Masters Degree Completed in Quality Assurance and Regulatory Affairs



This week I completed my last and final class on the Temple University Quality Assurance and Regulatory Affairs degree program. I am now set to graduate with the masters degree, after my final grades come in. It has been an honor and a pleasure to study with the best and brightest industry professionals in the America's oldest Regulatory Affairs degree program. When I first set out to study for the Drug Development certificate three years ago I really wanted to explore a new area out of curiosity, not really knowing what to expect from industry and wanting to venture outside of my comfort zone in academia. My hardcore academic friends remain baffled by such a decision to go back to school and study anything at all, after having done a neurobiology PhD and a decade of postdocking. Three years later, I have acquired a broad spectrum of knowledge about the pharmaceutical development processes and gotten some insights into planning regulatory strategies with the FDA. I have also held some interesting study group interactions with industry classmates and met some great teachers along the way.

No one grows up saying "I want to be a regulatory affairs professional" or "I want to be a Quality Assurance specialist" and as an academic scientist, complying to SOPs is the last thing on your mind while you try to make discoveries. However, studying these classes has opened up my eyes to entirely new worlds of career possibilities and focused my attention on some of the biggest issues the biotech industry and world governments face today. Furthermore, during the time I attended classes, I have seen in real-time the impact of food and drug regulations on the industry. Sometimes there are devastating consequences when organizations either ignore or defraud the FDA and mishandled QA inspections - just look at Theranos and Dr Reddy's. Sometimes there are exciting prospects when the FDA Advisory Committee is presented with controversial data for life-saving but minimally tested biologic therapeutics (Sarepta's Exondys 51 drug). The most striking lesson I learnt was in Food and Drug Law class: that the CEO is ultimately responsible for the company's failings (Park Doctrine, Acme food scandal). Even if employees failed to keep rodents out of the food storage facility, that deficiency was ultimately because of mismanagement from the chairman, who was subsequently fired because of it! A powerful lesson!

While I have not managed to find a direct entry point into a career in regulatory affairs or quality assurance I hope my degree will provide leverage for future interactions with regulatory and quality people in industry and maybe someday land me in the good books of FDA reviewers. Who knows, I might even be able to work with them in future!



    Breaching Industry's High Castle


Many of you know by now that I have found a new job in industry. I have been trying to transition from academia into industry for a while. Such career changes are tricky and everyone I know of has had to face their own difficulties. A couple of years ago, when I went to see a Henry V production in Center City I was captivated by several lines from the famous battle speech:

"Once more unto the breach, dear friends, once more,
Or close the wall up with our English dead!
In peace there’s nothing so becomes a man
As modest stillness and humility,
But when the blast of war blows in our ears,
Then imitate the action of the tiger:
Stiffen the sinews, summon up the blood,

Henry V's Siege of Harfleur before the Battle of Agincourt

While I do not advocate filling up a castle wall with dead Englishmen, I draw strength from this passage. On my down days when I wake up, I repeat this short verse to myself so that I can summon up some courage to go off to work and wipe off the previous day’s failings. In a similar vein, this verse works well as advice for job seekers who have faced challenges and rejections to keep persevering.

In many ways when an academic PhD student or postdoc, with no connections and no experience, applies for a position in an industrial company (particularly a major company), they become the invading soldier trying to breach a castle. A company is set up with high walls to protect its treasures and its people. The king (or queen) is the CEO, the court its board of directors and the castle occupants its employees. When an academic student comes from another land - the land of academia - to ask for a position in the castle, he/she can face tough resistance. One can arm oneself with weapons such as online courses, a business degree, a leadership experience, or an industry contact from a careers networking event. Often the failed applications and tough hiring processes are just a right of passage through life.

It is important to remember that finding a suitable job takes time, effort and a lot of luck. It helps to be stoic. As the philosopher Nicholas Chamfort once wrote, “ A man must swallow a toad every morning if he wishes to be sure of finding nothing still more disgusting before the day is over” If you are a scientist applying for a breakthrough job or a breakthrough grant in industry, or just a person looking for the next job, it helps to expect rejection everyday for years and years. If you land a position early, good for you, but expect rejection in future. You just have to be patient, keep fighting and repeat to yourself, "Once more unto the breach, dear friends, once more...".

Image Reference:

Monty Python's Holy Grail,

Siege of Harfleur:





> A photo of the George Smith lab, June 2017 at Temple University before lab meeting, with my goodbye cake.


It’s the end of an era and the beginning of a new one as I finally finish my postdoc fellowship. I think I have pushed the postdoc experience to its ultimate limit, having worked in a trainee position for nearly 9 years (details about why it has taken me this long and some of the career hurdles that are out there can be found in my previous posts here and here as well as a few in future). It may sound cliché but I will miss my friends and colleagues at Temple University and the neuroscience community in and around Philadelphia. I’m grateful for the help I received and the life experiences I have had, both good and bad, over the last decade. So grateful was I that I bought a cake for my last lab meeting for everyone in the lab to share.

I wanted to finish with a witty job-leaving quote but on scouring the internet I found an overwhelming barrage negative anecdotes! I guess a lot of people hate their jobs when they leave. Here is one of the few positive ones:


Image Ref:, Reid Hoffman and Ben Casnocha



    Regeneration Paper Out



This week our laboratory's research paper was accepted at PLOS ONE. This wraps up my last few years of experiments looking at the effects of tubulin acetylation on axonal regeneration in vitro and in vivo. Although our investigations led mostly to negative data, I hope that it contributes to the body of knowledge in the regeneration field.

Back in 2013, we followed up on a study by the Valeria Cavalli laboratory in Washington University, St Louis, studying how histone deacetylase (HDAC5), when exported from the nucleus to the axonal cytoplasm, could be important for axonal regeneration after injury. HDAC5 is an enzyme normally found in the nucleus of cells, which, along with other HDACs, deacetylates histone proteins, inhibits gene transcription and is widely thought to inhibit axonal regeneration. The novelty of the finding by the Cavalli lab was that inhibiting HDAC5 in the axonal cytoplasm diminished axonal regeneration. Furthermore, they proposed that this was due to HDAC5 having a function in deacetylation of microtubules in the axonal cytoplasm, which promoted a more dynamic microtubule pool to augment axon growth.

I wanted to look at whether axonal regeneration could be enhanced when HDAC5 was over-expressed in adult DRG axons and in injured axons of the sciatic nerve in rats. I also wanted to see if expressing alpha tubulin acetyl transferase (aTAT1), which specifically acetylates tubulin, would have the opposite effect on axonal regeneration to HDAC5. Although aTAT1 is known to affect sperm motility and development, few labs have hitherto reported on the effect of aTAT1 in axon growth of adult neurons. Contrary to our expectations, we found an increase in axonal growth after over expressing aTAT1. We suggested in the paper that this increase could have been due to unknown functions of aTAT1 at play outside of its catalytic activity. Furthermore, over expressing HDAC5 in the axonal cytoplasm did not increase axonal growth. None of the genes we tested had a significant effect on improving axonal regeneration in vivo in lesioned sciatic nerves.

Even though we did not find any significantly ground breaking improvements in axonal regeneration, I hope that the finding of aTAT1 enhancing axon growth in vitro will provide a basis for further study into its role for regeneration. The study of posttranslational modifications in neurons, particularly with respect to how microtubules can be altered, has exploded since I began the investigation. To truly stimulate axonal growth and microtubule dynamicity after injury it will likely require not just an acetylation modification but multiple changes throughout the cytoskeleton.

This manuscript was my first corresponding author paper in which I delt with the submission, cover letter and editor correspondances. This followed the usual long series of processes involving conceptualization, design and writing of the manuscript with my professor. The process gave me a finer understanding of the submission process for peer review papers, at least with PLOS ONE. The review process was remarkably smooth for me considering the editor's demands were not beyond my capabilities in the lab. I also dealt with a constant back and forth communication in the last week with the journal publisher, correcting the paper at a granular level in order to fit it with the format of the journal. What really struck me was the requirement for raw data disclosure, essentially an agreement that I would upload all my raw data (MS Excel files) with the manuscript to show that I had not made up the results. This is something new to the journal which none of my immediate colleagues had discussed before in previous years. It's a sign of the times - in the era of p-hacking and overwhelming observer-biased publications in the biological sciences I think it is a step in the right direction. Enforcing raw data uploads maintains some honesty and data integrity. It also gives other people - scientist or non-scientist - a chance to point out if I have made a mistake.


    Oligonucleotide Therapeutics


One of the most overlooked drug development platforms being used today lies in oligonucleotide therapeutics. Unlike small molecules, biologics and medical devices, oligonucleotides should strictly be classed into a system all on their own. Oligonucleotides are short, chemically synthesized nucleic acids of between 10 and 30 units in length. They have been used in research for over half a century (including by myself), mainly for their ability to modify gene expression. It is this property that makes them appealing for treating diseases, especially ones that are genetically inherited.

In 1968 the Nobel Prize for physiology was awarded to Robert Holley, Har Gobind Khorana and Marshall Niremberg for their contributions to the understanding of how the genetic code is used for protein synthesis. Khorana was one of the first scientists to synthesize a DNA duplex using oligonucleotides. In the 1970s and 1980s, discoveries were made into how oligonucleotides could bind to RNA to block translation and eliminate gene products.

A variety of oligonucleotides have been created and they are classed into four main categories according to mechanisms of action.

1. Antisense oligonucleotides (ASOs) are the most common. These are single stranded DNA or RNA molecules that target messenger RNA (mRNA) inside the nucleus. ASOs can speed up mRNA degradation by activating cytosol RNAase H (Gapamer), block mRNA translation before ribosomes can perform translation (antagomir and steric block) or they can alter splicing to restore stability or function of healthy proteins (splice switching).

Antisense oligonucleotides are chemically modified deoxynucleotides, like those of DNA or rbonucleotides (RNA): Their sequence is 3' to 5' so they are complementary to the sense sequence of a molecule of mRNA, 5' to 3'. They can physically block ribosomes from moving along the mRNA, preventing synthesis of the protein, they can hasten the rate of mRNA degradation or they can prevent splicing errors.

2. Small interfering RNAs (siRNAs) are double stranded RNAs that also target mRNA. They hijack the gene-silencing pathway in cells to trigger degradation of unwanted mRNA that harbor mutations.

3. Micro RNAs (miRNAs) are small non-coding RNAs that regulate post transcriptional gene expression. They can block activity of harmful miRNAs (anti-MiRs) in diseased bodies or they can mimic healthy miRNAs that need to be unpregulated.

4. Aptamers form 3D structures that bind to tertiary structures of proteins. They act as ligands to help for protein entry into cells and vesicles. They can be conjugated to oligonucleotides to aid entry into the cell.

Types of oligonucleotide therapies:

In the early days of oligonucleotide therapy development there were many hurdles that prevented progress towards marketing approval. Molecules were unstable and easily broken down by endonuclease enzymes, a naturally occurring enzyme in the bloodstream. Systemic delivery was therefore ineffective.

Later on, new drug delivery systems were engineered. Oligonucleotides were packaged into liposomes and lipid nanoparticles, delivered directly to the liver. This overcame much of the bioavailability problem. ASOs have been conjugated to sugars such as N-Acetylgalactosamine (GalNAc), to increase potency. Conjugated siRNA was developed using dynamic polyconjugate technology (DPC), to link sugar chains to protect the RNA molecule. Adeno-associated viral vectors have also been used to package oligonucleotides to enhance targeted delivery.

Strategies for improving oligonucleotide delivery:

To date only four oligonucleotide therapies have been approved by the FDA and have remained on the market. These include:

Pegaptanib (approved in 2004, for OSI Pharmaceuticals) - treats neovascular age-related macular degeneration. Pegaptanib is an Aptamer which binds to VEGF proteins blocking its activity. It is delivered through intravitreal injection into the eye.

Mipomersen / Kynamro (approved in 2003, for Ionis and Genzyme) - treats hypercholesterolemia. Mipomersen is an RNAse H stimulator which mediates cleavage of the cholesterol inducing Apolipoprotein B mRNA. This is delivered through subcutaneous injection.

Eteplirsen / Exondys 51 (approved in 2016, for Sarepta Therapeutics) - treats Duchenne muscular dystrophy. Etelplirsen induces exon skipping which induces the expression of truncated but functional dystrophin. It is delivered through intravenous infusion. Eteplirsen had a particularly controversial approval pathway at the FDA since the clinical trial involved just 12 patients and a number of safety and efficacy questions were raised. It was originally voted down by the FDA Advisory Panel before approval.

Nusinersen / Spinraza (approved in 2016, for Ionis and Biogen) - treats Spinal muscular atrophy. Nusinersen mediates exon 7 inclusion and by doing this produces more functional SMN protein. It is delivered through intrathecal injection following a spinal tap.

Oligonucleotide therapies past and present:

One other ASO therapy was approved back in 1998 called Fomivirsen. This was used to treat cytomegalovirus retinitis in HIV patients. It acted by mediating cleavage of human CMV mRNA and had to be delivered by intravitreal eye injection. However this was discontinued after competition from more effective HIV drugs drove it out of the market. Pegaptanib also met a similar fate when better therapies were achieved through monoclonal antibodies.

The recent approvals of Eteplirsen and Nusinersen mark a new chapter in the revival of oligonucleotide therapies. It is hoped that better delivery systems being developed will enhance bioavailability and potency of these molecules. One has only to look at to find that over 100 clinical trials are currently ongoing for over 70 oligonucleotide therapies. Market research predicts RNAi therapeutics to reach $4.58 billion by 2022.


Catherine Offord, The Scientist, Dec. 2016; Oligonucleotide Therapeutics Near Approval

Godfrey et al., EMBO Mol Med. 2017 Mar 13. pii: e201607199. Delivery is key: lessons learnt from developing splice-switching antisense therapies

Lundin et al., Hum Gene Therapy. 2015, 26:8, 475-485. Oligonucleotide Therapies: The Past and the Present

Corey DR., Nat Neurosci. 2017 Feb 13. doi: 10.1038/nn.4508. Nusinersen, an antisense oligonucleotide drug for spinal muscular atrophy

Zhao W et al., Drug Des Devel Ther. 2016 Nov 24; 10:3851-3865. Design, synthesis and evaluation of VEGF-siRNA/CRS as a novel vector for gene delivery.




    Using Brain Implants to Aid Walking after Spinal Cord Injury


Last week a new study came out showing how monkeys can fully regain walking and locomotion after paralysis by having electrodes implanted in the brain and spinal cord. The study (Capogrosso et al.) heralds a new way in which a wireless connection can be made from the brain to the spinal cord, by using a brain-spine neural interface. The first electrode is implanted into the motor cortex region that controls leg movement. The second electrode is implanted into the lumbar region of the spinal cord, below the injury site. The brain electrode array detects tiny currents emanating from neurons in the brain and sends them to the lumbar region’s electrode, which stimulates leg muscle contraction, bypassing the lesion.

Gregoire Courtine showing a model of the monkey brain with the implanted electrode:

The director of the study, Gregoire Courtine, has been working on ways to use electrical stimulation for regeneration for many years, first using rats and now using macaque monkeys. A brash and charismatic neuroscientist, Courtine started his career in Reggie Edgerton’s lab looking at epidural electrical stimulation and previously gave a TED talk advertising his success in getting spinally injured rats to walk on treadmills. This time, to design the electrode array, Courtine and his team used healthy monkeys to record electrical signals that descend from the brain to the leg and signals from the spinal cord into the leg muscle while in a walking state. These signals were then “replayed” after the spinal cord injury to allow paralyzed monkeys to walk. The signals for muscle movement had to be decoded and sent back in electrical pulses to the spinal cord electrode through a computer.

The novelty with this device is that the signal can be relayed between electrodes in real-time, something which has hitherto been a challenge. A few years ago I wrote on this blog about a novel clinical trial that used a brain-computer neural interface that can enable a a quadraplegic patient to move a robotic hand, to grasp a drink. It was the first time voluntary hand movement could be restored. That study also resulted from an experiment in monkeys four years before. The new study provides a greater leap, according to Courtine, since it shows that weight-bearing function and muscle coordination can be restored to enable voluntary leg movement, which requires more robust regeneration than the incremental motor movement needed to recover hand grasping. It is hoped that this electrical device will be translated from monkey to human treatments as quickly as the trial using the robotic hand.

Courtine has been collaborating with a laboratory in Beijing, China in order to carry out the experiments in monkeys. Due to strict ethical and administrative restrictions it has been difficult if not impossible for investigators to use non-human primates in Europe and the US for such experimental trials. The development of this innovative technique in Courtine’s Swiss lab has led to the beginnings of a new human clinical trial, in which two paralyzed patients are already undergoing treatment with implanted electrical pulse generators to re-activate their leg muscles. Given the speed at which these complex clinical trials were translated from monkeys to humans, it raises the possibility that more cures can be developed in China and other emerging-market countries that do not have strict regulations on drug development and medical devices. These new trials come on the heals of a big paralysis trial that saw federal funding withdrawn earlier this year in Louisville Kentucky when the FDA stepped in due to certain violations.

Regulatory agencies such as the FDA, EMEA and PMDA are frantically scrambling to keep up with innovations and to gain an advantage in the race to approve new treatments in humans. In August the FDA’s medical device division (CDRH) held a workshop with patients and doctors to decide on how best to approve implantable neuro-stimulation devices to treat neurological diseases, diabetes, lupus and macular degeneration. This was just one of several dozen public workshops and committee meetings held this year alone to speed up the delivery of medical devices for patients with neurological problems. The FDA has a research program dedicated to the development of safer and more effective neural interfaces for regulatory approval which will play a crucial part in reviewing applications for electrical stimulation treatments in the coming years, as the field continues to advance.

FDA neural interface program:


Brain-Spine Interface paper

New York Times feature

Nature feature

Clinical trial in Louisville Kentucky

FDA medical devices




    What Black Mirror Teaches Us About the State of Scientific Research


This month Netflix began to air season 3 of Black Mirror, an acclaimed British black comedy TV anthology that explores the dystopian, sometimes horrifying aspects that modern technology has on our lives. Think of it like a modern day “Twilight Zone” that is well worth a binge-watch. The first episode, entitled “Nosedive”, took a stab at Facebook, Uber, Yelp and social media’s ratings economy. In this world, people are forced to rate each other out of five stars depending on how well they feel their interaction went (rather like the real-life Peeples app that got publicly rebuked). The higher the star rating, the more entitlements you garner and the more choice you have in attaining a privileged life. The main protagonist in this episode, Lacie Pound, wanted to buy an upscale house but she needed to improve her metrics through interacting with “quality people” in order to qualify for a discount. Lacie’s pursuit of this ambition leads her to reconnect with a highly rated but superficial, abrasive friend and ultimately on a failed quest to attend said friend’s wedding. Her desperate attempt to impress people and to chase a higher score ultimately leads to her downfall. Seeking approval from friends and strangers to grow social capital is fundamental to human nature - this behavior is probably what drove our ancestors to crawl out of caves and invent the wheel instead of swinging aimlessly from trees. But the crippling dependence of one’s life and ambitions on constant social validation in a quantified form highlights a sinister aspect of our society we should all want to avoid.

A scene from "Nosedive":

How is this relevant to scientific research? Well, quite a lot. As scientists we are constantly seeking approval and second guessing what reviewers will say. The peer review system is a long established tradition that is considered a hallmark of scientific integrity. The principles of review date back to 18th century England, when manuscript referees were first proposed at the Royal Society - ironically as a way to advocate science to the public. To publish a scientific paper today, you must submit your findings to a journal editor. He / she will send off the manuscript to two or three reviewers, who may or may not be your competitors in the same research discipline. Whether the paper gets approved, sent back for revisions or denied depends entirely on the opinions of the reviewers. If a reviewer was on friendly terms with you then your manuscript may have a better chance of passing through the gauntlet. On the other hand if a reviewer has a dim view of you or your pervious work they may also be biased against your subsequent manuscripts. A similar process happens when you try to fund grant proposals. In the case of NIH grants your proposal is sent to a scientific review officer, whom you have to talk to and try to impress. The officer will assign your proposal to a study section of 20 or more reviewers. The more people you know and are friendly with on that study section, the higher the score you are likely to get. Hence, armed with a high score, you may want to score their grants high too. It’s all very quid pro quo.

Since demand for publication in high profile journals such as Nature, Cell and Science comes at a premium, peer reviewers and editors tend to give higher scores to authors they know, or from established laboratories which are already well funded. Such well funded laboratories also attain better scores at subsequent NIH funding cycles and will go on to produce even more work in high tier journals. Indeed big laboratories tend to be reputable because they previously made major breakthroughs. However, increasingly these labs gain funding and publish papers regardless of whether the research is genuinely accurate or novel. A recent survey showed that up to 80-90% of scientific data in published literature cannot be replicated. Much of this is due to flawed experimental design and sloppy treatment of statistics. Sometimes, though this is due to fraud and is a result of people gaming the system. The top percentile of scientists gain the most recognition and success often at the expense of the majority of poorer scientists. Subpar work that is not only unretracted but celebrated in prestigious magazines is causing a lot of consternation - rather like how global inequality (or opinions about it) has given rise to the likes of Donald Trump.

At the fundamental level promotions and jobs in academia depend on your metrics of publication success, which in turn can depend on who you know and how well you interact with your peers. It is accepted dogma that young investigators have to attend meetings and become chummy with journal editors who might review their papers and grants. A scientist, just as Lacie Pound from “Nosedive” must go on a quest to increase their social standing with well-established people at fancy social functions, such as a Gordon meeting or Cold Spring Harbor retreat, in an attempt to move upwards in academia. A failure to establish a good reputation could mean the drying up of further funding or publications. The problem is that scientific research is supposed to be objective, where exploration and creativity are championed over social mobility and nose rubbing. In our case medical advances for diseases like cancer, heart disease and Alzheimer’s will be dependent upon objective judgment of verifiable data. When scientists are forced to pursue bibliographic metrics for financial stability and recognition, this leads to stagnation of actual scientific discovery.

A survey of how many scientists have experienced failure to reproduce results from other labs:

Even more pernicious to science is the phenomenon that large numbers of people can make what seem like independent judgments on complex questions until everyone assumes it to be correct (wisdom of crowds according to Joseph Campbell). In the “Nosedive” episode, everyone’s score can be viewed in real time beside their face. When Lacie talks to an office friend who offers her a cookie she wonders why his star rating has been reduced to a “3” range. But she becomes quickly influenced by her colleague to give him a lower rating simply because public opinion at the office turned against him. It is easy to spread both good and bad information quickly, especially on social media. In science, public advocacy can have a similar role. There are obviously good sides to science advocacy when it is not commandeered by a political goal but too often this is not the case. When Andrew Wakefield published his misleading studies linking the MMR vaccine to autism, public perception about vaccination turned resulting in millions of families refusing to accept this essential protection. This war against vaccination continues to wage today, years after the papers were withdrawn. When David Goulson and Jonathan Lundgren made claims that neonicotinoid pesticides caused ailments in bees and a drop in the bee population, the idea spread like wildfire. However, Goulson and others were later found to be part of a pesticide action and conservation group, an activist network devoted to the eliminating pesticides by publishing dubious claims in high impact journals.

The other side of the problem is that the public can be used as a weapon against individual scientists if and when the social media consensus sees fit. Strangely enough the final episode of Black Mirror this year featured a story around killer bees. In a not so distant future natural bees have died out and a government sponsored company has engineered millions of drone bees to replace them. Simultaneously a computer hacker has decided to play a deadly game of online bullying by hacking one drone bee everyday to specifically target and kill the most hated and villified person on Twitter. All this was done before he turned the entire bee population on the netizens who sent out hate-tweets themselves, thus causing an apocalyptic killing spree. While the science behind designing a drone bee population that can pollinate and make honey is very aspriational, the act of using Twitter as hate mail and destroying lives is not. Knee-jerk instant public shaming is now a real problem in society and in science. Just last week a Princeton professor named Susan Fiske wrote about the "uncurated, unfiltered denigration" of individuals using "new media" (Twitter and Facebook) which is destroying people's careers. Anonymous trolling and online firestorms can now haunt any researcher who has had a paper retraction featured on Retraction Watch, regardless of whether the violation was big or small. One of the most famous victims of mass Twitter hysteria was Tim Hunt, the Nobel Laureate from University College London who was shamed and had to resign after making coarse remarks about women in the lab. After building a decades long career in biochemistry and winning the Nobel prize, his 39-word tweet undid him in just a few days. It is true that women are under-represented in science and it is true that Hunt should have paid more attention to what he tapped online. Even I remember scolding and sharing this story on my then active Facebook account. But the vitriol that is thrown out at scientists and academics who do not conform to today's views of political correctness and the speed with which they are hurled out the door is entirely new to our digital age. Lest the public can process what scientists say more slowly and carefully the world could end up actually killing off smart research minds in future.

Tim Hunt: Nobel Laureate in pharmacology who was disgraced by one Tweet:

What can be done about this dysfunction?

We need to build back a certain level of trust between laymen, scientists and communicators of science. A couple of ideas have emerged recently following a backlash of complaints about gaming the publication system. One is that we can evaluate scientists based not solely on their bibliography metrics but on how much value their work contributes to society. Writing in Nature Comments, Rinze Benedictus and Frank Miedema of Utrecht University suggest a new way to evaluate faculty candidates which they have recently instituted at their departments. Candidates are asked to write an essay describing which publications they think contributes the most to society. They are also judged on multiple elements, only one of which includes bibliographic metrics. New faculty are effectively judged by their citizenship values on top of publication record. Here is a table of some of the elements which I think are very good ideas:

A second idea is that graduate students can give feedback on how well faculty perform. At Utrecht University, graduate students are invited every year to award “supervisor of the year” to high-level faculty. They are also encouraged to discuss ways to improve the curriculum with faculty. This kind of feedback, however relies on the individual experiences of students and their relationships with their mentors.

Many of these suggested evaluations are subjective in and of themselves. Furthermore, as much as I have lauded citizen science and the public advocacy of one’s own research, there are pitfalls with presenting data too early. Thus, one cannot eliminate the importance of considering good publication records and grant award history altogether. However, by instilling the values of citizenship and societal contribution, an institution can create more integrity among staff and students. Only by meeting higher, modernized standards of science integrity can we shield ourselves against Twitter hate campaigns and career-wrecking online firestorms. As humans we are always seeking approval from others and to some extent this has benefited us throughout evolution. But it is important not to be blinded by quantifiable data or by public hysteria so that we no longer provide opportunities for talented people to rise up through the ranks of a work force.



Peer Review, trouble from the start

Fewer Numbers, Better Science

Advocacy research discredits science

Nature Survey, non reproducibility

Too much public shaming:

Susan Fiske Essay:

Tim Hunt incident




    A Journey into my Genome (2): Volunteering my own DNA


An explosion of personalized genetic testing has occurred over the last few years. There are now at least 39 direct-to-consumer genetic tests being marketed in the US. Many of these companies have sprung up due to the trend in the medical community prescribing drugs or diagnosing diseases based on personalized genetic information. Some are also taking advantage of the fad idea that your DNA can tell you how to make better lifestyle-style choices, such as eating certain foods or taking nutritional supplements.

Last year I sent a sample of my saliva to 23andMe in an attempt to test out my genetic propensity for developing Irritable Bowl Disease (IBD). What I got was a mixed bag of raw data, some of which suggest a higher risk and some a lower risk of developing IBD. The inherent danger is that if I were a layman who did not understand genetics and molecular biology I could easily have over-interpreted my probability of getting any one disease and jumped to the conclusion that I was sick. My conclusion was that more research needs to be done, both on my part as a consumer and on the part of the scientific community in understanding what they are in fact dealing with.

This year I decided to submit my genetic data to a scientific trial called DNA.LAND. DNA.LAND is a genome sequencing project that collects data from other genealogy and genomics laboratories to make a larger pool of data for a more thorough understanding of human genetics. The founders of this crowdsourcing study, Yaniv Ehlich and Joseph Pickrell, are hoping to attract as many people as possible to share genetic data so that they can gain better insight into how genetics affect our health, as well its relationships with genealogy and other human traits.

If you had your genome already sequenced by companies such as 23andMe you can send the raw data directly to DNA.LAND.
Here is how I did it:
1. I registered myself at
2. I read through and ticked the consent page.
3. I logged into my 23andMe profile, clicked on the “Browse Raw Data” section
4. I downloaded a zipped text file.
5. I then uploaded the text file to DNA.LAND that followed the registration page.

Submitting your genetic information is purely voluntary and based on personal motivation. You will have to read and sign a consent document which specifically warns that they cannot guarantee you from a breach of data. The risk of genetic data being stolen is low but not impossible. Interestingly the study leaders, Erich and Pickerell have published their own genome in the public domain to assure everyone about the relative safety of their service.

At the heart of it DNA.LAND hopes to entice people into submitting their genetic data by rewarding volunteers with badges that can be shared on social media and tidbits of information. You can answer a questionnaire and loosely based on your genetic data the algorithm can assign your most likely eye color, coffee consumption habit, educational attainment, near sightedness and ancestry. To me this all seems gimmicky. The inferred traits are based on very low confidence levels and there are even bugs in the questionnaire. The emphasis on family ancestry is totally lost on me. I know I am of direct Chinese descent from my Chinese parents and I am pretty sure no one else in my family has ever submitted genetic information to these testing facilities. Perhaps people who desperately want to know their origins would find this more beneficial. However, I have to commend the creators for at least attempting to increase subject recruitment. As of writing this, the website currently boasts that over 33,000 volunteers have submitted their precious DNA data. Understanding human genomic information will ultimately require such data from millions of people and this study is just a start.

Some of my predicted character traits based on a very brief readthrough of my sequence data from DNA.Land:

The value of doing personalized genetic testing is increasingly being questioned. Just last week a study came out concluding that testing for inherited thrombophilia does not help to predict whether patients will get lethal blood clots. Furthermore, the expense that taxpayers are footing in medicare supplements for this test alone can mount to over $500 million. There is also a section of this market directed at high performance athletes and personal fitness that seems suspicious. Companies such as DNAFit, Genomic Express, Kinetic Diagnostics claim to offer advice for an ideal regimen of stretching techniques, sprinting styles and dietary requirements based on an athlete’s personal genetics. Such companies often cite scientifically dubious studies that support their claims, based on a limited number of people and a lack of replicable trials. Consequently a publication from last year in the British Journal of Sports Medicine condemned the use of direct-to-consumer DNA testing on young talented children to help pre-determine which sports they should train for. A lot of these DNA testing companies are based more on commercial interests than solid science.

Condemning Direct-to-consumer DNA testing for sports:


Ultimately what we need are a set of standardized, well established criteria for testing companies to use when sampling our DNA. In April this year, the FDA set up a public workshop on next generation sequencing to mull over the issue of a lack of guaranteed quality at testing facilities. Multiple panels of genetics experts were assembled to discuss how to come up with a guidance for a standardized approach to sequencing DNA. Some fundamental concerns include whether to use Short Nucleotide Polymorphisms or InDels to correlate your genetic variations with a disease prevalence in the population. What method would be more accurate? How could a genetic correlation for one disease versus another disease be verified if there are not enough recorded incidences? Such basic questions need to be answered before we can trust sequencing technologies.

Until we reach a point where we can understand enough about analyzing our genetic material and rely on verified benchmarks, we may as well be reading horoscopes. Come to think of it, maybe I would have better luck if I asked a witch doctor about whether I will develop IBD.




British Journal of Sports Medicine:

STAT News:

Thrombophilia Study:

FDA Public Meeting on Next Gen Sequencing:


    ImPACT: A New Device to Treat Traumatic Brain Injury



A piece of great news came this year for clinicians and scientists working to treat traumatic brain injury. Two novel medical devices were approved by the US Food and Drug Administration at the end of August. They are called the Post-Concussion Assessment and Cognitive Testing (ImPACT) and ImPACT Pediatric for children. They are essentially computerized tests that assesses cognitive skills of people with suspected concussion or brain injury. ImPACT is a software that can be installed on any computer and used to help with diagnosis and treatment of people ages 12 to 59. ImPACT Pediatric is used to assess the same types of injury in children ages 5 to 11. According to the manufacturer, this is how it works for athletes:

You do a baseline test before the sports season.The baseline scores are collated and stored in private servers. After a suspected concussion during the season, you report to the healthcare provider and they administer another test to you: word memory, reaction time or word recognition. The results are collected and compared with the baselines. These tests can be administered again during rehabilitation and treatment. The tests should take around 25 minutes and is done online.

As of now the software can only be used by trained physicians, nurses and people who have undergone specialized ImPACT credential certification courses. This device is not a cure or even meant to be a stand-alone diagnosis. However it will allow health care providers to more quickly diagnose brain injuries to athletes on a field, or to anyone with a brain injury in any situation. The ImPACT website proudly boasts that its product has been sold and tested at thousands of colleges, universities and clinical trials centers and that over 250 peer-reviewed publications have been written about the effectiveness of the device.

More than two million people visit the hospital with traumatic brain injury every year and this contributes up to 30% of injury related deaths. Usually doctors perform a neurological exam to test cognition, motor functions, sensory functions and reflexes. Patients with more severe life-threatening injuries undergo magnetic resonance imaging (MRI) tests, computerized tomography (CT) scans. Until now there has not been a unifying benchmark test that can be used reliably to test for traumatic brain injury. To me, the introduction of the ImPACT medical device portents two exciting opportunities. One is that, obviously, this device could help save many lives by eliminating the delayed diagnosis of people who suffer severe brain injuries. All those athletes who come off the field from an injury can now look forward to a safer, more precise method of diagnosis to determine whether they can continue playing or not. Secondly, from a regulatory perspective, this is a de novo review pathway for novel, low- to moderate-risk devices and it is a one of a kind invention. That means future medical devices could be approved more quickly through the same pathway.

For more information go to:

FDA Press Release:

FDA Information on TBI:


    Retiring the Mouse Model Gold Standard



Sometimes I stumble on a great story while driving around and listening to the radio and it makes me ponder about the science that I do. Case in point, last month while listening to a replay of Freakonomics with Steven Dubner, I heard a program featuring a dozen people commenting about scientific ideas that are ready for retirement. It was based on an Edge column in 2014, “This Idea Must Die”, in which John Brockman invited dozens of world renowned scholars and experts to voice their opinions on outdated scientific ideas. Such ideas have led to practices that have been unknowingly accepted by the public but have not proven beneficial to anyone. One particular interview struck me: Azra Raza’s segment about why mouse models should no longer be used.

Ever since Charles Darwin’s The Origin of Species by Natural Selection was published, the idea of using animal models to test human disease has played well with biologists. We do after all share a common ancestor with all animals and we can trace certain characteristics back to the same lineage of genes. Just take a quick browse through pubmed on any biological problem or disease and you will find the variety of commonly used models such as nematode worms, fruit flies, zebrafish, rats, yeast and other animals great and small. Mouse models have been the gold standard of biomedical research for years. They are powerful because they can be generated in great numbers quickly, producing a large amount of data for scientists to do statistical analysis and publish findings. It is easy to genetically manipulate mice, it is cheap and affordable to house them in universities and ethics committees have no problems approving their use on protocols.

But here is the rub. According to Raza, a physician and research scientist working on myelodysplastic syndrome (acute leukemia) at Columbia University, the use of mouse models to study cancer treatments is outdated. Raza said that the origins of using mouse models came from successes in the 1970s by translating a mouse leukemia toxin into a clinical treatment. Unfortunately this chemotherapy has now proven itself to be extremely damaging but the lasting repercussions from the initial success of this study have spurned many other research disciplines to use the same animal model. She cites a paper in which 150 different drugs were tested on mice to treat sepsis but all of them were ultimately proven useless in the treatment of the human version of the disease.

Part of the reason is that laboratories often use “xenografts”, transplanting a human patient’s tissue into the immunosuppressed mouse to test for a drug candidate’s efficacy. The resulting effect of a drug on the mouse would be radically different from that of the human. Furthermore, while drugs therapies in cancer have seen rising FDA approval rates in recent years (up to 20% of NDAs are being approved), 90% of all candidate molecules are still failing toxicity studies and this is attributed to using mice. Raza goes on to indict the current academic environment as being a chief culprit in the over-use of mouse models. Research scientists are goaded into applying for grants using murine models because the archaic system of NIH funding favors the use of these models over all others. In fact, many eminent scientists have built entire careers out of using mice and publication bias in the literature (p-hacking aside) has historically favored using murine models. Try publishing any paper in a high impact factor journal based on cell or tissue culture studies and every so often a reviewer will ask for an in vivo mouse model.

A similar problem exists in neuroscience discovery and translation of drugs for the treatment of neurological disorders. A recent paper in the journal of Institute for Laboratory Animal Research cast doubt on the use of mice to study diseases of the brain. For example, of the 200 different potential interventions that have been published on a mouse model of Alzheimer’s Disease (APP mouse), not one has been reported effective in humans and up to 96% of those Alzheimer’s drugs have been lost to attrition. Another scientist reported that of 100 potentially promising candidate drugs tested for Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease), not one eventually showed success in human clinical trials.

It seems there are four common misconceptions that scientists have been overlooking in using mouse models:

Getting rid of your mouse problem:

The upshot is that researchers are beginning to realize the risks of relying on traditional mouse models for a wholistic interpretation of disease. Here are a few solutions suggested by Joseph Garner in the ILAR journal:

1. Reverse translating human biomarkers back into animals

Pharmaceutical and biotech companies like to focus on the magic word “Biomarkers”, which are simply clinical measurements that tell you how far a disease is progressing. Pinpointing the exact biomarker, often based on a biochemical change, is essential to determination of a treatment course and ultimately the design of the drug. If we can find and validate a predictable biomarker in humans we must ensure it can be tracked in the same way using scalable methods in mice before using them as a standard model.

2. Adopting human clinical trial designs in animal models

The best human clinical trials are standardized by giving placebo (sugar pills) and the test drugs to a randomized group of up to thousands of patients in a blind fashion. The physician does not know which pill they are giving to the patient. Thus, it makes good practice to blindly give placebo and treatment regimes to mice during an experiment to mimic human models. In human trials, the dose and administration of these pills are scaled up gradually if the test patients do not suffer serious adverse events - damaging side effects. However, patients vary in sex, height, weight, age and medical histories. People often take these drugs at home, under different conditions, perhaps under stress of looking after family, or in the office while at work. Dropout or lagging behind on medication is common in these trials. In clinical trials these variations have to be built into the statistical analysis. Similarly such variations must also be designed for preclinical testing of mice - testing different demographics of mice by gender, age, weight and genetic strains. Genetically identical mice can vary drastically by behavioral anxiety and stress - often depending on how high up their cage is from the animal room floor.

3. Enriching mouse cages and reducing animal handling stress

While housing animals in a comfortable, clean, dry cage with food and water is an absolute basic key to all experiments and common sense for all laboratories, handling them to prevent stress is another matter. The difference between a student who nervously handles a mouse causing it stress before a behavioral test and a mature scientist who handles an experienced mouse that has been trained in a task is enormous. Increasingly it is common practice to get multiple experimenters of varying levels to train animals. The animals should be trained and familiar with a task before any measurements are made. This gets the animal handler familiar with managing mice and it gets mice familiar with being touched, then participating in a task, thus eliminating environmental bias.

4. Validating changes in the protocol against success and failure

As with cancer drugs, many neurological drugs are on the market to treat symptoms of a disorder without treating the underlying mechanism of disease. Sometimes these compounds reveal damaging side effects years later. The problem lies in not having understood the disease mechanism well enough before rushing to manufacture the drug. On the other hand, if scientists focused on an empirical biomarker that can be translated from humans into mice, such as insulin resistance against diabetes, we would be able to directly measure disease progression from birth to death. The drug design would be, as the FDA demands, more safe and efficacious.


The goal, I ultimately hope, is that we shift from an inefficient, burdensome framework of using tired old animal models to screen for drugs that only work for a minority of patients into one that develops treatment products that work for a majority of people on a personalized level. The emergence of new clinical trial technologies such as “mouse avatars”, growing a patient’s own tumor in a mouse line to test for treatments is a step in the right direction. However we can do more in future, by eliminating the animal model altogether. We could use purely an in vitro paradigm, such as growing a patient's own stem cells or tumor grafts in a culture dish and then use computer modeling to test environmental factors that could cause epigenetic changes. This way we might come closer to solving the biggest medical problems.



Edge article by Azra Raza -

Freakonomics -

ILAR paper -

Misleading Mouse ALS studies -

Preclinical Research -

Mouse Avatars - 3



    Brexit Britain - I Weep for You


Images of me growing up in Europe: Top Left: at the Stuttgart Christmas Market, 1989. Top Right: In Paris by the Eiffel Tower, 2007. Bottom Left: in Trafalgar Square London, standing next to my Dad feeding the pidgeons, 1990. Bottom Right: standing with my Dad and stepbrother by the Freiburg clocktower, 2007.


I was born in China and moved to Germany with my parents when I was six. When I was seven I moved with them to Cambridge and then to London, where I grew up. My Dad went off to work in Germany and every summer vacation he used to drive my family through the countrysides of Belgium, the Netherlands, Luxembourg, France and Southern Germany.

I went to school with children whose parents had immigrated from across Europe. In university my best friends were from the European continent - Greece, Cyprus, Poland and Turkey. In graduate school, over half of our department was made up of European scientists, many funded by collaborative EU grants.

A couple of weeks I thought I had no stake in the Brexit referendum, because I have not been back to Europe in nearly a decade. But after further examination I realized that it influences me on a very deep level. The decision for Britain to leave the EU was shocking to much of the world and on a personal level it is a challenge to who I am. As a trans-national, multicultural citizen, the very notion of closing off borders, reducing trade and ignoring what “experts” have to say goes against my very notion of being human in the 21st century. As the famous English TV physicist Brian Cox recently said, of ignoring experts, “It’s entirely wrong, and it’s the road back to the cave”. Yet that is what happened when millions of people chose to listen to scaremongering propaganda, by voting leave.

In many ways, seeing this decision on June 23rd was like seeing my parents get divorced or seeing a family dog die in a slow-motion traffic accident. The once great empire of Britain, my former adopted nation, has voted itself into a secluded corner and gone down in a whimper. The whimpering sound of Boris Johnson, the “Leave” campaign mascot and many other so-called leaders backing down from running for political leadership. To say that I feel disheartened and disappointed is putting it mildly.

Those who will bear the brunt of the storm, once the UK formally leaves the EU, will be of my generation and younger. The students who will not be able to take advantage of the Erasmus programs for European scholarships to top universities. The businesses that will shut down in the UK and move elsewhere for more practical trade. The scientists and doctors who will not be able to work and serve the National Health Service. Clement Attlee is probably turning in his grave, and in all likelihood, so is Winston Churchill.

In some ways our generation is partly to blame for the result of this vote. The sad fact is that so few British citizens below the age of 35 actually showed up to participate. Only 36% of 18-24 year-olds and 58% of 25-34 year-olds bothered to turn up at the voting booth. And of those who voted, I wonder how many actually understood what they were voting for. Maybe everyone was just tweeting and Facebooking nonsense emojis. Sometimes I feel a pang of narcissistic guilt for not keeping some semblance of an address in the UK and throwing in a postal vote to tip the scales. Not that my one vote to stay would have made a difference against nearly 2 million extra votes for leave.

An irony that the country that brought western democracy to the world, preaching the benefits of globalization has chosen to be the first one to withdraw from it. The fact is, the old system of democracy is breaking down and we are at a loss as to how to reform it. To add to that, globalization has created a flawed system of winners and losers whose wealth and opportunity disparity have led to a social rift. Britain will need time to heal and so will Europe. Perhaps the people of Britain will find a way, through social media or otherwise, to bring about compassion to mend the divisions that have been set up. Perhaps one day Britain can even use an effective online ballot to avoid voting disasters like this. But the economic divisions will not be mended so easily.

For now, I will mourn the loss of British global influence and European unity. I will settle back and reminisce on the halcyon days of sitting in my Dad’s car, seeing the peaceful, flat and verdant European countryside roll by like a dream.


Image References





Over the last year as I have shifted my research focus more towards the in vivo aspect of experiments I have begun to get more intimate with surgical techniques. Under supervision of my colleagues and my boss in the lab I have learnt how to perform laminectomies, inject into the brain and perform spinal cord lesions. All of this is done in rats in a controlled, regulated situation, under standard procedures. None of these techniques are difficult once you learn the neuroanatomy, you find the right tools to use at every step and you know how the animal reacts to anaesthesia. But the fright of dealing with injecting a panicked animal or having botched a surgery for the first time haunts you none the less. Furthermore, if an animal suffers from complications, dies or does not undergo quite the right procedure you can easily end up losing 3-6 months of valuable experiment time. In doing these surgeries I have become fascinated by the unusual mindset that a surgeon must have when he or she first cuts into flesh, while balancing the importance of the work with the dangers of killing the subject. I suspect that for surgeons who work on actual patients in the hospital, whatever fealings I have must be exaggerated a thousand fold for them to function on a daily basis.

Wondering about what real neurosurgeons would do, I read a couple of books written by preeminent surgeons on their profession. The first one was Do No Harm, by Henry Marsh. Marsh is a celebrated British neurosurgeon who works for the NHS at St Georges Hospital in London. In the early 1990s he went to Kiev Ukraine to set up a humanitarian collaboration with their surgeons. He wanted to improve and revamp some of their ailing medical facilities, by bringing more state of the art equipment to treat, what Western countries would have considered, simple cases. A documentary film was made of his work in 2004 featuring one such visit to Ukraine. In his book Marsh detailed some of the most interesting but graphic surgeries he carried out over his career by dividing each chapter according to a specific brain condition - usually a type of tumor or stroke. The second one I read was When the Air Hits Your Brain, by Frank Vertosick. Vertosick was a consultant to the old TV show Chicago Hope and used to work in Pittsburgh before he had to retire from surgery ironically suffering from Parkinsons Disease. In the book he describes his adventures growing from a neurosurgery intern to a resident, dealing with some harrowing cases in the ER, paediatric and trauma units.



Both these neurosurgeons share common threads of behavior, such as a sense of superiority over other medical disciplines, a morbid sense of humor, an itch to constantly make and fix things with their hands and an overwhelming feeling of responsibility for their patients. But what strikes me is their fear of the sheer uncertainty in the surgical procedure itself. Surgery, more than any other process in the biomedical and medical field is prone to human error. The slight misplacement of the scalpel results, in my case, in a lost experiment and a few wasted months. But in the case of Marsh and Vertosick it would cause a loss of life or the livelihoods of many people.

This brings me to the crux of this blog. A couple of weeks ago a research paper came out in science magazine detailing a new robot that could perform flawless surgery. It is called Smart Tissue Autonomous Robot (STAR). It is the latest gadget to come out of Sheikh Zayed Institute for Pediatric Surgical Institute in Washington DC that uses a fully automated system to perform soft tissue surgery. The authors report that the robot can perform a linear suture and an end-to-end anastomosis, resulting in the successful removal of a pig's appendix. This is all guided by a novel algorithm commanding a phlenoptic 3D near infra-red fluorescence (NIRF) scanner which helps the robotic arms position accurately and sense weight and pressure changes. In this procedure the robot was automated 60% of the time but 40% of it still required minor adjustments. The animals survived the surgery with no complications. If all goes well, such a robot could be programmed to do increasingly more complex surgeries with accurate repetition that even the most skilled human would struggle with. It could drastically cut the risk of invasive surgeries in future, although it would not completely replace the need for a human surgeon - someone still has to operate the executive programs. It does herald a future in which surgery will inspire less fear and experiments can be more consistent.

A video from AAAS about the STAR surgery robot:

The research paper from Science:







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Previous Posts

Theranos - Moral Lessons for the Biotech Industry

Gene Therapy for Spinal Cord Injury

FDA - Golden Age for Gene Therapy

Pricing Gene Therapy

Lentivirus - Not just Retro Chique


AAV - An Awesome Vehicle!

The Year of the Gene Therapy

Masters in QARA

Industry High Castle


Regeneration Paper Out

Oligonucleotide Therapeutics

Brain-Spine Neural Interface

Black Mirror

A Journey into my Genome (2): Volunteering my DNA

ImPACT Traumatic Brain Injury

Retiring the Mouse Model Gold Standard

Brexit Britain I weep for you


Seven Years in Visaland

Photo Website

Restimulating the Party

Start Talking Science

A Journey into my Genome

Patent Law IX, The Limits of Biotech Patents

Patent Law IX, The Longest Patent Extension Battle

Patent Law VIII, Invasion of Patent Trolls into Biotech

Patent Law VII, DTC Genomic Testing

Patent Law VI, Supreme Court and Laws of Nature

Patent Law V, The Dark Web

Patent Law IV, Gaming the Hatch-Waxman Act

Patent Law III, The Brave New World of Biosimilars

Patent Law II, The Everlasting Patent

Patent Law I, CRISPR-Cas9

FDA Law Intro

The Big Idea

Accountability for Retractions

Neuroscience Drugs

Locked-in Syndrome

SCI scar Inhibitor




Neuropathic Pruritus

Mitochondrial Disease, 3 parent baby

Multiple Sclerosis and Axon Injury

Pint of Science Philadelphia

The Mesoscale Connectome

Tracing Neuronal Circuits

Pint of Science


The Brain Initiative

Two more online courses done

Fellowship Awarded

One week

Shriners Fellowship

PVA Fellowship

SfN Itinerary

Online Course Certificates

Systems Biology