#sciencekaleidoscope

[anatomyofscience]

CRISPR/Cas9

Faster, cheaper and more accurate than any other previously developed method of engineering DNA. CRISPR/Cas9, based on the mechanisms of bacterial defence system, enables scientists to modify and replace genes. The technology was awarded the Breakthrough Prize of 2015 by the Science Magazine and sparked heated public debate on numerous occasions.

Here’s why #CRISPR is still trending in media.

CRISPR was used to edit human embryos

The two papers, both published by Chinese scientists, reporting the use of CRISPR/Cas9 for genetic modification of human embryos stirred controversy around the world. The first group to cross this scientific line was led by Junjiu Huang and published their results in the online journal Protein & Cell (1). Although the authors used non‑viable human embryos (so-called 3PN embryos) to minimise ethical concerns, the paper was still rejected by top journals such as Science or Nature partly due to ethical objections. The team attempted to edit the gene responsible for β-thalassaemia, but reported low efficiency and many off-target mutations (called indels). The second, very recent publication, reported a number of similar technical problems associated with the use of CRISPR/Cas9 (2). Interestingly, this time the gene-editing technology was used to modify the form of CCR5 gene allele to reduce human susceptibility to HIV. The method, however, yielded only 5-15% efficiency and a number of unwanted mutations of CCR5 gene. As much as the idea of a human race that is completely resistant to HIV infection and free from any genetic disorders may appeal to some of the readers, CRISPR/Cas9 technology is still not ready to be used for clinical purposes. Low efficiency and the risk of unwanted off‑target mutations would result in a significant loss of viable embryos and other unpredictable developmental consequences that will be passed on future generations. This adds a scientific issue to the bigger view on human gene editing focused mainly on ethical concerns about designer babies. Generation of genetically modified humans remains strictly prohibited, and there is no indication that this will change any soon. If anyone is particularly interested in this idea, a book GMO Sapiens: The Life-Changing Science of Designer Babies seems to be a good read.

Scientists in China are not the only ones interested in genetic modification of human embryos. Kathy Niakan, a stem cell scientist from London’s Francis Crick Institute, was given a license to carry out similar experiments. However, the aim of the Niakan’s investigation is purely for research, rather than clinical purposes. The group proposes to study the first 7 days of a fertilized egg to deepen the understanding of how the human embryo develops. Such experiments are expected to have an overwhelming scientific impact that may lead to the development of greater ways for prevention and treatment of developmental disorders and an improvement of IVF technology. Gene editing to produce modified human embryos, even if only in laboratory environment, is nonetheless very controversial from the view of general public. Will the next researchers take a step further and try to deploy CRISPR/Cas9 modification in the clinics for reproductive purposes?

Who owns CRISPR/Cas9?

Although some insist that CRISPR technology should not be patented at all, the patent dispute between Jennifer Doudna (University of California) and Feng Zheng (Massachusetts Institute of Technology) has been the subject of major attention. Patents go to the first to invent something and MIT paid for an accelerated review of its patent application. Zheng was then awarded the first patent for CRISPR/Cas9, which UC later claimed. The case is still awaiting a resolution with the most probable scenario being one of the sides to provide the earliest lab records for the discovery of CRISPR. This patent litigation is considered to be challenging and complex even for the most experienced patent practitioners. By bringing the attention of the attorneys and biotechnology industry interested in the invention, the popularity of CRISPR/Cas9 is spreading far beyond research institutes.

Ideas.ted.com

The lesson coming from all CRISPR/Cas9 stories is the importance of patience, in-depth consideration, but also critical thinking towards the breakthrough biomedical discoveries that can directly affect the human health. To avoid misuse and disappointment, the clinical application has to be approached step by step while supported by strong scientific evidence. In the case of CRISPR/Cas9, we are still far from seeing its full medical potential.

Magdalena Plotczyk

References

1.   Liang P, et al. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell. 2015;6(5):363–72.

2.   Kang X, et al. Introducing precise genetic modifications into human 3PN embryos by CRISPR/Cas‑mediated genome editing. J Assist Reprod Genet. 2016

[anatomyofscience]

Amniotic Membrane Transplantation in the Human Eye

Corneal disease is a major cause of blindness worldwide, second only to cataract, and its epidemiology involves an extensive variety of infectious and inflammatory eye diseases that can also be highly dependent on the geographical area under study. To place the disease into perspective, according to a report by the WHO, there were 45 million individuals worldwide in 2001 who were bilaterally blind and another 135 million that had severely impaired vision in both eyes.

As a response to this, there are several treatments that range from the use of topic anti-inflammatory drugs or antibiotics, to corneal transplantation –more specifically, amniotic membrane transplantation –, which is the subject of this brief discussion.

The amnion is the sac surrounding and protecting the developing embryo.  Ever since 1910, when a surgeon first reported the use of fetal membranes as surgical material in skin, the use of amniotic membrane in surgery has been revised. In the following decades, numerous researchers reported the advantageous role of the amniotic membrane for the treatment of a variety of ocular surface disorders, without a clear or approved medical application, resulting in the abandonment of the technique.  Nevertheless, recently, it has been making its way back into ophthalmological practice. The relevance of the subject is the scope that the application of amniotic membrane transplantation (AMT) in the management of ocular surface disorders offers.

There are a number of applications for AMT given its transparency, low cost, availability as a surgical spare tissue, non-immunogenicity in a cryopreserved state, anti-inflammatory properties, and the natural antimicrobials present in its epithelial layer. Also, amniotic membrane contains growth factors and expresses anti-inflammatory cytokines that accelerate the healing of the tissue. Among the indications in ophthalmology are the persistent epithelial defects unresponsive to medical treatment, and its use as an alternative to conjunctival flaps, botulinum toxin injection, or tarsorrhaphy; with a very high success ratio. Regarding tissue engineering methods, AMT has a potential use in combination with limbal transplantation in patients with diffuse limbal stem cell deficiency and in diseases such as Stevens–Johnson syndrome or chemical and thermal burns.

Generally, for the preparation of the membrane, after harvesting human placenta from a healthy woman during a cesarean section, the amnion is isolated from the chorion, washed in sterile physiological solution, put on nitrocellulose membrane fragments, and cryopreserved. The amnion as a scaffold with an intact epithelial layer has been proposed as an optimal choice for clinical usage since it has been proven to accelerate epithelialization of eye defects by promoting the migration of epithelial cells, their adherence to the basement membrane, and differentiation; along with the prevention of apoptosis. It also induces cell proliferation by secreting molecules with immunoregulatory and angiogenic properties.

However, as every technique, amniotic membrane transplantation in the human eye also has its limitations. One of them is a shown failure in the case of its use when impending or recent corneal perforation is present. Another example would be the higher rate of recurrence – almost five times higher – of pterygium when compared to an autologous conjunctival graft during the removal of pterygia (bearing in mind that it could be used as an alternative in some specific cases). Moreover, the beneficial effect of amniotic membrane in the management of ocular surface disorders is still in need of well-designed clinical trials to obtain more solid information. Therefore, clinicians should be judicious when considering AMT applications.

By Tania Choreño Machain

[anatomyofscience]

SURGERY AS ART

Last May I attended a very interesting discussion between Professor Iain Hutchison and Maggi Hambling at King’s College of London. What could a Maxillofacial Surgeon possibly discuss with a world famous painter and sculptor?

For those who don’t know any of them, Prof. Hutchison is a famous Maxillofacial Surgeon and the founder of an amazing organization called “Saving Faces”. On the other side, Mrs. Hambling is a British contemporary painter and sculptor (her most famous piece is Oscar Wilde’s sculpture close to Trafalgar Square).

Going back to my question and being a surgeon myself, I was trying to grasp the idea, the underlying meaning of sophisticated use of English language and surrender myself to the beauty of the conversation.

 I was constantly thinking about it and only when I let myself go and let the romanticism kick in I had a realization: Surgery is not just another way of saving people but rather a form of ART. YES! That it is! A form of ART! A surgeon creates, manipulates in order to create something, even from scratch. We are sculptors but with a different power in our hands. We create and at the same time help people to ameliorate their living standards!  

By Ioanna Dimasi

[anatomyofscience]

Baby girl is first in the world to be treated with 'designer immune cells'

Genetically engineered cells successfully used to treat aggressive form of childhood cancer, but landmark treatment had only been tested on mice

Genetically engineered white blood cells used in first-in-man leukemia treatment. Way to go UCL! 

"The technology itself has got enormous potential to correct other conditions where cells are engineered and given back to patients or to provide new properties to cells that allow them to be used in a way we can only imagine at the moment."

“the successful results of the treatment must be replicated before assumptions can be made on the future of cancer treatment.”

[anatomyofscience]

“Stress made me infertile! But how?!”

--By Sparshita Nag

Well that’s not an uncommon question these days, is it? I’ll start with an example.

Neil and Maya—aged 36 and 34 respectively have been married for 6 years now. Both of them are corporate executives and have predictably stressful work profiles. All is seemingly well in their lives except for one thing. They have not been blessed with an offspring till date. This is in spite of absence of any contraceptive measures on their parts. A visit to the gynaecologist confirmed what they were scared to confront all this while. It was a probable case of infertility. While Maya presented with irregular menstrual cycles, a series of tests revealed Oligospermia/Low sperm count in Neil. “Stress-induced infertility(SUI)” concluded the doctor and advised lifestyle modifications to relieve stress as a panacea to this problem.

Stress and infertility. They sound as unrelated as two words could conceivably be. But statistics suggest that in recent years, this has gained the notoriety of being the commonest cause of inability to conceive. Although one would be tempted to point out that it may directly affect the consummate relationship of a couple, most cases present despite normal relations between the couple. “So how does that work?”, a person unrelated to biology would wonder. Well, that calls for us to focus on the games that hormones like to play in our bodies and their beautiful, balanced interdependence and co-existence. A little perturbation and we turn symptomatic in different ways. Stress induced infertility is the result of disturbance of one such delicate hormonal balance.

In this context, we will be talking about male infertility. The discussion would include two glands in the brain namely the Pituitary and the higher-up authority called the Hypothalamus. Also included would be Adrenal glands located above the kidneys and of course, the male gonad--Testis.

Sperm production or spermatogenesis as it is technically referred to, requires the male sex hormone called Testosterone. This hormone is produced in the Testis from a precursor called Dehydroepiandrosterone (DHEA). This conversion happens under the influence of Leutinising hormone(LH) from the Pituitary Gland in the brain which is in-turn controlled by the Hypothalamus. This constitutes the so-called Hypothalamo-Pituitary-Gonadal (HPG) Axis which is cyclical and follows a feedback mechanism. An excess of any of the downstream components signals the release of the respective upstream component to be suppressed thus retaining the so-called hormonal balance in the body. 

Now, the Adrenal gland seated above the kidneys produces a hormone called Cortisol. It’s secretion drastically increases in stressful conditions. In medical science, the word stress refers to anything that our cells are not made to handle in normal health. And that could range from busy work profiles to a surgery to any illness. This hormone although not a part of the HPG axis, has an external suppressive effect on Leutinising hormone that directly reduces Testosterone production and hence the sperm count.

Can regenerative medicine help? Well theoretically speaking, yes. A possible idea could be to direct stem cells to form sperms outside of the body that can be used for in-vitro fertilization with the egg from the female partner and a normal pregnancy continued provided the female is in good health. Unfortunately, previous research attempts to generate sperms artificially in such a manner have been unsuccessful in attaining complete morphological and functional resemblance to sperms produced naturally in the body. But a lot of work is going on in this area and scientists hope to come up with a solution soon.

It must however be noted that stress induced infertility is technically reversible and does not necessarily require medical intervention. Reducing work stress levels by taking a short sabbatical from work, paying attention to what we eat (yes, fat is another reason for high cortisol levels), maybe initiating a moderately active lifestyle with yoga, brisk walking or zumba sessions could aid in curbing the excessive cortisol secretion to allow the HPG axis to spring back to normal health. Most importantly, we need to cultivate a positive attitude towards life. You see, one way of looking at this is by considering our cells to be infants who look up to their mothers for care and protection. The onus of protecting our cells from external damage lies on us. We are supposed to provide them with a healthy atmosphere within to support proper growth and function. Like the adage goes, “Prevention is better than cure”. Of course we have doctors and medical science to help us. But then again these healthcare delivery professions are limited by what has been found out till date which is in no way enough to cure each and every ailment.

So let us all be good parents to our cells and help them to help us function properly. After all, health matters!

Signing off, Sparshita :)

[anatomyofscience]

Why the ‘Game of Thrones’ in medical science?!

---Sparshita Nag

Can you imagine the video game giant Nintendo being as successful as it has been, without its dedicated team of game developers? On the flipside, do you think Mario would’ve become a household name without the phenomenal execution of marketing strategies by Nintendo? I’m sure everybody agrees that this company or its team of R&D would not have existed at all had it not been for a steady base of pint-sized consumers going crazy over how to help Mario rescue his princess!

In crude economics terminology, the source/inventor, mediator and benefactor are inter-dependent on each other constituting a universal system so as to be able to maintain equilibrium in the demand-supply curve.

Now let’s shift the frame to something more familiar. How about Medicine? Sounds good? Well....In a world full of morbidities and fatalities, putting myself in the shoes of a patient honestly makes me bow down in gratitude before God for creating Doctors. Really, what would a Malaria patient in Africa or a RTA (Road traffic accident) victim with fracture shaft femur (a broken thigh bone) or a cancer patient anywhere in the world do without doctors? Boy this does feel good to write (read ‘it bloats my ego like never before!’) given I am an MBBS myself....conducting normal deliveries, resuscitating a newborn with respiratory distress,  diagnosing an acute myocardial infarction and thrombolysing the patient to alleviate pain, assisting in immobilizing that heck of a broken arm or even suturing that gaping wound, I have done it all! I am also proud to have colleagues all around the world working in the harshest of conditions away from home and family to relieve the world of suffering. We save the world! Applause! Nevermind that there is still a significant number of conditions that we ‘cannot cure’ simply because the treatment is ‘Not Available’ (Read that again).

Some wise saintly friend (my Conscience) once commented, “What if you did not have pharmaceutical drugs, diagnostic equipment or any surgical tools? Would you still be able to call yourself an independent medical practitioner or cure any of the conditions stated above? In essence, will you be able to deliver health to an ailing patient as easily as you do now?” This really got me thinking...Well, my conscience was right. After all, the biomedical engineers design surgical tools/diagnostic equipment, pharmacology researchers develop drugs which follows leads from what basic scientists discover after toiling for hours in their laboratories about the physiology and pathology of the organ system under study.

I agree that we doctors do relieve a patient’s suffering and have an inhuman work pattern at times but at the end of the day, we are the mediators of what is being discovered/invented in the labs. Now this again makes me bow down with gratitude before God...only this time it is for Doctors as well as a wee bit for Medical Researchers too......(A tight slap on my face from my Conscience followed!! Whatt?? Why??)...oooookay....a 70-30 gratitude share for docs and researchers....that should do it? (A persisting venomous look from my Conscience)....ugh 60-40?! (Conscience progresses to a Parkinsonism-like masked facies...probably saw a slight lateralisation of lips too).....alright...alright...50-50. And that’s it! I do acknowledge that we depend on the research fraternity for what we deliver, but even they depend on us for translating their research...so equal gratitude fits best here...(my Conscience finally smiles brightly!).....time for a secret here...I still am as happy as I was before, even after pulling down the gratitude levels for docs....Reason? I am currently a medical researcher in-the-making!! Surprise!!

As insensitive as this may sound, a word of gratitude to the patients for falling sick. After all it’s them that keep the medical profession alive and kicking and fuel medical research. May God bless one and all with good health, but after a bout of treatable sickness. No offence intended! Guess what? My elation continues.....because I happen to be a patient too! Anyone can be! (Don’t worry I won’t bow down before God this time! I don’t want a broken back now)

So what is the take home message then? We all are part of a system in our professions with varied roles as an inventor, an executor/mediator or a benefactor. We are dependent on each other to serve a greater cause, which in case of medicine is fighting the disease. Like one of my friends summed it up, medical research is like catching that specific fish from the high seas while medical practice is akin to the fish-market both catering to fish-lovers!! Funny but undeniably true!

So rather than getting sucked into the unfortunate  reality of fierce professional rivalry over who gets more patients and perks (Doctors, are you listening?) or who has more journal publications/H-index to their credit (Attention Researchers!!) or even waging a war between these two professions to establish dominance like our animal brethren do, life would be easier if we all learn the art of  mutual co-operation and knowledge transfer in addition to doing our bit to contribute towards the greater cause of eliminating sickness from the face of the world. We all are a team. Let’s keep it that way. Let’s just do away with this ‘Game of Thrones’ now! However if competing is in your nature, why not do it with yourself?

As for the fact that we may very well be out of work in absence of sickness, let us not underestimate the efficient adaptive mechanisms of the creepy-crawly microbial beauties! Rest assured, cuz no amount of Dr. Mario would probably ever be enough to stop them forever!                            ---------------------x----------------------x---------------------

[anatomyofscience]

“What is so wrong with using human embryonic stem cells in research?!“

-- By Sparshita Nag

“I am all in support of Stem Cell research until it is Embryonic Stem Cells that are involved. I would go to hell if I did such a thing”. Thus spoke a dedicated follower of the Mayo Clinic blog below their post on their latest research utilizing Adipose Derived stem cells for Amyotrophic Lateral Sclerosis (the disease that has affected Stephen Hawking)

Anybody even remotely related to biology would know the furore caused in the past years over the use of embryonic stem cells(ESCs) in research, about how it was unethical to do so and the various governments yielding to pressure and stalling any further creation of new cell lines thereby crashing all hope of changing the research scenario for good,  in a jiffy.

Point is, what led to the development of such a negative impression about the use of these cells? Whether or not this situation could have been handled more delicately is the million dollar question. However, here comes the role of effective communication in science to the general public.

To begin with, Embryonic Stem cells are an easy enough target of controversy thanks to their very name. It appears and I’m quite sure it is also popular belief that these stem cells are derived from in-utero embryos from a live pregnancy. Some also like to think that aborted foetuses are stealthily whisked into labs and macerated to obtain these cells. Think about a layman getting such a perception and the hue and cry raised on this subject is almost justified!

The truth as we know is that these cells were actually obtained from spare embryos created in labs during in-vitro fertilization procedures with prior full written and informed consent of the donor parents. These are the embryos that are in excess of the one that is artificially implanted into the uterus of the ovum-donor (mother) and would otherwise be “discarded as anatomical waste into the bin”. 

Technically speaking, these cells simply cannot be sourced from abortuses because mostly, abortuses are foetuses and not embryos. What’s the difference? Well, an embryo is the stage from Day 2 to Day 9 post fertilization in the womb. After this stage, it is called a foetus. The whole notion of extracting ESCs from live pregnancies also becomes invalidated given most pregnancies are diagnosed after 15 days of fertilization when the baby does not remain an embryo anymore! If a point is made by Ethics organizations about “killing a life for research”, it could very well be argued that being utilized for research certainly allows the unborn life to serve a purpose for greater good rather than being thrown into the incinerator and destroyed!

I strongly feel the need to convey and educate the general public about this to prevent stem cell researchers being considered as merciless butchers of innocent unborn lives. Responsible reporting has a huge potential in busting the existing myths to modify public perception towards the use of these absolutely fantastic cells in research. After all it is media that conveys the breakthroughs and controversies in the otherwise guarded research world to the general public.

As a member of the Triple Helix Society in UCL, I had the privilege to attend a talk on “Power writing in Science” by Mr. Olle Bergman of Lund University, Sweden. Olle, a chemical engineer by education was drawn towards a career as a Communications Consultant, Public speaker and writer with the aim of popularizing science among lay public by presenting complicated concepts in a simplified, illustrated and entertaining manner. The session was an enriching experience for aspiring writers in science who share the same ideology as his. Not only did he share tips on how to go about it but importantly highlighted the fact that how presenting facts in a crisp, clear and honest manner could go on to shape favourable public perception and participation. It could prevent any misunderstanding that could otherwise interfere with potentially beneficial research work (as in the case of the fate of Embryonic Stem Cell research).

Olle aptly quoted H.L. Mencken in his talk saying, “There are no dull subjects. There are only dull writers”. Taking a cue from this, I wish to encourage people of science to open up regarding their research, to reach out to the general public. They have full right to know where their taxes are being utilized. What better source of information for them than the researcher himself/herself? With an array of social media platforms and blogging available, it is not a difficult task I believe. 

Scientific journals were supposed to serve the purpose of popularizing research. Unfortunately in this era of cut-throat professional rivalry, they have instead fallen prey to commercialisation and now serve as a means to climb the career ladder. Commercialisation is something that plagues the media too which is probably why spiced-up controversies/hyped versions of the true picture make way to our breakfast table through newspapers more easily than sensible, plane-jane version of a news report. Let’s face it, media successfully taps the inherent “scandal-loving” nature of humans here. In addition, our branch of study (Regenerative Medicine) being a relatively new and sensitive concept, misunderstandings can be fairly common.

It is our duty to give general public the full correct picture of our work to save our sacred profession from being sometimes misunderstood. It is us who should shrug-off any traces of ego, be pro-active in educating people about what we invest our neurons in and how it would benefit the community! Of course we should also highlight the cons alongside the pros. Our transparency would prevent impulsive, unwarranted and unwanted public reaction, be it positive or negative. Maybe the general perception on Embryonic Stem Cell research would have been different today if public education on the matter had been more honest and enthusiastic.

Let us not allow such misunderstandings to ruin any valuable scientific work or waste government resources anymore. Come on fellow researchers, Let’s write!

Signing off

Sparshita, on behalf of the team :)

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[anatomyofscience]

‘A Cure for a Broken Heart’

By Alisha Sund 

I recently read an article on New Scientist about love and how the definition changes depending on your major. I personally, agreed with the neuroscience definition:

"a neurobiological phenomenon that falls into three subtypes: lust, attraction and attachment – all of which increase our reproductive and parental success"

 The article is pretty cool though, it basically suggests that experiencing unrequited love manifests as feelings of depression and sadness that can make people do crazy stuff. It's funny because it can actually be classed as a condition - having a 'broken heart' and going by the definition I provided above it alters neurotransmitter secretion in our brain. So the concept is can we 'cure' a broken heart by administering pharmacological drugs that can affect neurotransmitters, much like say an individual with Parkinson's is administered Levodopa (restores levels of dopamine) to control tremors.

 The idea is to sever the bond you have with that individual so you no longer feel attached to them and - Voila! You're no longer fixating on the person you're supposedly in love with. I guess this is a little risky though - taking pharmacological drugs such as anti-depressants like SSRI's (selective serotonin releasing inhibitors) or dopamine agonists like Levodopa have been associated with structural changes of the brain, which could potentially lead to some serious consequences. 

 Although the thought that popped into my head was incorporating deep brain stimulation into this - which is basically implanting a device into someone's brain that can transmit electrical impulses, it's a more direct way of affecting neurotransmitter levels which is believed to govern emotion in this case. Obviously going through a surgical procedure would be pointless but if depression is considered a psychological condition then why can't having a 'broken heart' be too? I guess you can argue both ways though, this reminded me of a movie called 'Eternal Sunshine of the Spotless mind' where the main character breaks up with his girlfriend and undergoes a procedure to remove his memories of their time together. I know - this is clearly impossible, how can someone specifically pinpoint memories from one individual and extract them? And how would they prevent friends and family from mentioning the said person to the individual undergoing this procedure? I guess that's why it's a movie, but I'm sure anyone with a science degree would agree watching movies like this are just portraying incorrect information to the public. Kind of like when I tell people I study 'Nanotechnology and Regenerative Medicine' and they assume I'm creating nanobots...

Signing off, Alisha, on behalf of the team Edited by: Sparshita