The Bio Revolution – where science meets science fiction

What do we need to do to avoid the apocalypse, the extinction of our species, a planet without any humans?

Yes, I’m still talking about science. About real, hard bioscience. The science of the biorevolution. Even though many of the technologies of the biorevolution sound like science fiction: gene editing, artificial intelligence, synthetic biology.

Scientists employ these technologies to make human life longer and healthier, and to shape nature into a more human-friendly environment.

We are at the center of this revolution, trying to bend the rules of biology to our will.

The rules that govern biological systems form the very essence of our existence; they are the rules by which we live and die. Humanity stands as the pioneering species that consciously defies these rules, transcending the grip of our biological imperatives like natural selection and Darwinian evolution.

Our journey on this path commenced thousands of years ago when we began to domesticate, or some might say, allowed ourselves to become domesticated by the plants and animals surrounding us, marking the start of our long-term symbiotic relationship with wheats and wolves and cattle, a relationship that altered our destinies as much as that of the planet.

The biotechnological advances of the late 20th and early 21st centuries—genetic screening, gene editing, neuroprosthetics—have catapulted this transition from a horse-drawn carriage to a rocket's pace. These technologies, in their pursuit of altering the course of evolution, fundamentally stretch the boundaries that have defined life on this planet for eons. Scientists now craft entirely new biological entities—organisms that live by their unique rules, propagate, evolve, and proliferate, heedless of the artificial boundaries and policies set by humans.

The biorevolution has become too fast and too complex for regulators and politicians to understand and too powerful for scientists to self-regulate.

Will the biorevolutions and its technologies lead us into a utopia in which physical and mental suffering, hunger, disease, and even aging and death become things of the past? Or are the changes we're making to human biology the first step toward our downfall as a species? Will they usher in an age of modern-day eugenics, exacerbating social inequality and erasing biodiversity?

While humans aren't great at foreseeing the consequences of their long-term actions, they excel at envisioning future doom scenarios—ranging from genetically selected superhumans in "Gattaca" to genetically-modified humans in "X-Men" to the myriad different versions of the zombie apocalypse.

Understanding where modern bioscience is headed is important to everyone because it will affect everyone. Viral diseases and bioweapons, methods for genetic selection and genetic upgrades, artificial intelligence algorithms, and neuroprosthetics will affect everyone. They will affect our understanding of humanity and our destiny as a species.

To avoid the apocalypse, the extinction of our species, a planet without any humans, we need to understand those technologies, need to apply them with care and try to consider the long term consequences of our actions.

Rewriting humanity

When it comes to scientific discovery, there’s big news and there’s small news.

Lately, we’ve been drowning in the big COVID news: numbers, vaccines, mutants, and so on, leaving us just enough air to swim to the surface here and there to absorb the most recent success or failure of our favorite soccer team.

Still, there are science news important enough to penetrate the COVID bubble in our brains.

One such piece of news is Intellia’s first ever in vivo gene editing in humans - a milestone for a technology that can literally change humanity’s source code.

A permanent change

The US biotech Intellia was cofounded by Jennifer Doudna, one of a number of scientists who discovered the functionality of the bacterial CRISPR/CAS9 system through multiple discovery and one of two leading CRISPR scientists who were awarded the Noble Prize in 2020.

Gene therapy (the introduction of foreign genetic material into humans to cure disease) has been tested in patients for three decades though it was only in the 2010s that a few gene therapies saw approvals by the European and US regulatory agencies. CRISPR/CAS9 comes with a new level of precision that classical gene therapies don’t have. It allows making a change at a specific location in the genome, working with the cellular DNA repair machinery to excise and reknit DNA. With such a tool we can alter, remove or repair genes. If successful, CRISPR/CAS9 therapy could become a one-shot cure for many genetic diseases. It could also be a means to alter the human germline to select for desirable traits, like height, eye color, intelligence, or resistance against certain diseases. The latter was infamously attempted by Chinese researcher He Jiankui, now sentenced to three years in prison for trying to make human babies resistant to HIV...

While a number of researchers in biotechs and universities had used CRISPR-based gene therapy in patients, they performed the editing outside the body - a so-called ex vivo approach. Here, cells are extracted from the patient, genetically modified in the lab and then the altered cells are put back into the patient. Needless to say, ex vivo therapies are difficult, time consuming, prone to variability, and, most importantly – only work for diseases where it is possible to remove and add back cells into the patient. This is mainly true for blood diseases, such as Sickle cell anemia.

Intellia now performed a so-called in vivo approach, changing the gene directly in the patient. To be precise, they removed the gene which codes for the transthyretin protein, from the liver cells of patients, suffering from ATTR amyloidosis. This rare and fatal disease is caused by a mutation that causes buildups of misfolded transthyretin protein in the organs of the human body. A month after a single injection with Intellia’s CRISPR therapy, the researchers saw a decrease in protein levels of 80-96% in three patients.

On our way to Gattaca?

With CRISPR/CAS9 at our hands, will we soon be able to cure all genetic diseases including cancer? And if the method is so straightforward, how close are we to ordering our CRISPR kits for home use on Amazon and start improving our genomes, to turn ourselves in Gattaca-style beautiful and intelligent people?

Both scenarios are further away than it might appear at first glance, and not just because of ethical constraints. Changing the genome is not as easy as it sounds. While the technology appears ready (at least as ready as it gets, considering that it was discovered a mere decade ago), other factors challenge the use of CRISPR/ CAS9 just as much as classical gene therapies:

1.       We don’t understand the human genome well enough to make the changes we want.

2.       We don’t get the CRISPR/ CAS9 therapy (or any other gene therapy) where it needs to act.

Our lack of understanding is one of the major reasons of why, with all our fancy technology we in some respects haven’t moved a lot, have not cured cancer or Alzheimer’s or a myriad of other diseases. While we have some idea of deregulated genes in those diseases, we don’t fully understand how the disease manifestations are produced through the interplay of genes, epigenetics, and lifestyle factors. Trying to alter complex genetic networks will yield no result in the best case, and unintended consequences in worst.

There are diseases, however, where the removal of a single malfunctional gene, might be enough to halt their progression and potentially cure them. This is the case for numerous monogenic diseases, like the one that Intellia tackled - ATTR amyloidosis.

But even in cases, where the culprit gene is clear and we know where to put the DNA scalpel, we still need to be able to access the gene. Doing this is easier in a petri dish (as done in the ex vivo approaches for modifying blood cells or when manipulating human germ cells) than inside a human being. To be effective, enough of the gene therapy needs to reach the diseased tissue before the therapy is being diluted, neutralized or excreted. The human body is designed to get rid of foreign agents and not to neatly deliver them to the spot where the researcher wants them to act. Notably, one of the body’s major detoxifying organs is the liver, and most unwanted agents, be it an excess of alcohol, drugs or a gene therapies, will find their way there. For true in vivo approaches (meaning a therapy that is delivered systemically rather than locally, for example by direct injection into the eye), the liver is likely the easiest tissue to reach.

High stakes and low-hanging fruits

Researchers call those, comparably easy applications, the low-hanging fruit. While the groundbreaking example of Intellia would qualify as such as low-hanging fruit, it is an important proof of the technology, nonetheless. Does this mean it will work for more complex applications, such as multigenic diseases or difficult to reach tissues?

We don’t know yet.

But in science, problems are there to be solved and often serendipity is the scientist’s best friend. When Doudna and her peers were researching the bacterial immune system components, they hadn’t planned to hand humanity a tool that can rewrite its source code. During decades of hard work, they stumbled upon this particular application, and they were smart enough to understand what it could do and to contextualize its consequences.

Chances are, scientists will overcome the hurdles that CRISR is facing in more complex applications too. Maybe intentionally and maybe accidently, and probably through a combination of both. How soon, we can only guess.

But one thing is clear, we must acknowledge CRISPR/CAS9’s full potential with all its good and bad implications for humankind and prepare for the ethical challenges that it will bring.

The pandora’s box problem in science

Earth-shaking discoveries

There are many discoveries in science, which make but a small impact on the world, discoveries that are tiny pieces of the puzzle, adding together to answer the grand scientific questions. 

There is another type of scientific discovery, the one which has the potential to impact the fate of humankind in some profound way.

How does it feel for a researcher to make this kind of discovery?

Is it elating?

Terrifying?

A bit of both?

I wouldn’t be able to tell, anything I discovered in my time as a scientist unfortunately (or maybe fortunately) didn’t have the potential to shake the foundations of humanity (or shake the foundation of anything, except maybe my ego).

But what if your discovery does just that?

Shake the foundations of humanity.

Scientific discovery suffers from a pandora’s box problem. Once a finding has been communicated to other scientists, it is impossible to take it back.

Scientists call to action – or non-action

It tells you something about the impact of a technology if the scientists themselves, those closest to the discovery are the ones to sound the alarm bells. 

In the (in)famous 1939 Einstein–Szilárd letter, written  Leó Szilárd and signed by the pacifist Albert Einstein, the physicists warned President Roosevelt about the possibility to develop the atomic bomb (enabled by the first nuclear fission experiments).  They urged the president to act - out of fear that Nazi Germany could be first to develop this weapon of mass destruction.

Some fifteen years, the release of two atomic bombs and the loss of over 100 000 lives later, Einstein (together with a group of other Noble Laureates) signed another document, the Russell–Einstein Manifesto, which highlighted the dangers of nuclear weapons for mankind and besieged decision makers to seek other problem solving strategies than nuclear annihilation.

After the first experiments on recombinant DNA opened the door to manipulating microbial – and, in sight at the horizon, also human - genomes, scientists gathered at the 1975 conference on gene therapy in Ansilomar, CA, to discuss the limits, which were to be imposed to the newly discovered technique.  It was the scientists themselves who committed to a voluntary moratorium, before rules for experiments on recombinant DNA were discussed at the conference.

When scientists found that a component of the bacterial immune system, the CRISPR-CAS9 system holds unprecedented potential for manipulating the human genome, the discoverers of the technology and other scientists called for a moratorium on heritable genome editing; in 2015, a few years after the seminal publication on the CRISPR from the 2020  Nobel Laureates Jennifer Doudna  and Emmanuelle Charpentier, and again in 2019 after the 2018 designer baby shock.

The promise of CRISPR CAS9

What aligns CRISPR CAS9 to those earlier earth-shaking discoveries?

The technique is as elegant, as it is simple, as impactful as it is scary; it allows researchers to precisely alter DNA; the DNA of adult humans, of unborn babies and of the human germline, of animals in the laboratory and of animals in the wild, of cultured crops and wild fauna, of microorganisms that produce biomaterials, drugs and vaccines.

It’s not difficult to imagine the good, the bad and the ugly outcomes of such a technique, ranging from the cure of genetic diseases to engineering desired genetic traits into children, from eradicating diseases such as malaria by releasing genetically modified mosquitos into the wild to causing unforeseeable environmental catastrophes by tempering with ecosystems, from fighting pandemics to newly designed biological weapons.

How much of this potential is already being realized? And how much of it is utopian or dystopian fantasy?

While numerous patients with genetic diseases and cancer set their hope in the potential of CRISPR-based therapies currently tested in the clinic, in 2018 we saw a glimpse of the darker side. The Chinese Doctor He Jiankui , performed a medically useless experiment of genetically modifying two twin girls on the single embryo stage to make them resistant to HIV. He felt the need to shout out his results to the public (on YouTube, a well-known source for high-quality, peer-reviewed scientific results).  But what about the scientists who don’t seek the spotlight? How many more experiments like He’s are performed quietly, despite a ban on germline editing in most countries? And what is happening outside the regulated laboratory environment?

The relative ease of using the technique has sprouted a group of so-called biohackers, which reversed the Don’t try this at home tactic and experiment with CRISPR kits in their living rooms and garages.

While arguably the complexity of germline editing and IVF, currently lies beyond the type of experiment you can perform in your living room, the question remains how dangerous the technique can be in untrained hands?

One thing is clear though - however risky, however promising we might consider the CRISPR technology, it is out in the world – and there is no pushing it back into the box.

Tune in next week for a deeper dive into the science underlying the CRISPR CAS9 technology, the challenges which lie ahead to use it for curing human disease and its use by biohackers.