On the Shoulders of Giants

“I have seen a little further it is by standing on the shoulders of Giants.”

– Isaac Newton

We live in a very, very exciting and intriguing times. Technological progress is moving forward on a scale never seen before, society has changed immeasurably in the last 20 years and it is continuing to do so. We are truly living in one of the Golden Era of Humanity.

One foundation of this era is a discovery of basic physical unit of heredity – deoxyribonucleic acid, better known as DNA. For thousands of years, humanity was baffled with how a (wo)man comes to life, what magic is involved in creating a child and how do our bodies even function. Science finally lifted the veil of mystery of life in 1950’s with the discovery of genetic code. It was the single most important discovery Homo sapiens made since the discovery of fire.

We felt like gods.

Suddenly, everything was in our reach – humanity figured out how does it procreate, we understood how we grow, we confirmed that cell is a building block of life. We learned that genes encode proteins (life’s building blocks) in a very simple and elegant manner. We finally understood diseases and we thought that cure for all diseases is just around the corner. First obstacle was decoding of our great code. Back in the 1950’s and 1960’s, mapping 3 billion base pairs (by hand) was impossible task. Another great foundation of this Golden Era – computers and computer science – helped us to overcome this obstacle and at the beginning of new millennium, we decoded human genetic code. New era of medicine ushered, giving birth to entire new scientific fields: bioinformatics, chemoinformatics, molecular medicine, clinical genetics, biotechnology, medicinal chemistry, etc. It also revolutionized pharmaceutical industry – era of serendipity-based research ended (“luck-based” research – most of the drugs developed in the 20th century were developed by chance, not by systemic research), and era of molecular design, era of rational drug design (targeting of specific target – protein – with known structure and function) started. Multi-billion dollar industry per year emerged and impact on the world is tremendous. But this is only the beginning of the great transformation that is to come.

Key to this transformation is recombinant DNA (rDNA). Recombinant DNA molecules are DNA molecules formed by laboratory methods of genetic recombination to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in the genome. For instance, you can take gene from a fruit fly and insert it in genome of a tomato. Recombinant DNA is possible because DNA molecules from all organisms share the same chemical structure and they differ only in the nucleotide sequence within that identical overall structure. We were aware of this possibility ever since the 1970’s and we are able to do this for quite some time now. The trouble is, it is still very complicated, it is quite expensive and it is mostly limited to lower life forms. Back in the 1970’s, people had a ‘what if’ debate starting at Asilomar Conference Grounds on the subject of recombinant DNA and possibility that it would be easy, cheap and very fast. Preeminent genetic researchers of the time went to Asilomar to grapple with the implications of being able to decrypt and reorder genes. It was a god-like power – to plug genes from one living being into another. Used wisely, it had the potential to save millions of lives. But the scientists were also aware that their creations might slip out of their control. They wanted to consider what ought to be off-limits. Asilomar was about establishing prospective guidelines, a remarkably open and forward-thinking move.

David Baltimore, young genetic researcher from MIT, and four other molecular biologist stayed up all night writing a consensus statement. They laid out ways to isolate potentially dangerous experiments and determined that cloning or otherwise messing with dangerous pathogens should be off-limits. A few attendees fretted about the idea of modifications of the human “germ line” – changing and introducing new genes into a human being that would be passed on from one generation to the next – but most thought that was so far off as to be considered science-fiction, strongly leaning on the fiction side. Engineering single-cell bacteria was a nightmare (it was really, really hard), engineering human being was considered to be impossible all the way through the next millennium. The rules of Asilomar scientists hoped biology would follow didn’t look much further ahead than ideas and proposals already on their desks.

Forty years later, much sooner than prophesied thousand years, Baltimore joined 17 other researchers for another California conference. Topic was, once again, genome engineering. The stakes, however, have changed.

Everyone at the meeting had access to a gene-editing technique called Crispr-Cas9. Remember that abbreviation, as it will turn your world upside-down. The first term is an acronym for “clustered regularly interspaced short palindromic repeats”, a description of the genetic basis of the method; Cas9 is the name of a protein that makes it work. Technical details aside, Crispr-Cas9 makes it very easy, very cheap and extremely fast to move genes around – any genes, in any living thing, from simplest bacteria to full grown human being. These are monumental moments in the history of biomedical research.

Using this new technique, researchers have already reversed mutations that cause blindness, stopped cancer cells from multiplying, and made cells impervious to the HIV virus. Agronomists have rendered wheat invulnerable to killer fungi like powdery mildew, hinting at engineered staple crops that can feed a population of 9 billion on an ever-warmer planet. Bioengineers have used Crispr-Cas9 to alter the DNA of yeast so that it consumes plant matter and excretes ethanol, promising and end to reliance on petrochemicals. Startups devoted to Crispr-Cas9 have already launched. International pharmaceutical and agricultural companies have spun on Crispr-Cas9 Research and Development (R&D). There is also a great TED talk from the creator of technology itself about usage and implications of Crispr-Cas9 and I highly recommend it, although I don’t agree with take away message of the lecture.

This technique is revolutionary, and like all revolutions, it’s perilous. Crispr-Cas9 goes well beyond anything the Asilomar conference discussed or even dreamed of. It could allow genetics researchers to conjure everything anyone has ever worried they would – designer babies, invasive mutants, species-specific bioweapons and a dozen other apocalyptic sci-fi tropes. It will, however, not come to that. Promising new research suggest that we could, using this technique, end world hunger within 30 years, completely eliminate blindness, deafness, genetic disorders of the face of the Earth, we could end polluting oil industry and still keep (clean) petrochemical industry etc. And it will cost us peanuts. World will not be the same place in 30 years, it will be nothing like we can even dream of at the moment.

Great inventions, especially ground shattering inventions like this one, comes with its own great intellectual property battle – who invented it first and who will make most money out of it? As media covered it, there are two groups of scientist battling over it – one that filed a patent request first and one group that claims it invented it before the first group. I will not go in the specific details of each group arguments, you can read all about it on this link. I see two great problems in this story.
First problem I have with this patent lawsuit is the patent right itself. On political and economic scale, I’m a libertarian (economic scale) liberal (political scale). I firmly believe in capitalist system and patent right is a core tenet of it. Quite simply put, patent rights systems is one of the pillars of capitalist system and it is a great concept of assuring that you, and you alone, will reap the benefits of your hard work. If you put your entire wealth, time and integrity in a project – be it a new product, music album, molecule, anything – and you make a breakthrough or develop new and never seen before product, you deserve to make a profit out of it. Patents are a great driving force of development, technological advancement and cultural renaissance we are currently living in. It is also a great concept of protecting “small” players (for example, small biotech start-up) from a “big” player (pharmaceutical giant) and ensuring that big player will not just take someone else’s research and develop new product line-up without honoring, recognizing and, ultimately, paying small player’s share.

However, there are some things that should not be patentable. Basic knowledge, basic techniques (basic does not mean simple) should be free for all. I’m a great advocate of the open source philosophy and I firmly believe in open science. Human genome project was approached in open science manner and it brought billions of dollars of revenue to the world economy per year, while every bit of information that was discovered on that project was published freely and stored on the databases that were open and accessible to each and every man on Earth – literally every gene, every protein, every piece of knowledge about DNA, RNA and proteins is on the Internet and you can access it now whenever and wherever you are on whatever piece of hardware, be it a supercomputer or 100$ smart phone.

Why am I drawing this parallel? Story of Crispr-Cas9 is very much like Human Genome Project. It is not a discovery made by a deliberate private investment. Crispr-Cas9 research has been an ongoing story for over 30 years across the globe and it was mostly funded by public money on public universities. That means that you (we) funded this project. It shouldn’t belong to the two or three persons alone, not when this discovery was possible due to collective work of thousand of researchers funded by general public. What was paid by general public should be freely accessible to general public – we have already payed for the discovery of the Crispr-Cas9 system, we should not pay it once again for every new product that will be made using this technology.
Second problem is that Crispr-Cas9, however revolutionary, belongs to the sphere of general techniques. That is not a final product – it is a mean of developing new products. For instance, genes are non-patentable category, no one can patent certain gene (believe me, many have tried). Imagine that every laboratory in the world should pay a fee just because their research somehow involves certain gene – entire field of modern biology and biochemistry would be non-existent. All this progress that we have seen in the last 20 years would not occur, we would still treat diseases as we had treated them in 1970’s, with the same success. If Crispr-Cas9 gets patented, we might lose decades of research in the same manner.

However, all is not so grim in this case. I had already mentioned that Cas9 is a protein, and Crispr is a technique. New proteins have been found recently that do the same thing as Cas9, some even better. Most prominent one is a Cpf1 protein. These proteins are in fact an antiviral defense mechanism in simplest bacteria and Feng Zhang, researcher behind Cpf1 protein, had said that there are many more defense system proteins like Cas9 and that “he has a feeling it’s just the tip of the iceberg”.

So, now we have a situation where a tip of the iceberg can turn our world upside-down. Even if this and all future proteins (like Cpf1) are patented, we will have a market competition between them. That means that every team will try to deliver this technique at the lowest price, best precision and greatest speed. Situation simply cannot be better for scientific community and Humanity as a whole. We will either have great market competition of different genome editing techniques or every research will be done in the open science manner.

I would like to add up just one more thing. This entire patent battle of Crispr-Cas9 gets science all wrong. We have a situation where two labs have made a groundbreaking discovery. The sociologist Robert Merton, who made a career out of studying scientists, writes about how every field of research builds upon an “accumulated cultural base”. What he means is that discoveries don’t drop out of the air: they’re the products of their time and incremental increase of thousands of contemporary researchers.

Two teams that are now bickering over the patent rights and potential (probable) Nobel prizes have come to the same conclusion in the early 2010’s having approached the problem from two different sides. From the early 2010’s onward, it was a race of who will polish and publish these results first. My point is, work of both of these laboratories should be acknowledged and applauded, as they have independently came to the same conclusion and the same final genome editing technique.
This situation has actually been pretty common throughout history. Isaac Newton and Gotfried Leibnitz independently discovered calculus in the late 17th century and then spent years fighting over who got there first. Charles Darwin and Alfred Russel Wallace both came up with the theory of evolution through natural selection, though these two had a more amiable relationship. Back in 1922, the sociologists William Ogburn and Dorothy Tomas catalogued 150 examples of independent discovery and invention. Scientist naturally flock to the interesting scientific problems of their time, and again naturally, they use the tools of their time to solve them. No wonder they often come up with the same solutions.

Science, more than every other field of human activity, is all about cooperation and communication. Amount of knowledge is massive and there is no living human being that can revolutionize scientific field all by himself. We all depend upon our peers and the ones that came before us, be it Giants like Darwin, Einstein, Tesla or “ordinary” scientists of their time that didn’t make it to the spotlight of history.

So, in the light of this, I would like to end this blog as I have started it, with Isaac Newton’s words that every true scientist, and every true man, should live by:

“I have have seen a little further it is by standing on the shoulders of Giants.”