screening tests to help guide treatment for hard-to-diagnose, or rare, diseases. One-third of those patients got a precise diagnosis, matching the best rates anywhere in the world. In short, Fudan and WuXi NextCODE have, in just one year, effectively launched the field of sequence-based rare disease diagnostics in China and created a program that rivals the largest labs in the U.S.

We had the distinct pleasure of hearing directly from doctors handling these cases and scientists building the database supporting this collaboration at our recent ASHG breakfast, “Using NGS to diagnose rare disease—experiences from three continents.” Dr. Lin Yang, MD, PhD, a clinician at CHFU’s National Children’s Medical Center, presented the hospital’s experience with this rapidly expanding new program.

The service was created thanks to the unique partnership established between the hospital and WuXi NextCODE. WuXi NextCODE contributes its know-how in clinical-grade genomic sequencing, massively scalable informatics, and RareCODE test, backed the most powerful interpretation tools and clinical genetics expertise available.

CHFU, meanwhile, brings to bear the services, knowledge, and skill of its pediatric specialists and the national center of excellence in pediatric medicine housed at the hospital. Notably, CHFU’s Institute for Pediatric Research had previously developed more than 100 tests for single-gene genetic diseases, established multidisciplinary teams of clinical experts to address rare disease, and is among the very first hospitals in China to adopt next-generation sequencing.

Armed with our IT, knowledgebase, and diagnostic tools, this pioneering collaboration has advanced a national center of excellence for diagnosis, treatment, and further medical genetic research. At its core are not just the expertise of both teams, but also a rapidly growing database of mutations causing rare diseases, which the team hopes to grow into the largest in China, and perhaps the world.

Just over 5.5% of babies in China are born with some type of evident syndrome or birth defect. There, as elsewhere, these can impact the skeleton, metabolism, nervous system, circulation, respiration, digestion, and more. These can also be very complex, with multiple phenotypes or overlapping disorders. Some of these are due to causes other than genetics. But a large proportion represent genetic syndromes, of which many are de novo or have never been seen, or at least written about, by other clinical groups.

CHFU started doing single-gene sequencing to help resolve such cases as early as 2010. By 2012 the hospital was also running array CGH, and in 2013 it launched a number of panel tests and an NGS data-analysis pipeline. This history of pioneering genetic analysis put the hospital at the forefront of medical genomics. And things really moved forward fast after CHFU created a joint molecular diagnostic laboratory with WuXi NextCODE.

The two groups confer weekly on difficult cases and, as of now, they have completed some 12,000 genome analyses in just one year, providing a diagnosis in 33% of cases. These include the smallest patients, from the neonatal intensive care unit (NICU)—more than 2,200 of whom received focused exome sequencing and analysis. Just over 13% of those infants received a diagnosis. This lower rate of diagnosis among newborns reflects the greater challenge of working with patients whose signs and symptoms are just appearing. But this number is rising and, as the NICU is a first-tier clinical setting, every diagnosis can be a lifesaver.

Parents and other family member are also often sequenced to determine if the mutations are passed down or have occurred spontaneously (i.e., are de novo). All of that data is incorporated into a database, helping to grow knowledge about the mutations that cause rare diseases.

While there is no specific treatment for most of the syndromes identified, there is an improving picture for a growing number. Patients may receive a lifesaving, or life-changing, treatment plan, or referral to specialists based on their anticipated future needs. Regardless, it is important for the family and doctors to understand as much as possible about what the problem is. It is also helpful for parents and relatives to know that there are potentially pathogenic mutations that run in the family.

At ASHG, our head of communications, Edward Farmer, sat down with Dr. Yang, other scientists and physicians from CHFU, and our CSO, Jeff Gulcher, to talk about the growth of the WuXi NextCODE joint rare disease lab and some of its early successes. I’ll be posting Dr. Farmer’s interview with them here in the days ahead, so be sure to check back and learn more about the launch of rare disease testing in China.

WXpress News Site Highlights our AI Strategy

Hannes Smarason genomics AI

In an interview with WuXi AppTec’s WXpress news site, WuXi NextCODE CEO, Hannes Smarason, summarizes how genomics AI can make drug development better, faster, and cheaper.

How will WuXi NextCODE bring AI to the forefront of drug discovery and development? I mapped that out recently in an interview with WuXi AppTec’s WXpress news site. Below, I summarize some of the key points from the article.

Our advantage
The core of our strategy is to bring together three different things: Cutting-edge algorithms, domain expertise, and large data sets.

Executing on the strategy
Because of our history pioneering this field, we already have a wealth of samples as well as a very sophisticated and robust way of mining that data to help discover novel treatment pathways and for possibly re-purposing drugs. We are also continually developing new algorithms and other methods to distinguish between people who will respond and those who won’t when given a particular treatment.

The benefits of AI for drug development
Incorporating AI creates a much more data-driven rather than hypothesis-driven process. That improves the likelihood of identifying patterns and novel insights that may have been overlooked using conventional methods. That means finding the truly causal genes or pathways that drive disease. The goal is to have a more powerful starting point for the development of treatments.

Early validation
Our deep-learning algorithms have already been used to uncover a particular mechanism that appears to be a key driver in the development of the vascular system. That mechanism had not previously been described. Yale biologists then validated that discovery in an animal model, proving that our AI method had accurately predicted the role of this particular pathway in vascular development. So, when used correctly, AI can open up a whole new druggable pathway.

Challenges and hurdles
We must look at AI as a force-multiplier, as opposed to a replacement for independent thinking. That’s one reason having domain expertise in genetics and biology is absolutely key. The second thing is that you have to have access to a wealth of information, including cohort studies as well as genomic and phenotypic data.

The role of AI in evolving drug discovery and development?
Much like any major technological development, it’s going to start up slowly and then gather momentum. We believe that because of AI’s unique ability to bring large and complex data sets together and identify patterns within them, that in the end, it’s going to have an exponential impact in advancing and applying precision medicine. The result is going to be game-changing benefits to patients around the globe in terms of better diagnostics and better-targeted drugs.

Read the full interview.

WuXi NextCODE at ASHG17: Part II of our “Genomes For Breakfast” Series Featuring Major Precision Medicine Efforts in the US and Qatar

WuXi NextCODE ASHG2017

At the second WuXi NextCODE “Genomes for Breakfast” session at ASHG2017, Annerose Berndt, vice president of clinical genomics at University of Pittsburgh Medical Center, and Khalid Fakhro, director of genetics at Sidra Medical and Research Center in Qatar, outlined ambitious plans in large-scale genomics and precision medicine.

In my previous post, I described how Kari Stefansson started off this year’s ASHG breakfast session with a deep dive into deCODE’s toolbox and the powerful results the company has delivered.

Another of the renowned speakers at our “Genomes for Breakfast” session was Annerose Berndt, vice president of clinical genomics at UPMC (University of Pittsburgh Medical Center). She outlined UPMC’s ambitious plans in large-scale genomics and precision medicine. UPMC has a quite uniquely holistic role in underpinning the present and future healthcare of more than three million people in western Pennsylvania. It is an insurer, delivers healthcare through a rapidly growing network of dozens of hospitals, and conducts cutting-edge research in the life sciences and medicine, including through the University of Pittsburgh. It also has affiliated hospitals in nine countries apart from the U.S.

Last year, UPMC received one of the largest grants from the U.S. Precision Medicine Initiative and is investing in a large-scale genome sequencing effort that will both deliver patient care—through rare disease diagnostics and better-targeted cancer treatment—and create a major database for population-scale genomics research. Providing the integrated informatics, database, and tools for projects of such scale and combined clinical and research applications is what our platform does like no other, and we were very pleased to have UPMC present alongside and meet with our partners pursuing similar projects.

Closing out our population-focused breakfast we had the honor of hearing from our longtime collaborator Khalid Fakhro, director of genetics at our partner Sidra Medical and Research Center in Qatar. Sidra’s work, both on the Qatar Genome Programme and as the key maternity and pediatric hospital in Qatar, holds great promise for delivering higher-quality care to patients in Qatar and to advancing precision medicine around the world.

Echoing themes from Kari’s talk, Khalid outlined how Qatar’s population of 300,000, with its high consanguinity rates, is a fertile ground for identifying novel rare disease variants.

Leveraging data from 1,000 healthy Qataris and 600 families with rare disorders, Sidra has developed and published the first allelic map for any population in the Arab world. They are using WuXi NextCODE’s database and tools to drive forward with novel discoveries in a range of diseases, including congenital diarrhea and collagen disorders.

With the opening of Sidra’s hospital this year, and the integration of yet more data from the Qatar Genome Programme into our platform, Khalid emphasized that Qatar is well positioned to undertake not only a cutting-edge rare disease diagnostic testing program for pediatric patients but also drug target discovery. Much as deCODE has done with cardiovascular disease and numerous other conditions, the hope is to begin to analyze data for families and across the population in conditions such as type 2 diabetes. Such findings might well point to novel pathways that can be used to design treatments for those suffering from rare and common diseases alike.

I’ll also post soon about our second rare-disease focused breakfast session at ASHG: “Using NGS to diagnose rare disease—experiences from three continents.” Look for my next post about ASHG17.

WuXi NextCODE at ASHG17: Part I of our “Genomes for Breakfast” Series Highlights Leading Global Efforts to Understand and Diagnose Rare Disease

Kari Stefansson led the group of renowned scientists and clinicians who presented at

Hannes Smarason WuXi NextCODE ASHG2017

Kari Stefansson led the first of two sessions focused on rare diseases at WuXi NextCODE’s annual “Genomes for Breakfast” series at the ASHG 2017 meeting in Orlando, Florida.

WuXi NextCODE’s annual “Genomes for Breakfast” sessions at the ASHG meeting in Orlando, Florida last week. Two of these sessions focused specifically on rare diseases, one from a population perspective and the other from a clinical perspective.

We were honored to host all our speakers, each of whom are leaders in their fields. They included some of our distinguished longstanding and newer partners as well as some of our own WuXi NextCODE colleagues. We had near-capacity crowds of some 300 attendees for each of the breakfasts. That setting provided an inspirational showcase of progress in understanding rare disease and also how WuXi NextCODE’s global platform can help accelerate this critical work.

The goal for us all is to enable rapid and affordable diagnosis of rare diseases in as many countries as possible. And WuXi NextCODE is uniquely positioned to support this endeavor.

As only he can do, Kari kicked the population session off with a deep dive into what he has gleaned from looking at the unique genetics resources he has amassed at deCODE genetics in Iceland over the past 20 years. These resources are of astonishing scale, including the directly sequenced whole genomes of nearly 50,000 Icelanders and 10,000 others; imputed whole genome from 400,000 Icelanders; and SNP data from nearly a million people around the world.

It was an even more notable event, because this year, Kari received the William Allen Award, the ASHG’s highest honor; so the full breadth of the work he and his deCODE colleagues have achieved was featured at several points in our events and elsewhere during the three-day meeting. Underscoring the reach and global outlook of deCODE’s work, Kari pointed out that deCODE is currently collaborating with over 250 international groups and 25 consortia. And his talk was particularly significant for us, because deCODE is not only the world’s first and largest population genomics effort, it is also the crucible in which our technology was forged and the inspiration for the large-scale genomics efforts that we partner with around the world.

Leading off the first breakfast session, entitled “Using Population Genomics to Understand Common and Rare Diseases,” Kari spoke to how deCODE has set out to capture and correlate not just variation in the genome and phenome, but also how genetic diversity itself is actually generated. He pointed out that you could look at life forms as entities whose function is to protect DNA, rather than the other way around. Understanding how DNA changes through generations is a mission-critical task for applying genomics to human health. Where are the sites of the most recombination? Under what circumstances and where are you most likely to see de novo mutations arise?

A pivotal 2002 paper from deCODE provided the world with the first high-resolution recombination map of the entire genome. That map was used to complete the assembly of the Human Genome Project (HGP): Before that paper was published, the HGP’s assembly was about 91% accurate. After the data from deCODE were incorporated, the map reached 99% accuracy.

One of Kari’s observations was that all physiological function is spread across populations in an essentially normal distribution. Looking at extremes—the rare phenotypes—is important, because they often reflect rare genetic factors that can reveal important information about biochemical pathways relevant not only to those carrying the mutations, but also to the rest of the population that has more common, but less extreme, perturbations in those pathways. In this sense, rare variant identification is important for public health in two ways: to diagnose and better treat those with rare disorders, and to find drug targets that can benefit all of us. Rare disease, it turns out, is a common challenge that we all need to meet together.

Kari was followed by two other outstanding speakers and WuXi NextCODE partners: University of Pittsburgh Medical Center’s Annerose Berndt and Khalid Fakhro of the Sidra Medical and Research Center in Qatar. I will provide details about their talks in my next post.

Why We Need Big Infrastructure For Tackling Rare Disease

Hannes Smarason big data rare diseases

Having bigger databases, and having a mechanism that flags genomic variants, is key to optimizing patient care for entire families

Uncovering the genetics of schizophrenia is vital but challenging. As I wrote in my last post, mutations in more than 100 spots in the genome have been linked to the condition. But which ones actually play a role in the disease, and which ones are just there for the ride—innocent bystanders that just happen to occur alongside the real culprits? That’s the crucial question for scientists seeking new treatments for this condition, among them leading researchers and clinicians at our close partner, Boston Children’s Hospital (BCH).

One thing we’ve learned recently is that even a small amount of knowledge about genetic underpinnings of disease can have a big potential benefit for patients. For example, the 16p13.11 region deletion I described in that last post ended up being very important for several patients later, particularly one father and his son, recently described by our colleagues at BCH. This case highlights the importance of expanding the scope and scale of such research, and of updating and alerting patients as more is discovered—not just in schizophrenia, but across rare disease.

In their previous work, the BCH team used chromosomal microarray analysis to determine that a young boy with symptoms of schizophrenia, including psychosis, was missing an entire chunk of DNA—one copy of the chromosomal region 16p13.11, which spans several genes.

Schizophrenia in children is rare, and some researchers believe it could be an extreme variation of the disease, and so might hold important clues for the treatment of this condition in both young and old. A search of our and BCH’s databases showed that several other young patients also showed variations in that region. Just as important, it was confirmed that a parent of one of those patients also carried that deletion, and it seemed likely that another parent (not available for testing, but with reported symptoms of schizophrenia) also likely carried the deletion.

Clearly 16p13.11 seemed to be emerging as a “hotspot” for variations linked to psychosis. But the scientists were only finding this because they could go back and search the databases, and they were working their way backwards from pediatric cases to learn information that might have been medically relevant to the parents as well. All this suggests that having bigger databases, and having a mechanism that flags such variants, is key to optimizing patient care for entire families.

One case uncovered by the BCH scientists, regarding a young man who we will call Jack, brought this into sharp focus. As a teenager, Jack had undergone detailed genetic screening at BCH because of symptoms that included learning disabilities and recurrent seizures. It was determined that he had a 16p13.11 deletion, but at the time of his screening, that mutation hadn’t yet been linked to psychosis. So it became just one more detail in Jack’s medical record.

Separately, a few years later, Jack’s father was diagnosed with ADHD and treated with a high dose of mixed amphetamine salts. Within a few weeks Jack’s father experienced a manic-psychotic episode. He was prescribed an anti-psychotic and eventually recovered. Unfortunately, his son was deeply affected by his father’s breakdown and became withdrawn and depressed. Eventually, Jack also developed psychotic symptoms, which were so serious he was hospitalized.

Jack’s symptoms, thankfully, responded to anti-psychotic medication, but his doctors wondered if there was any connection between the breakdowns suffered by the father and son.

A check of Jack’s medical record revealed the 16p13.11 deletion. And seeing that detail after the link had been made between 16p13.11 and psychosis, his doctors immediately speculated that it might be a cause of Jack’s symptoms. Further, they suspected that mutation could be the “linchpin” causing psychosis in the father and the son. Jack’s father was tested, and he also carries a 16p13.11 deletion.

So here’s the lesson: if Jack’s doctors had known about the link between 16p13.11 and psychosis as soon as it emerged, they might have also suggested testing Jack’s father. If they had, the BCH doctors “believe that the psychosis could have been averted in both father and son.”

In light of this case, the BCH researchers write that they see a keen need for broad, integrated, and sophisticated infrastructure to support genomics-driven precision medicine. They have several recommendations, including that physicians need to receive regularly updated risk information about specific mutations; genetic reports on parents who are “carriers” but seem unaffected should note that problems could arise later, and families that include carriers of variations that increase risk should be monitored and given counseling.

Such activities will be well supported by tools such as WuXi NextCODE’s Genomically Ordered Relational (GOR) database and global platform for diagnosing rare disease and building a global knowledgebase. This can act as one of the key spokes in the “wheel” of genomic diagnostic process. But we also need to build in others, such as means to automatically alert doctors to important knowledge updates, monitor patient records, and connect doctors to specialists who can help refine a diagnosis as new discoveries are made. We and our partners at BCH are committed to helping create these tools.

*  *  *  *  *  *  *  *  *  *  *  *

Headed to ASHG? If you are attending ASHG this month, join us to hear more about how rare disease studies can inform our understand of common diseases at two of our “Genomes for Breakfast” events: “Using Population Genomics to Understand Common and Rare Disease” (Oct. 18), and “Using NGS to Diagnose Rare Disease—Experiences from Three Continents” (Oct. 19).

From Rare to Common: How Rare Diseases Could Advance Schizophrenia Treatment

Rapidly advancing our understanding of rare diseases is a key area of focus for us at WuXiNextCODE. We believe genomics can both transform our ability to understand and diagnose rare conditions, and that this is going to point us is the direction of developing new treatments. At the same time, there is a growing body of evidence and even approved new therapies that show that an understanding of rare diseases can also shed new light on the genetics of complex diseases, such as heart disease, arthritis, and schizophrenia.

Understanding complex diseases is a mammoth challenge because multiple genes are usually involved as well as environmental factors. It’s particularly hard with neurologic conditions. No animal models can really mimic what happens in people’s brains, and human studies usually only provide hints of the information needed to identify potential treatments.

But rare diseases are often caused by single variants that perturb specific and identifiable biological pathways. That’s why recent genetic studies of rare types of early-onset psychosis have inspired so much interest among researchers studying schizophrenia. This disease affects more than 50 million people worldwide, but early-onset cases are very rare, suggesting they may be extreme manifestations.

A new line of inquiry into this condition emerged after a group of our close collaborators at Boston Children’s Hospital, including a scientist now at WuXi NextCODE, used chromosomal microarray analysis and whole exome sequencing in a six-year-old with profound symptoms of psychosis. They discovered this patient had a variation in the ATP1A3 gene, which was not previously associated with schizophrenic symptoms. The team wondered: was that mutation helping cause his symptoms? Would the same mutation be found in other children with early-onset schizophrenia? Could this new lead point to a biological pathway common to many people, young and old, with these same symptoms?

That would be a real breakthrough, both for this child and potentially for many other people.

The Puzzle of Schizophrenia Genetics

Schizophrenia is one of the most serious and common mental illnesses. It is often very difficult to treat, in part because of available drugs’ side effects. There are already about a dozen anti-psychotics on the market for this condition. Besides causing serious side effects, treatment must also usually be life-long. Doctors often have to try different drugs until they find something that works and which the patient can tolerate. Even then, the patient’s response can change over time.

The genetics of the disease are still not well understood. Studies of families and populations show it is heritable – the more affected close relatives someone has, the more likely that person will develop it. Many families are afflicted by both schizophrenia and bipolar disease, suggesting the two conditions are biologically related.  Both conditions seem to be associated with multiple mutations to possibly dozens of genes. Still, even in identical twins – who share exactly the same mutations – it’s not uncommon for only one twin to be affected.  Clearly, there is something other than genes afoot.

Scientists, notably including our colleagues at deCODE genetics, have put their fingers on a few genes and key pathways. Another large genomic study, with more than 30,000 cases and 100,000 controls, pointed to over 100 potential spots in the genome with mutations associated with schizophrenia. Both have found an association with mutations in a region called MHC (Major Histocompatibility Complex), a result that reinforced a then percolating idea that schizophrenia might be related to immune dysfunction.  And then just this week, Chinese researchers reported a new trove of suggestive genetic factors. But despite these massive gene hunts, we are still far from a complete picture of what genes cause this disease and how.

A Promising New Lead?

As described in the BCH blog Vector, The BCH team who found that ATp1A3 mutation in the six-year-old boy decided to do some more digging. The chromosomal microarray analysis showed that he was missing an entire chunk of DNA – one copy of the chromosomal region 16p13.11.  Next, they searched their database and found several other children with variations in that area.  One had a duplication of the 16p13.11 region, rather than a deletion. She had started experiencing hallucinations at the age of 4.  Those findings prompted the BCH researchers to launch a large-scale study, which has already enrolled at least 50 children with early-onset psychosis and will be able to leverage WuXi NextCODE’s informatics and global knowledgebase to find more cases, at BCH and beyond.

The researchers hope that ultimately their studies will not only help children with early-onset schizophrenia but also point to the biological pathways that cause the more prevalent form of the disease, which usually strikes adolescents and young adults.

Such research will hopefully provide firm leads on novel pathways that can be used to identify new drug targets. There is a tremendous need for new medicines. Most of the antipsychotic drugs we have today were developed back in the 1950s and act on the dopamine and/or serotonin receptors. They don’t improve all of patients’ symptoms, and as noted earlier, they can have serious side effects.

By uncovering new biological pathways, groups like the researchers at BCH, able to leverage massive global genomic data like that we are able to provide, aim to uncover such targets and begin the journey to providing better options for patients with rare and common diseases alike.

If you are attending ASHG this month, join us to hear more about how rare disease studies can inform our understanding of common diseases at two of our “Genomes for Breakfast” events:  Using Population Genomics to Understand Common and Rare Disease (Oct. 18), and Using NGS to Diagnose Rare Disease – Experiences from three continents (Oct. 19).

 

 

 

One-Two Punch: The Rise of Combination Cancer Therapies

Wuxi NextCODE genomics and combination therapies

Genomic sequencing is key to developing drugs that can be repurposed alone or used in combination to treat new types of cancer.

One of the biggest new innovations in oncology is the use of combination therapies, and a recent FDA approval for a pair of drugs (dabrafenib and trametinib) for lung cancer underscores that. This is a big step forward and we expect to see many more combinations approved in the future.

But determining which are the right pairings for which particular tumors requires a lot of data. You have to figure out which patients carry particular mutations. That requires accurate testing tools, powerful analytics, and then reams of data to guide you. That’s one of the reasons WuXi NextCODE and others are so focused on building genomic databases and advanced genomic interpretation tools.

”Just collecting and sequencing a cohort is challenging,” says Jim Lund, Director of Tumor Product Development at WuXi NextCODE.  “But having detailed clinical information along with the samples is critical. That multiplies the value of your study.” This type of data creates a “two-way street,” explains Shannon T. Bailey, Associate Director of Cancer Genetics at WuXi NextCODE. “Genomic analysis doesn’t just tell you which drugs you should use, but which treatments will have no effect.”

So what was the latest step forward? Dabrafenib (Tafinlar®) and trametinib (Mekinist®) are now approved in combination for treatment of metastatic non-small cell lung cancer (NSCLC) for patients whose tumors have a specific alteration, called V600E, in the BRAF gene. About 1%-2% of lung tumors carry that mutation, which drives tumor growth and spread through the MAPK signaling pathway. The two drugs target this pathway but through different mechanisms. Dabrafenib is a BRAF inhibitor, and trametinib is a MEK inhibitor.

Perhaps 1%-2% doesn’t seem like a lot of patients. But three things are important here:

  1. Lung cancer is a common and usually deadly disease, so a new approval for even a small number of patients will still have a lot of impact. We must chip away at the mortality rate for this condition however we can, even if the progress seems incremental.
  2. Experts have a lot of hope that combination therapies will deliver the punch we’ve been looking for against many previously intractable cancers. That opens new paths for people who otherwise faced hopelessness.
  3. The more patients receive these combinations, the more we can learn about what works, and why.

The data from today’s patients are a key part of what guide the treatments of tomorrow. This particular approval builds upon more than a decade of data from clinical trials. BRAF V600E has long been a prime suspect as a driver of several cancers. In 2014, the FDA approved this same combination of drugs for melanoma patients whose cancers were positive for the BRAF V600 mutation.

“Genomic sequencing has allowed researchers to identify specific genetic links between different cancers and then repurpose drugs developed for one cancer to treat another form of the disease,” says Lund. “This is data driving precision medicine.”

In tandem with the approval of the two-drug regimen for NSCLC, FDA also gave the OK for the Oncomine DX Target Test, a next-generation sequencing test that can detect BRAF V600E in tumor samples. It screens for multiple biomarkers including BRAF, ALK, ROS1, and EGFR genes. These can all help guide prescribing decisions.

“When we characterize lung tumors from patients, it’s a good idea to test the samples for all the changes that could be targeted by different drugs,” said Bruce E. Johnson of the Dana-Farber Cancer Institute, in a press release about this recent approval. Johnson co-led the clinical trials that were the basis for FDA’s approval of the combination therapy.

It’s also important to realize how difficult it is to carry out these trials. As I noted earlier, this is a very rare mutation. To recruit the 59 patients for the combination trial that led to this NSCLC approval, researchers screened about 6,000 patients. This feat alone represents a “major achievement that underlies the difficulties in completing such a trial,” the study researchers wrote, in an editorial that accompanied the paper about their findings.

These types of advances are spurring researchers to seek more links between established therapies and known mutations. “There are many additional drugs that can be repurposed alone or in combination to treat new types of cancer, and genomic sequencing will be key to both the research and clinical implementation of these new advances in cancer treatment,” says Lund.

WuXi NextCODE, meanwhile, is trying to accelerate progress by providing a comprehensive but user-friendly informatics suite that “allows clinicians to perform complex big data queries and interpretation on a case by case basis, and to annotate that data even if they lack formal computational training,” says Bailey.

Our vision is that eventually, clinicians and individuals all around the world will be deploying their genomes to contributing to our overall knowledge of “which drug—or, perhaps, which combination—works for which patient.”

New Breast Cancer Study Underscores the Need for More Sequencing

Gene sequencing for breast cancer. More than the usual suspects at play.

Ever since actress Angelina Jolie’s highly publicized preventive mastectomy ignited discussion about BRCA 1 and BRCA2, almost everyone has heard about these genes and how they can increase risk of breast cancer.  Some people even refer to them as “the breast cancer genes.” But how genes cause this disease is much more complicated than just through the most well known BRCA mutations, as a recent study in JAMA of Ashkenazi Jewish women has demonstrated. http://jamanetwork.com/journals/jamaoncology/fullarticle/2644652

This intriguing study raises a crucial question: How much sequencing is enough when diagnosing breast cancer in the age of targeted therapies? The number of these therapies keeps growing, as does our knowledge of the links between what drugs work for women with particular mutations. But at what point should we say we have uncovered enough mutations to make a proper diagnosis? And in a field in which we know there’s a lot we don’t know, is there such a thing as enough?

The good thing is that sequencing costs are going down. “It used to be that just testing for a single gene cost several thousand dollars,” says Jim Lund, Director of Tumor Product Development at WuXi NextCODE.  “Now a panel of genes costs that and whole exome sequencing is slightly more.” At the same time, the number of mutations that are discovered and studied is increasing – in the genomes of patients and the genomes of their tumors.

The data here has a message about data itself: in principle, we should be generating as much sequencing data as possible. By generating it, storing it for vast numbers of patients and their healthy relatives, creating more comprehensive databases of all disease-linked variants, and then reanalyzing patient and tumor samples as more is learned, we can improve the risk assessment and the speed and accuracy of diagnosis for patients everywhere. Since we can do this, the question isn’t whether we can afford to do more sequencing, but why anyone would argue that we can afford not to.

The researchers who led the recent JAMA study used multiplex genomic sequencing on breast tumor samples from 1007 patients. They tested for a total of 23 known and candidate genes.  It has been well documented that women of Ashkenazi descent have a higher risk of breast and ovarian cancer, and that is at least in part because of three particular BRCA1 and BRCA2 mutations. These are called founder mutations, because they probably originated among some of the earliest members of this ethnic group, and have been propagated because of a strong history of marriage within the same community.

But the researchers working on this study wanted to know if there were mutations in other genes besides BRCA that made it more likely these particular women would develop breast cancer. The patients were from 12 major cancer centers; had a first diagnosis of invasive breast cancer; self-identified as having Ashkenazi Jewish ancestry; and had all participated in the New York Breast Cancer Study (NYBCS).

Surprisingly, only 104 of the patients were carrying one of the infamous founder alleles. Seven patients had non-founder mutations in BRCA1 or BRCA2, and 31 had mutations in other genes linked to increased risk of breast cancer, including CHEK2. The vast majority of these women carried none of the mutations that are “obvious suspects” for breast cancer. “We do not know why those women got breast cancer,” says Shannon T. Bailey, Associate Director of Cancer Genetics at WuXi NextCODE.

It’s important to note that thousands of different cancer-predisposing mutations have been found in BRCA1 and BRCA2 alone. Every population studied to date includes people with such mutations.  The three founder mutations that have been established as being common among Ashkenazis are estimated to account for about 10% of breast cancers in this group. The rest of BRCA1 and BRCA2 mutations are considered extremely rare under any circumstances.

“If you look at the genes on the panel used in this study, it looks as if they are mostly associated with DNA damage and there are no cell cycle regulating genes included,” says Bailey. “But there are all kinds of mutations that cause breast cancer, even in noncoding regulatory zones.” As a result, even the best designed panel may fall short.

That’s why this study is so important. It tells us that even with founder mutations, family history matters but it doesn’t yet always tell you everything you’d like to know. Of the women with the founder BRCA mutations, only about half had a mother or sister with breast or ovarian cancer.  It’s also already well known that just carrying a BRCA1 or BRCA2 mutation is no guarantee the patient will get cancer. For reasons we don’t yet understand, these mutations raise overall risk, but not everyone who carries one will develop the disease. So while BRCA mutations are important, we need lots more information about other genes too.

The authors of this JAMA report suggest that Ashkenazi patients with breast cancers should have “comprehensive sequencing,” including, perhaps, complete sequencing of BRCA1 and BRCA2 and possibly testing for other breast cancer genes as well.

And what about other patients?  WuXi NextCODE’s Lund points out that even the most highly regarded recommendations for breast cancer testing do not cite specific panels. Those recommendations come from the U.S. Government Task Force [https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/brca-related-cancer-risk-assessment-genetic-counseling-and-genetic-testing] and the NCCN Clinical Practice Guidelines. Women with a family history will likely get more comprehensive testing, but beyond that it is not clear exactly how to proceed in every case.

At WuXi NextCODE we believe that this is clear evidence pointing to the value of doing more sequencing across all ethnic groups – for healthy individuals, patients, and their tumors, and pushing towards sequencing as standard of care. This would expand our knowledge of the genetic risk factors for breast and other cancers; provide vast new cohorts for research; and deliver the most actionable insights to patients, from risk assessment through diagnosis and then ongoing as new discoveries are made.

All of the participants in this JAMA study consented to have their sequence data used to advance research. They are already helping to do that, and this is just one study of thousands that are now underway and that are helping us to expand our data- and knowledgebases with the ultimate aim of delivering even better outcomes for all people and patients everywhere.

Let’s Speed the Genomic Revolution, UK CMO Says

Sally Davies genomics

Whatever path various societies take to tap the power of the genome to improve human health, a recent report from England’s Chief Medical Officer, Dame Sally Davies, calls out key elements for realizing that future sooner rather than later.

England’s Chief Medical Officer wants to build on the success of Genomics England’s 100,000 Genomes Project and take her country swiftly into the age of precision medicine. The goal is to get patients optimal treatment more quickly and with fewer side effects. That means using genomics to more accurately guide prescribing—initially for cancer, infections, and rare diseases—but increasingly for all conditions and overall wellness and prevention.

Dame Sally Davies’ vision is anchored in the work that Genomics England is engaged in today and to which WuXi NextCODE and other leading genomics organizations have contributed. It’s a rallying cry that many voices are joining and underpins our work not only in England, but also similar efforts we are helping to advance in countries near and far, from Ireland to Singapore.

Her call is particularly forceful in three areas that she rightly singles out as critical to realizing the potential of precision medicine to revolutionize healthcare:

  • Industrial scale: Genomics has in many ways been treated and developed as a “cottage industry,” yielding important advances. But the need is massive scale in the era of population health (e.g., whole-genome sequencing, or WGS).
  • Privacy AND data sharing: Dame Sally wants to provide and ensure high standards of privacy protection for genomic data but is adamant that this should not come at the price of stifling the data sharing and large-scale collaboration that will transform medical care and many patients’ lives. She wants to move beyond “genetic exceptionalism,” which holds that genomic data is fundamentally different or more valuable than other data. Like other sensitive data, we can protect genomic data well and use it for public benefit.
  • Public engagement: She calls for a new “social contract” in which we, as individuals and members of society, recognize that all of us will benefit if we allow data about our genomes to be studied. That holds whether we are talking within our own countries or globally.

In England, as elsewhere, these shifts require the input of political leaders, regulators, and a range of healthcare professionals, including researchers as well as care providers. Crucially, such a transformation also requires a level of commitment on the part of patients throughout the National Health Service (NHS) and citizenry in general. If England takes this bold step forward, it could have tremendous effects. But “NHS must act fast to keep its place at the forefront of global science,” said Davies. “This technology has the potential to change medicine forever.”

To date, more than 30,000 people have had their genomes sequenced as part of the 100,000 Genomes Project. But there are 55 million people in the UK, and Dame Sally would like to see genomic testing become as normal as blood tests and biopsies for cancer patients: She wants to “democratize” genomic medicine, making it available to every patient that needs it.

We share and are, indeed, taking part in helping to realize much of Dame Sally’s vision as we work to accelerate Genomics England’s work and engage with our partners globally. As we know, different societies have different models of healthcare and different approaches to research and care delivery. But the ability for people anywhere to tap into the power of the genome to improve their health is at the very core of our own mission as an organization, and we applaud Dame Sally for calling out some of the key elements for realizing that future sooner rather than later.

Whatever path different societies choose to follow toward precision medicine, her recent report provides one enlightening view of a starting point for making the leap.