Genetic Superheroes

The results of Stephen Friend’s ambitious study was finally published online in Nature Biotechnology on 11 Apr. From sequence and genotype results of 589,306 healthy individuals gathered from various sources such as 23andMe, 1000 Genomes, the Children’s Hopsital of Philadelphia and more, researchers looked at mutations in 874 genes believed to cause 584 distinct severe Mendelian childhood disorders. The diseases were chosen based on three characteristics – high severity, early age of onset and complete penetrance (i.e. if the mutation is present, you definitely get the disease). This approach, performed on self-reported healthy individuals > 18 years old, allowed  one to find the “Genetic Superheroes” or people that have overcome a mutation known to confer a very severe disease at a young age.

They found 15, 597 candidates initially, which was filtered down to 303 due to low confidence in sequencing reads, unexpectedly high allele frequencies, or the inability to access individual genomic data. Further filtering was performed by a panel of experts and excluded persons uncertain to be completely resilient to the disease, persons having heterozygous mutations (where one healthy allele prevents disease manifestation), and persons having mutations with insufficient evidence linked to disease. Finally, a group of 13 individuals were identified to carry heterozygous dominant or homozgous recessive mutations linked to 8 different severe Mendelian childhood disorders that would normally manifest before 18 years of age: cystic fibrosis, Smith-Lemli-Opitz syndrome, familial dysautonomia, epidermolysis bullosa simplex, Pfeiffer syndrome, autoimmune polyendocrinopathy syndrome, acampomelic campomelic dysplasia and atelosteogenesis.

Of these 13, there was enough DNA material to Sanger-sequence only 5 to reconfirm the findings. And most unfortunately, all 13 could not be recontacted due to lack of a recontact clause in the original consent forms. Something which will definitely be addressed in the future.

The inability to recontact any of the 13 was the main caveat of the study. Not only because of the missed opportunity to confirm that they were really “superheroes” absent of disease, but also because there was no chance of furthering the investigation to find out which genes conferred their resistance to disease. Furthermore, the individuals identified may also be genetic mosaics – where though the mutation may be in the cells collected (usually derived from cheek swabs), the mutation may not be expressed in the cells associated with the disease e.g. in lung cells involved in cystic fibrosis.

Because most of the data were genotypes and not whole genome sequences, it was difficult to identify “resilience genes” that conferred the protection from disease manifestation with the existing data . Carrying out such studies are also hindered by the small number of these identified “genetic superheroes”. The authors argue however that N of 1 studies (i.e. sample size of 1) can yield relevant  information if the disease was highly penetrant and whole genome sequences were available.

Definitely an interesting concept with the potential to change the way drugs are made. Identifying “resilience genes” for example is a great way to find a gene candidate worth modulating with small molecules/biologics. It also allows researchers to understand the disease and narrow in on which pathways are of particular importance.

Already, there are ongoing efforts to utilize this approach to speed up drug development. NIH Director, Francis Collins, launched a $230 million Accelerating Medicines Partnership (AMP) among 10 biopharmaceutical companies and non-profit organisations focusing on four diseases – Alzheimer’s disease, type 2 diabetes, rheumatoid arthritis and lupus. The large databases containing information linking genetic and clinical information will be shared with the biomedical research community  in an effort to speed up the identification of relevant gene targets or biomarkers.

With the dropping cost of genetic sequencing, these databases look set to grow. Proper database management and the ability to filter through all that information are current challenges. But at least it is a step in the right direction to revitalize the search for novel drug targets.





Your bioshots for the week:

1. Roche invests in bromodomain (BET) inhibitors

Roche announced it is acquiring Cambridge, Massachusetts’s based Tensha Therapeutics for US$535 million. Their  interest lies in the company’s lead compound, TEN-010, a small-molecule inhibitor selective for the bromodomain and extra-terminal domain (BET) protein family. Bromodomains are said to be “epigenetic readers” that monitor histone acetylation/methylation marks, binding to them and regulating transcriptional activity.

There are already drugs like Xanax which inhibit BET (though weakly) on the market. But several other more potent BET inhibitors have conferred protection in various cancer preclinical models, regulating oncogene MYC transcription and other cancer-related genes such as Bcl2 and NFkappaB. There is significant interest in this class of molecules as GSK, Merck, Bristol-Myers-Squibb, AbbVie, Gilead and Daichii Sankyo all have their own BET inhibitors in clinical trials.

2. Exosome Diagnostics launches the first exosome RNA-based liquid biopsy

Exosomes are microvesicles released from cells which contain DNA, RNA and protein resembling the molecular milieu of the parent cell. They are found in most bodily fluids and have the ability also to enter cells and change their biology. Exosome Diagnostics was founded by Johan Skog, who during his work at Boston-based Massachusetts General Hospital, found exosomes could enhance tumor growth by transporting mRNA, miRNA and angiogenic proteins, and could potentially serve as blood-based diagnostic markers (Nat. Cell Biol. 10, 1470–1476, 2008). Their newly launched ExoDx Lung(ALK) test characterizes both exosomal RNA and ctDNA, detecting  mutations in EML4-ALK, an oncogenic fusion protein transcript found in patients with non-small cell lung cancer (NSCLC).

3. Wuxi Apptech acquires Crelux

Munich Martinsried-based Crelux has been acquired by Shanghai-based Wuxi AppTec. Crelux provides structural-based drug discovery solutions with expertise in in silico, biochemistry and X-ray crystallography techniques which Wuxi AppTec will benefit from. In turn, Wuxi AppTec hopes to extend its European presence and cater better to its European clients. See press release here.

4. GSK CEO Andrew Witty steps down

After intense pressure by investors, Sir Andrew Witty has announced he will be stepping down in March 2017. Sliding sales figures from a combination of factors including patent expiration, poor executive decisions to sell its oncology business to focus on lower risk products, and rampant bad press from China bribery scandals have made Dr Witty’s time at GSK an especially tumultuous one. The lookout for potential candidates has started, with CFO Simon Dingemans being an option but investors are insisting on external candidates to present a fresh perspective. Novartis’ pharma chief, David Epstein, being a potential choice.

5. Chinese scientists genetically modify human embryos, again

Scientists from the Guangzhou Medical University have used the CRISPR/Cas9 system to genetically modify human embryos. The 26 embryos used in the study came from 213 fertilized eggs obtained from a fertility clinic. These embryos were classified as “unsuitable” for clinical use due to an extra set of chromosomes. Mutations were targeted towards immune cell gene CCR5, in the hope to regulate resistance to HIV. However, only 4 out of 26 of the embryos were successfully edited with several showing off-target gene mutations. This study comes after a previous study also performed in China Guangzhou, which triggered the world-wide debate on ethical concerns regarding human gene editing. An international scientific summit in December 2015 however concluded that although implantation of gene-edited embryos cannot be done in women to induce pregnancy, basic research in this area should continue. U.K. officials have also approved an embryo-editing study seeking to understand early human development.

6. Sean Parker invests $250 million on cancer immunotherapy 

Co-founder of Napster and Facebook’s first President Sean Parker launched a US$250 million grant, creating Parker Institute for Cancer Immunotherapy, an institute that will bring together more than 300 researchers from 40 laboratories across six cancer centers. This article by Sharan Begley breaks down his decision into 5 questions. Cancer immuotherapy has already received tremendous research funding support – $100 million was given by former New York City Mayor Michael Bloomberg and clothing magnate Sidney Kimmel. Biotech billionaire Patrick Soon-Shiong and Joe Biden have also both launched their individual cancer “moonshot” plans, both highly funded and involving massive collaboration between numerous institutes.

7. Pfizer and Allergan call off merger 

After months of negotiation, a new temporary ruling by the U.S. Department of Treasury on April 4 which made the tax-incentive derived from the merger no longer as lucrative as it would have been, has led Pfizer to cancel its plans to acquire Ireland-based Allergan. Pfizer may now look to split up its business into smaller units while Allergan, disappointed with the deal fall-through, obtains a $400 million break fee. See the Pfizer press release and interview with Allergan CEO on CNBC expressing frustration with the move made by the US government.


7 tips on writing effectively

Writing is imperative in life, and together with speech is the main thing that elevates humans as a species from the generic ape. Despite this, inefficient communication takes place on a daily basis. Think about that last lengthy WhatsApp message or email you had to scroll through twice just to clarify the point the author was trying to make. Working in science, this problem is amplified by the use of jargon; field-related terms that people enjoy using to make themselves sound smarter.

Writing is a means to get one’s point across to another person(s). You need it in all kinds of situations – selling products or oneself (advertisements, job applications), recording (history, data), informing (news), creating a following or a movement (politics, religion, environmentalism), capturing imagination (books, stories) and self-expression (blogs, Twitter, Facebook).

So are you an effective communicator? In this day and age, one is also not given much time to communicate. Since 2000, the average human attention span has dropped from 12s to 8s (which is shorter than a goldfish: 9s) . So how do you effectively capture and maintain the attention of your readers? Let me list the ways:

1. Make a visual impression

A whopping 65% of people are visual learners. This means that long paragraphs of complicated texts are prone to make your readers “zone-out”. Images and videos are often effective at capturing attention. Once you have the attention, don’t lose it by having long unending paragraphs. Space out your points into separate paragraphs and make it easily understandable. The use of bullet-points or lists are also effective means of getting points across. Stories/anecdotes are also somewhat visual as they create a scene in one’s mind and can be great hooks for capturing attention.

2. Give the reader what he/she wants

I used to struggle with blog posts, and sometimes still do! But one thing that helps me focus my content is pretending if I were the reader. What would I want to read about? This runs in parallel with writing. Writing is a form of learning. So I usually write about what I want to know more of. This forces me to research the topic of interest and formulate my own opinions. In the end, you need to cater your script to what the reader/buyer/employer wants.

3. Simplify but don’t be boring

People have different styles of writing, it’s important to keep your own style. At the same time it’s essential to be effective at getting the point across. A book that comes highly recommended is Strunk and White’s “Elements of Style”. It’s a classic which teaches you the “rules” of English. The entire book contents appear available on this site.

An excerpt: “Vigorous writing is concise. A sentence should contain no unnecessary words, a paragraph no unnecessary sentences, for the same reason that a drawing should have no unnecessary lines and a machine no unnecessary parts. This requires not that the writer make all his sentences short, or that he avoid all detail and treat his subjects only in outline, but that every word tell.”

The book also recommends writing in the active voice which I highly employ i.e “She enthusiastically juiced the orange.” versus “The orange was juiced by her with great enthusiasm.” It sounds more impactful, doesn’t it? However, its good practice to vary sentence structures so you don’t bore the readers.

4. Different cultures, different styles

Just as we respect the behavioural norms of each culture, writing also has to be molded according to the culture of the target audience. I just found an interesting method of classifying cultural behaviour – the Lewis Model. Similarly, writing style is influenced by these different cultural characteristics. I found it interesting for example that in Germany, people detest self-praise. So when applying to rent an apartment for example, it would be unthinkable to write “We are friendly and pleasant people.” Chances are, that would only arouse suspicion! Same thing goes for when applying for jobs. It may be better to take a more aggressive and direct approach when applying for a job in America than for one in the UK/Germany. Asia is somewhere in between in my opinion.

5. Using fancy words

Yup try to avoid this. Not only does it come across as trying too hard, it may also be unfamiliar to the reader, burdening him/her with the effort of looking it up. Save the fancy words for novels, poems, and other “artistic” works of self-expression.

6. Coherent flow

Just as in a presentation, it helps to start a written script with an outline of what the article will be about (after your attention-grabbing hook). Main points are highlighted in the body, and at the end it is imperative to conclude well. I must admit I am not great at this but you can find some useful tips here from Elizabeth Soumya’s blogpost. The conclusion should ideally have an element of surprise but still be coherent with the rest of the article. Good methods are using quotes, startling statements, thought-provoking questions, stories, or a link back to the beginning.

7. Ask for opinions

Your view of your own writing is probably far more idealistic that it actually is. It definitely helps to ask people for their opinions on your written piece. Oftentimes, this leads to improvement and also learning moments that help guide your future writing style. Don’t protect your ego, expose it!

So when was the last time you’ve carefully scrutinized your own writing? Try it out, you may learn a thing or two.