Genome Editing: Cntrl to Edit

On 25th November 2018, Jiankui He, a professor from the South University of Science and Technology of China released a video on YouTube© announcing the birth of twin girls he claimed to have performed ‘gene surgery’ on to prevent HIV infection. The news exploded on media with comments of disbelief, censure and some cautious appreciation from the scientific community as well as the public. So, what is ‘gene surgery’ and what is the controversy about?

We carry, in each of our trillions of cells, a copy of the human genome. The genome is made of DNA, a very long polymer made of pairs of four chemical building blocks (denoted by the letters A, T, G and C). It is this very precise sequence of A, T, G and C, all 3 billion pairs of them that we call the human genome. Changes in this sequence lead to the interesting differences between each of us.  But, these changes also may result in mutations that cause diseases. These changes in the DNA sequence happen as DNA is copied again and again in the course of evolution.  Many of these changes are lost in the mists of time as nature selects the most adaptable individuals, but rare changes survive through generations.

Human beings have been experimenting with DNA since its discovery in 1869 by Friedrich Miescher. We have learnt that changes made will be passed on as cells replicate their DNA every time they divide. We have long figured out how to make changes in the DNA in the test tube. We now routinely introduce new DNA into bacteria with technology now known as recombinant DNA technology. We have made numerous changes to bacteria so they can produce hormones, growth factors and other proteins for human use. We have introduced new DNA into crop plants to protect them from pests, droughts or to increase their nutritional value. These genetically modified organisms (GMOs) continue to be controversial, but have been adopted in many parts of the world, including India. In the last 20-25 years, a number of clinical trials in patients have shown promise for the use of gene therapy for treatment of incurable diseases. Gene therapy currently involves the introduction of genes into patients with non-functional copies of the same genes such as in the case of patients who lack the Adenosine Deaminase gene due to which they suffer from Severe Combined Immunodeficiency (ADA-SCID).

Complex organisms including humans have a sophisticated immune system that protects the body from infectious agents such as bacteria and viruses. The adaptive immune system is highly versatile and retains the memory of previous infections to respond more efficiently and strongly against a second infection by the same species, a property that is utilized very efficiently in vaccinations. Until a decade ago, bacteria were not thought to have any such ability. But bacteria turned out to be smarter than we thought. In 1987 it was discovered that bacterial genome contains bits and pieces of DNA from viruses that came to be known as Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR). By late 2000s it became clear that bacteria were storing these snippets of DNA from viruses as a memory of a previous attack and that when next time the same virus infects the bacteria is now armed with DNA chewing enzymes (CRISPR associated or Cas proteins) that cut the viral DNA down and thus prevent infection. This in itself was a great discovery.

As often happens in science, this intriguing fundamental discovery soon led scientists to wonder if the bacterial protein, Cas, could be trained to cut any piece of DNA you provide in the guise of a virus! Since then there has been an explosion of research on CRISPR-Cas systems to develop better and smarter ways in which specific regions in DNA could be cut, modified or removed from cells, animals and human stem cells. The myriad possible applications of such a system made it also a very lucrative business concept. The financial implications of such a technology resulted in a hotly contested three-year patent war between the Broad Institute of MIT and Harvard in Cambridge, Massachusetts and the University of Berkeley, California, which the US Courts finally awarded to the Broad Institute.

The very simplicity and elegance of the CRISPR-Cas systems have made it possible for us to dream of making changes in the genome of human beings for beneficial purposes. But, the major technological challenge to this system remains in its fidelity. In other words, although the Cas protein is designed to cut one site on the DNA, it often makes mistakes and cuts in other places in the genome. This can lead to changes in other places in the genome, with undesired side effects. This is a danger, especially when working with humans.

Jiankui He shot to fame in November 2018 as the first person to make a change in the genome of a human embryo that was allowed to be born. Now, there are two babies, known to the world as Lulu and Nana, whose DNA have been engineered to remove a protein known to help in HIV infection. The intended consequence is to protect the babies from acquiring the HIV infection from their father who is HIV positive. But where else has the Cas protein cut their DNA? Jiankui He says, nowhere else. Scientifically, this is the claim currently up for scrutiny. Ethically, as a society, we brace for questions of unintended consequences, in case our experiments falter.  On the other hand, we can also look back and see that many new revolutionary changes happened by foolhardy jumps into uncertainty by individuals.

We humans have not yet managed to create life, as we had long aspired to do. But today, we hold the key to editing life. But do we even want to do it? What and how should we ensure we do not err? How, or can we even stop Dr Frankensteins from entering the playground?

This article appeared in the Manorama Yearbook 2018.

Why support science?

Science, according to the Oxford English Dictionary is, the intellectual and practical activity encompassing the systematic study of the structure and behaviour of the physical and natural world through observation and experiment. The ancient man who watched the flow of water, the growth of the barley seeds or the orbit of the sun did so for the wonder of it. It is the wonder, that has always driven science. The wonder that revealed the secret workings of nature, which we harness today to run our world of drugs and crops and computers. To equate science to technology or product development is short-sighted if not suicidal.

In the scientific method, I would notice an interesting behaviour of nature, would create a hypothesis to explain the observations and then do experiments to test whether the hypothesis holds true or not. If not, I go back to the drawing board to start with a new hypothesis. So, science by definition is about mistakes made and mistakes corrected. It is about being wrong until you arrive at the truth. This makes science a slow and iterative process that takes time, expense and effort. Today, with large number of researchers connected through rapid exchange of knowledge, discoveries happen faster. We are able to take on huge challenges and solve deeper mysteries. We are able to dig for Higgs Bosons and solve the mystery of the Zika viruses.

United States of America, the undisputed leader in scientific research and discoveries spends more than 2.5% of their GDP on research and development enterprises (from a study by Nature journal in 2015). The USA employs an estimated 790 per lakh of their labour force into scientific research. In contrast India has spent less than 1% of its GDP on research and employed only 40 researchers per lakh labour force for last decade or more. But we are really comparing apples and oranges here. Indian science has reached where it is now through 70 years of struggles as India worked on building indigenous infrastructure, as we reeled under sanctions by international communities and as we learned to live in a globalised economy. The priorities for Indian science and the mandates for the scientific community have been changing as the Indian Republic grew and matured. The goal posts have been shifting constantly. The goal was never a Nobel prize, but food self-sufficiency and affordable drugs and low cost satellite launches. And Indian science has met these goals more than admirably.  But the work is not done, not even begun.

For India to be competitive and at par with the scientific enterprise in developed nations, we have to have consistent and generous funding for science. Consistent, predictable funding is the most important component for any enterprise to succeed. Science even more so. Challenging projects need long incubation periods before fruition. Long term commitment to funds means initiation of more such projects. Unpredictable funding makes people risk-averse and small, short term, less gain goals are set and met. This leads us to fall back in the longer marathon of large, ambitious discoveries. 

Generous funding will come from a nation’s realization that science is important for us as human beings and for us as Indians. Science is the only way we may even begin to solve the problems that humanity as a whole faces and the specific problems of malnutrition and poverty and disease that India faces. These are not new problems; they have been our companions since Independence. A concerted effort by successive governments to jump start the stalling engine of science India is needed; increased funding, increased faith in science and increased trust in scientists.

The India March for Science, which followed and has the support of the international March for Science held across 600 communities in April, is being led by such a need. The March should remind us that science is part of our everyday lives. That science is absolutely essential for the survival and prosperity of any human endeavour. That science is important, essential and that we cannot live without it!

The opinions expressed here are personal!

A part of this article appeared in the the Hindustan Times on 9 August 2017.

Homo naledi: an ancestor or a cousin?

This September a new member was added to our family tree¹. His name is Homo naledi. He was found, two years ago, buried in the damp dark depths of the Dinaledi chamber of the Rising Star cave system in the archaeological hotspot known as the Cradle of Humankind in South Africa.

Two cavers while exploring in the caves accidentally broke through a crevice and discovered buried fossils of a human-like creature 30 metres below ground level. They took their news to Lee Berger, a paleoanthropologist and archaeologist at the University of the Witwatersrand in Johannesburg. Lee Berger was intrigued, but his large frame could never get through the 20 cm wide opening into the chambers were the fossils lay buried. But he had a plan.  

Paleoanthropologists are generally thought of as secretive scientists who shy away from limelight and conduct their research in dark obscure spaces, slowly and painstakingly brushing away the dust of millennia to uncover fragments of fossils that may tell a tantalizing story about our past. But Berger had a different style. When Berger realized he needed help with the excavation underground, he shot off an advertisement on Facebook® inviting people with archaeological, paleontological or excavation skills to come join his excavation; but he had other conditions, they should not be claustrophobic or afraid of the dark and they should be small.

The excavators he selected from the many who applied were six slender young women, who came to be known to the discovery team as the ‘Underground Astronauts’. They crawled through narrow openings, climbed up ragged walled caves and dropped down a chute into dark damp chambers where they for hours together excavated the fossils: gently, carefully, painstakingly.  They worked in 6 hour shifts for 21 days to uncover, surface-scan, photograph, clear the soil, label and pack the remains one by one to be send up to the base camp. A group of senior palaeontologists, anthropologists and archaeologists had assembled in an over-the-ground base camp to guide the below-ground excavators. The activity below was monitored through cameras and microphones and lights and scanners that fed into computers in the base camp. 

What the ‘Underground Astronauts’ brought up were nearly 1550 fossils that are thought to belong to 15 or more individuals of different ages of a species long gone. A large team of scientists assembled to study the remains. Each part of the body had specialists who were experts on that structure e.g. hands, head, feet and so on. The team of scientists released the conclusions of their analysis this September to describe a human-like creature. He had remarkable arched feet for balance, just like ours, suggesting he walked upright. He had agile fingers like ours with well developed thumb muscles for fine manipulation of tools. But, unlike ours, his long curved fingers could also help him grasp and climb like more primitive hominins. He stood as tall as us but his brain was less than half our size. So, why is this discovery creating the ripples in the news?

Homo sapiens, our species, is thought to have emerged around 200,000 years ago². But the hominins, the larger group to which we belong, emerged around 7 million years ago. Australopithecus and Paranthropus groups, both more ancient than us, were more ape-like in their behaviour.  They climbed trees and but were beginning to walk upright; their brains though were much smaller suggesting lack of sophistication.

The genus Homo, containing perhaps our direct ancestors, Homo habilis, Homo rudolfensis, Homo erectus and Homo heidelbergensis existed in the last 1-2 million years. The more recent members of the Homo genus emerged somewhere in the last half million years of so. The Homo genus were committed to walking upright and are not known to climb trees having lost the adaptations for climbing and grasping.

One of our most recent cousins, the Neanderthals (Homo neanderthalensis) lived in Europe during the last ice age. Well adapted to the cold, they wore clothing, used tools and had cultural practices such as burying their dead. They were larger than us and their brains were as big as ours and sometimes bigger. Scientists believe that until their extinction around 40,000 years ago they coexisted, interacted and perhaps even interbred with humans in the cold climes of Europe. There are traces in our DNA that might have come from our Neanderthal cousins and mates.

Remains of another cousin of ours, Homo florensis, who perhaps also overlapped with modern humans, was discovered only a few years back on the Indonesian Island of Flores. The adult Homo florensis were no taller than a 3 year-old human child and had a brain one-third of ours. But they could hunt pigmy elephants with tools they made, make fire and cook meat. They lived successfully on the island till as late as 13,000 years ago, while the surrounding mainland was already inhabited by humans. But perhaps isolated from the surrounding mainland by kilometres of treacherous sea, humans and the Homo florensis never met.

So, what about Homo naledi? Did they ever meet us humans? Were they recent inhabitants of earth who retained their love for trees even as they walked and hunted on the ground? Or were they ancient cousins who came before the Homo genus descended from the trees? We do not know the answers to these questions. We do not know because, it has been very difficult to estimate the age of the Dinaledi fossils. Usually fossils are dated by the geological layer they are found in. The rock layers can be traced back to various volcanic eruptions, droughts, ice ages and other such major events on earth. But the Homo naledi was found in a deep cave in loose damp earth, with not even bones of other creatures nearby, which might have helped us guess at the era they lived in. Scientists are prepared for the long haul to determine the age of these fossils.

Until then we will be left wondering how did these creatures get inside a cave that is so inaccessible from the surface. They could not have accidentally strayed into a place so out of the way. Were they entombed there as part of some ancient burial ritual? How could creatures with half our brain size have concepts of afterlife and have cultural practices and burial rituals? Did they coexist with some other more intelligent species of the Homo genus? Did these compatriots dump them there, perhaps?

Like all scientific discoveries, this one finding opens up many more interesting, exciting questions. And like always the human mind will weave its stories about its own past, the only species that can encompass the whole past, present and future in its 1 kilo brain.

References

1.    http://elifesciences.org/content/4/e09560

2.    http://humanorigins.si.edu/evidence/human-fossils/species

This article appeared in the ACE Academy magazine TRUMP in October 2015.