Resuscitating the Brain: Introducing BrainEx

cerebral circulation
courtsey: wiki BruceBlaus

Healthy brain needs continuous and copious supply of oxygen for functioning. Cerebral circulation ensures that  oxygenated blood is   pumped in  and   oxygen depleted  blood is pumped out. If the oxygen  supply or in other words  circulation is interrupted,  then within seconds brain cells suffer irreparable damage and within minutes this  biological wonder called brain is declared dead. A point of no return. Well that  has been the belief so far.  

Now  Vrselja et al demonstrate that even several hours after death, circulation and cellular functions can be at least  partially revived in mammalian brain.  Sounds eerie indeed. But science fiction had already conceived this plot almost a century ago. Remember the 1925  Russian novel Head of Prof. Dowell  ?.  

But let us get back to  Vrselja et al.   To fully comprehend the significance and complexity of the experiments it is necessary to  highlight the essential features of their investigations. Experiments were conducted on pig brains  procured from USDA approved  food processing facilities within 4 hours post mortem.  Brains were surgically isolated just above the brain stem (medula oblongata), so as to keep the vascular  system intact. The vascular system is necessary to circulate haemoglobin based (but  cell-free)  blood substitute. The entire experimental set-up, blood surrogate, various pumps, monitors, control units and computers, scanners   is referred to as BrainEx. or simply BEx     

32 pig brains 4 hours after disembodiment were carefully scooped out of the skull and hooked on  to BrainEx maintained at 37 deg.C.  First  the research team    established  that  the specially  concocted  blood surrogate enriched with nutrient and medicinal molecules  flowed in and drained out through the major, minor and capillary vessels in the brain. Within an hour sodium and potassium levels registered normal levels. The team could  detect cerebral  metabolic activity as recorded by oxygen and glucose consumption data.   Drugs meant to increase the circulation did exactly the same. Most importantly circulation ensured that  swelling of brain (oedema) is contained and thus  structural integrity of the organ is preserved. The team could keep the system going for a full 6 hours. That meant a total 10 hours after decapitation. During these 10 hours, individual neurones fired at random however  there was no collective or concerted  activity.  Not yet. 

What does this mean and where does this lead us to? Vrselja and team  conclude that mammalian brain is much more resilient than our current assumptions. They are confident that more sophisticated  versions of BEx  could achieve much more.  However  an  ethical dilemma too is looming large. Younger and Hyun both Professors of Bioethics at Case Western Reserve University School of Medicine, Cleveland, Ohio, state that " even now clinicians and bioethicist disagree over how long is long enough for paramedics to keep trying to resuscitate". 

REFERENCES:
1. Professor Dowell's Head by Alexander Belyayev
2. Restoration of brain circulation and cellular functions hours post-mortem: Vrselja et al  
    Nature 18 April 2019 vol.568, pp336-343 
2. Part revived pig brains raise ethical quandaries: Farahany et al Nature  18 April 2019-  
     vol.568,pp299-302
3. Pig brain study could fuel debate around death: Youngner et al Nature 18 April 2019,  
    vol.568, pp302-304

On Alzheimer's Disease

The  French play Le Père by Florian Zeller showcases   Andrei, an old man whose memory is clouded by  Alzheimer's disease(AD).  Le Père received  the 2014  Molière Award for best play. The play has been translated into and staged in several languages. Imaginatively conceived and performed,  audience can empathise with  the vulnerability and frustration of Andrei as his memories fade and/or  at times randomly light up.  We recently had the privilege of  watching it at Ranga Shankara, Bangalore. 

 Courtesy Wikipedia 

Experts say it all happens in the hippocampus,  the seat of  short and long term memory , learning and hence  cognition.   One of the earliest  signs of AD is the  accumulation of   clumps of β-amyloid protein (βA proteins)  in between neurons, and entanglements of tau protein (𝝉 protein) fibrils  within. Both these break up neural communication network, leading to memory loss, cognition deficiency etc.  So naturally the question arises, can we clean up this messy stuff that builds up outside and  inside ? Or better still, can we  find ways to stop its production? Perhaps then we can re-establish  normal neuronal activity and thus restore  memories and cognition?  

Drug companies have invested billions of dollars  to find out a suitable answer. Still over the last 20 years only 4 drugs have hit the market. One novel approach has been  to develop  monoclonal antibodies, which  can loosen up amyloid plaques and lyse them. Though looked promising during  initial stages,  many candidates in this line-up  failed in later stages. In a field where   failure rate of 99.6% is routine, scientists are not disheartened.   Further more, realisation has sunk in that multiplicity of factors could lead to  AD.  And  hence  a single magic drug will not arrest or reverse  the progress of the disease for all.   

Tailpiece:

According to the World Alzheimer Report 2018, currently 50 million people are suffering from AD and by 2050 this number would be 150 million.  If left untreated we might eventually  reach an alarming  situation with majority of the world population afflicted  with  semantic dementia as described by Garcia in One Hundred Years of Solitude.  Macondo  was first robbed off its sleep and then people lost   their vocabulary!  

REFERENCES:
1.World Alzheimer Report 2018
2.The antibody aducanumab reduces Aβ plaques in Alzheimer's disease

3. Aducanumab at Clinical Trials on Alzheimer’s Disease (CTAD)4.Biogen Halts Promising Alzheimer's Drug Trials Due to Disappointing Results
5.Initiation of Phase III clinical trial of BAN2401 in early Alzheimer's disease
6.Semantic Dementia in One Hundred Years of Solitude

Seeing (in the dark) is believing.

Perhaps because we humans were destined to be  diurnal and not  nocturnal species, evolution  didn't  equip us with night vision. Instead we received cone cells for  color vision,  ideal for enjoying the wide spectrum of colours in broad day light.  On the other hand  nocturnals  developed a thin membrane tapetum lucidum,  behind the retina which functions as a rear light reflector  enabling vision in low light and  during night.  None the less we humans know how to jump over natural barriers with the help of technology; thus we have   extended our working hours into the darkness of night and peeped through night vision goggles and infrared cameras to see what cannot be seen with naked eye.  Night vision devices are available in a wide range of  prices/functionalities.  

Because we  are bent upon following knowledge like a sinking star, beyond the utmost bounds of human thought,  we have breeched another barrier. No  not for ourselves, but  for rodents. A research team led by  neuroscientist Tian Xue at the University of Science and Technology, Hefei, China has given the power of  night vision to mice through an  ocular injection  of nanoparticles.  Xue says it started as a crazy idea.    Nano particles of ytterbium and erbium, two metals that belong to the rare earth group caught the attention of the team.  Ytterbium can absorb infrared light and transfer it to neighbouring erbium which in turn responds with the emission of  green light. The team tagged these nanoparticles with a protein called ConA which preferentially attaches to the surface of photoreceptor cells in the retina  This concoction was injected into the rat's retina.  ConA latches on the retinal cells.   Once safely anchored there,  ytterbium and erbium nanoparticles work in unison converting infra red signals to green light which retina picks up, converts to electrical signals and sends to visual cortex for processing and decoding.  Xue and team ran a series of experiments to monitor the behaviour  of rats in dark and infrared light lit chambers. These experiments  proved conclusively  that the injected mice  could actually see in the dark. 

A concept has been proven and a patent has been applied for.  Xue et al are confident  of the  civilian and military applications of the technique.    It is indeed  debatable whether night vision would improve  the quality of human  life;  but certainly ghosts would scramble  to  hide in plain sight. 

Reference 

1. Mammalian Near-Infrared Image Vision through Injectable and Self-Powered Retinal Nanoantennae.                                                                                                                   Cell, 2019; DOI: 10.1016/j.cell.2019.01.038 Yuqian Ma, Jin Bao, Yuanwei Zhang, Zhanjun Li, Xiangyu Zhou, Changlin Wan, Ling Huang, Yang Zhao, Gang Han, Tian Xue.

2. Researchers enable "Super Mice" to see Near-Infrared Light

Dance Lessons for Humanoids

The website of Boston Dynamics features several videos on the acrobatics of Atlas, the Humanoid. With a height of 1.8 meters supporting a weight of 75 Kg, Atlas has a total of 28 joints and runs on battery power. It walks, runs, jumps, somersaults. Kengoro, the latest humanoid  from University of Tokyo, is 1.7 meters tall and 56kg in weight, and is fitted with  160 motors for anatomical flexibility. Kengoro has a unique cooling system which allows it to sweat.  But both sorely miss out on  aesthetics.     Perhaps  aesthetics was remote from the minds of their designers. 

Atlas,
Courtesy: Wikipedia

Sophia,
Courtesy: Wikipedia

Sophia, the humanoid designed by Hanson Robotics is a study in contrast. Modelled on the yesteryear British actress Audrey Hepburn, Sophia has more humanlike features.  Media is brimming  with her social capabilities.  The Hanson website states that  Sophia, (which means wisdom in Greek) is designed to achieve  meaningful   collaboration between humans and Artificial Intelligence.  Miim, very Japanese in her attributes is petite, with  just 158 centimeters in height and 43 kg weight. She can walk, speak and even dance.  She is the creation of National Institute of Advanced Industrial Science and Technology (AIST), Tokyo.

Current projections estimate that by 2025, robots will execute  25% of manual labor. However socially assistive robots in health and services industries need to be endowed with more human-like traits. One of the areas design engineers need to focus is robotic movements. The movements of the robot/humanoid are  jerky and abrupt.   It is necessary to impart more fluidity to these movements.  Muscles which smoothly contract and stretch allow humans to move gradually, gracefully.   Briefly reviewing the trends in the field  of Humanoid Designs, Amy La Viers, ( Director of Robotics, Automation and Dance Lab at the University of Illinois at Urbana-Champaign) observes that "The diversity of robot movements needs to be expanded  to include variable and complex motions."  She suggests that  roboticists must work in collaboration with dancers and choreographers to refine the movements of the robots.

Reference 
1. How long until robots rule the world?
2. A Music-Driven Dance System of Humanoid Robots

3. How to make a Humanoid Robot Dance?
4. Make Robot motions natural : La Viers, Nature pp 422-424 Vol.565 January 2019

A Twist: At a Magic Angle

Graphene Artist's representation
: Courtesy Wiki

It is unbelievably true. A small twist,  hardly 1.1degree and lo and behold you have a superconducting material. Scientists have been trying tirelessly to tame the phenomenon of superconductivity and to make materials that exhibit this property at room temperature.  Not that we are anywhere near room temperature  as yet, but something amazing has caught the attention of scientists. And it is about graphene  sheets.

Everything about Graphene has been unconventional,  from the very beginning. Graphene is a mono layer of carbon atoms  arranged in a hexagonal format. Scientists   Geim and Novosilov  (who later received the Nobel Prize in Physics 2010) were the first to  peel off such layers from a graphite lump using a scotch tape. 

A team of scientists 12 years ago demonstrated that  graphene  bilayer could be turned into  a tunable  semiconductor when a small electric voltage is  applied  across the sheet. 

And now MIT Professor  Pablo Jarillo-Herrero and his team of students are flying high as they  demonstrate that a slightly misaligned pair of graphene sheets, cooled to almost absolute zero, could switch its behaviour  between an insulator and an unconventional  Superconductor, when a voltage is applied.  

A slight twist of 1.1 degree- as simple as that?, Scientists all over the world are wondering.  At the recent Annual Meeting of the American Physical Society, when Jarillo-Herrero presented his results, the lecture hall was overflowing; audience spilled over and  stood wherever they could, to  hear him talk.  The theory behind the phenomenon remains to be worked with the rigour it demands. However the general assumption is that the 1.1 degree twist  drastically alters  the electronic properties of the ensemble. Graphene is a pure clean system and scientists are confident that it  is an easier system to study than those complicated mixed oxides which have earlier exhibited such property. 

Twistronics is the buzz word now.  As one scientist puts it everyone is taking their favourite thing and twisting it with their other favourite thing, all in the hope of striking  it rich with superconductivity.


References:
1. Insulator or Superconductor? MIT News 
2. Superconductivity with a twist: Gibney,E.; Nature 2019, 565 pp15-18
2. Y. Cao et al., “Correlated insulator behaviour at half-filling in magic-angle graphene superlattices,” Nature 556, 80 (2018).
3. Y. Cao et al., “Unconventional superconductivity in magic-angle graphene superlattices,” Nature 556, 43 (2018).
4.Carr et al., Twistronics : Manipulating the Electronic Properties of Two-dimensional Layered structures through their Twist Angle  APS March Meeting 2017 Abstract E33.003

When Machines face Moral Dilemma

Many believe that driverless cars or autonomous vehicles (AV) are just around the corner. Trial runs have been conducted, still  there are several more hurdles  to tide over  before they can meet  specifications set by SAE, (Society of Automobile  Engineers).   SAE classifies automotives into 6 levels  beginning with level 0 where the human driver is all  in all and level 5 where human is just a passenger .  According to  the NHTSA website (National Highway Traffic Safety Administration, USA)  Level 5 vehicle is " An automated Driving System (ADS) on the vehicle (which) can do all the driving in all circumstances. The human occupants are just passengers and need never be involved in driving". 

"Just passengers"? -  well that is interesting; I foresee a future when Driving Licence becomes redundant. But that  brings up  several intricate questions too.  True, AVs will be designed with super safety features.  But after all these are mechanical-electronic contraptions and hence breakdowns and/or  accidents cannot be eliminated altogether. How will the  insurance policy be formulated?  Who should be held responsible? Surely passengers can't be guilty.  Should a mandatory  AMC replace the insurance cover? If so, would the manufacturer be liable?   The answers are not yet  in place. 

AVs will have to share  road-space with  human-driven vehicles, pedestrians, pets, stray animals etc. hence  they should be equipped with enough  Artificial intelligence(AI)  to meet all possible eventualities.  Let us imagine a scenario of  an AV is  negotiating  a busy market street.  An accident is imminent and  unavoidable;  whether the vehicle stops or swerves    lives will be lost.  How should  the algorithm for  solving this dilemma be written-   to save the lives of the few passengers within or the  many pedestrians on the road?  To save   the elderly over  the young;  the rich rather than the poor;  the females  and not the males? It is indeed a frightening task to write algorithms that define machine ethics.  To write a moral code for the AI system, it is necessary  to know how humans make moral judgements.  Almost every component  one can think of,  social background, age, gender,  education level, prosperity, cultural traits etc. influences an individual's thought process and the ethical choices he/she makes. For the human mind it is a dynamic process and not confined within the commands  of an algorithm.   But is there a pattern?  Can we ultimately define  a Global Moral Standard ?

That is what Awad et al set out to map. They floated an  online  questionnaire  in 10 languages. There was  only one question but nine situations; each situation  had just two disasters  to choose from.   If an  accident and subsequent  loss of lives  are  unavoidable should  one try to save   a) humans or pets;    (b) passengers or pedestrians (c)  the young or the elderly (d) abled or disabled (e) male or female (f) few or many (g) rich or the poor. Their results  titled The Moral Machine Experiment appear  in a  recent issue of Nature. The online survey generated  close to 4 million responses spread over 233 countries/territories/societies.  In spite of overlaps and cross overs  Awad et al  could arrange the collage into 3  clusters: the Western, the Eastern and the Southern.  The Western  cluster included North America and most of  the European countries except France; the Eastern cluster spanned  the geographical east from Japan to Middle East and the Southern cluster  consisted of Latin American countries, France, old French colonies, Hungary, Slovakia, Czech Republic etc.  

Awad et al conclude that despite the diversity of responses they could  detect three strong preferences across the clusters : "the preference to save humans; the preference to save more lives; the preference to save  young lives."   

REFERENCES: 
1. The Moral Machine Experiment : Awad et al Nature 563, pp 59-64  (2018)
2. The social Dilemma of autonomous vehicles: Bonnefon et al; Science 352, 1573-1576 (2016)
3. Cultural differences in moral judgement and behaviour across and within societies: Graham et al , Curr.Opin. Psychol.8, 125-130 (2016)

How Old Are You?

Simple, straightforward question; but often the answer isn't either.   If only we could develop an Agemeter (or should it be Ageometer? )  just like the thermometer  for body temperature!. An  ageometer   with a  precision of 0.5  to give readings like 17.5,  18.0, 18.5, 19 .....    Age has always been important from the  medico-legal angle,  because  it bestows  varying levels of  rights and responsibilities on children, juveniles and adults and at times senior citizens. Currently a combination of methods are used to assess the age of an individual - examination of teeth, wrist bones etc.  But the error margins are often 3-4 years. 

Age Factor  has now spilled  beyond  medico-legal boundaries into  geo-political and socio-economic arena.  The recent mass  influx of refugees into  Europe is the single biggest  thrust  factor.   According to  recent reports  Europe has close to 4 million refugees.  As per the UN requirements,  asylum seekers   under the age of  18 are eligible for special benefits and that means  a drain on national resources.   A population fleeing from its war torn homeland can't  think of,  let alone pause to pick up  passports or birth certificates. Moreover families get separated often with none to vouch for the age of  orphaned youngsters. There is widespread   feeling that  refugees  deliberately forge their age to qualify for special benefit package.  With nationalism on the surge all over the world, resentment  against refugees are flaring up everywhere. 
    

It is in this context that  the Epigenetic Clock proposed  by Professor Horvath  (Dept. of  Genetics and Biostatistics, University of California, Los Angeles, USA) catches global attention.   There is scientific concurrence that   DNA methylation levels (referred to as DNAm), could be a measure of  the mammalian ageing process, though   the "How" and "Why" of the correlation remain blurred. Methylation  happens at the  cytosine nucleotide linearly attached to a guanine nucleotide. These are referred to as CpG sites.    Methylated CpG sites are thus  biomarkers, which have the potential to turn off genes. In his approach Prof Harvoth used  a special machine learning method  to identify  the biomarkers  located at informative genomic locations and then  an algorithm to predict the biological age.  Initially selecting  353 such sites,   Prof Horvath  demonstrated that this  method  could spell out the biological age for a majority of tissue  samples with a median error of 1.03 years.  However it is also a fact that  there were outliers with error margin as high as 5 years.  While scientists are focusing on improving the accuracy of the method,    Zymo a company based in Irvine, California bought exclusive rights for the technology.  DNAge Epigenetic Aging Clock service is now available for US$299.     

Tailpiece
The Old Town Hall  is one of the oldest buildings in Prague, dating back to 1338.  The astronomical clock installed in 1410  is the oldest, still ticking  astronomical clock in the world. 

Town Hall Tower with the
Astronomical Clock  

REFERENCES:

1. Forensic Age Estimation 
2. UNHCR- Refugee Children: Guidelines on Protection and Care
4. DNA methylation-based biomarkers and the epigenetic clock theory of aging 
5. European authorities demanding an Epigenetic Clock Zymo leading the way