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.”

The Good, the Bad and the Stupid

Before I start writing new post, I just want to say out loud that if any of the facts you read on this blog prove to be wrong, I would be very happy if you point them out to me. Mistakes can be made, facts can be overlooked and I don’t balk from apologizing if I’m wrong. This applies to this post and every post from now on.

So, as I promised in my last post, I will be talking about the mess with the Daraprim treatment and Turing Pharmaceuticals. As they tend to do, the press covered the story with the usual shallowness and they missed their target far and away. Yes, Martin Shkreli is a douche-bag and, yes, his move with Daraprim pricing is borderline, psychopathic villainy, but the main issues in this story remain unresolved, undiscussed and, mostly, unmentioned.

So, let’s start from the beginning. Toxoplasmosis is a parasitic disease caused by Toxoplasma gondii and infections with toxoplasmosis usually cause no symptoms in healthy adult population. Rarely, it might involve mild flu-like illness for a few weeks. Problem is, it can cause severe symptoms (such as seizures) in population of weak(ened) immune systems, such as newborns and patients with AIDS. Preferred treatment is pyrimethamin, better known as Daraprim in both USA and EEA area, taken alongside folic acid. The thing is, AIDS-infected patients often have to take that medication for life. There are other treatments, such as sulfadiazine or clindamycine, but doctors prescribe Daraprim because the side effects of Daraprim are well known and they feel safest when administering that drug. Other reason is that they avoid prescribing antibiotics if they aren’t absolutely necessary. Usage of antibiotics leads to development of antibiotic resistant bacteria and that might be the greatest health care issue of 21st century. I will talk more about it in a separate post. Daraprim is on the market since mid 20th century, patent protection ran out in ’70-ies and it was pretty cheap and easily accessible to the patients and everyone were happy until now.

GlaxoSmithKline was the holder of Daraprim up until 2010 when it sold the rights for selling of the Daraprim in the USA (and the USA alone – GSK still holds the rights on Daraprim in all other EEA countries AND Canada) to CorePharma. CorePharma sold it to Impax Laboratories. Impax laboratories did not do much with the drug, only major thing they had done with Daraprim was a change in distribution system – they went from typical wholesale distribution to a smaller and more tightly controlled, specialty drug distribution network, making development of new generic drug virtually impossible. Making generic drug is pretty straightforward process and there is only one critical step – you have to prove that your new (generic) drug has absolutely the same properties as the original drug (originator). If you cannot acquire enough of the originator or if owner of originator gives you “bad” drug (drug from production batch with some error or outright wrong formulation) and you embarrass yourself (and lose hundreds of millions of dollars in the process) in front of regulatory agencies, you cannot develop novel generic drug. Impax Laboratories did nothing with Daraprim per se, they only made making generic version of Darapim virtually impossible.

Enter Martin Shkreli.

Impax Laboratories sold the Daraprim market rights to Turing Pharmaceuticals, start-up company led by a young hedge fund manager Martin Shkreli. Right after acquiring market holding rights of Daraprim in the USA, Turing Pharmaceuticals raised price from $13.50 a tablet to $750, shocking 5555,56% increase in price. Mass hysteria ensued, Skhreli was dragged in the mud all across the Internet, pharmaceutical industry was (once again) vilified, everyone had all of a sudden had (the same) opinion about the pharmaceutical industry, American presidential candidates had speeches about it and promised to end the outrageous pricing of drugs. Yes, Martin Shkreli is an idiot devoid of all sense of morality (and if we were all wrong, and he did have a plan to make good use of the money he had intended to plunder with this Daraprim pricing, I will publicly apologize and cover the story about good guy Martin Shkreli) and that is where this story should end.

First of all, he is not the first to do this and he is not the only one to do it this year. Second of all, he is not a scientist, he is not an engineer, he is not a leader and he will never build anything except his bank account. He is hedge fund manager and his (and all the other hedge fund managers) interest is in short-term monetary gain. Players like these do not understand how does the pharmaceutical industry work, they do not understand the principles in building pharmaceutical empire, they do not understand that you have to spend 10 to 20 years on one (ONE!) drug to start making profit. These players enter the field of pharmaceutical industry, they wreck havoc for a couple of months, they sell the market holding rights back to pharma-savvy (yes, I made this phrase up right now) company and situation normalizes afterwards.

What is most important fact in this story, patients are not and will not be endangered by this move. First of all, there are stocks of Daraprim in hospitals (although they are dwindling). Second of all, in November 1992, the US Congress created the 340B program which is codified as Section 340B of the Public Health Service Act. This law protects specified clinics and hospitals from drug price increases and gives them access to price reductions. This law requires pharmaceutical manufacturers participating in the Medicaid program to enter into a second agreement with the Secretary of Health and Human Services – called a pharmaceutical pricing agreement (PPA – btw, hello Ubuntu users) – under which the manufacturer agrees to provide statutorily specified discounts on “covered outpatient drugs” purchased by government-supported facilities, known as covered entities, that are expected to serve the nation’s most vulnerable populations.

In other words, Medicaid patients and hospitals who service those patient, are protected by American Federal law from the burden of large increases like this. The 340B program is one of the most powerful contractual pharmaceutical pricing systems in the world to protect those people who are in need of expensive medications that are on those contracts. Moreover, Medicare and private insurance patients also have access to those prices if they can demonstrate need.

In other words, only population that would bear the burden of this increase is rich population covered by platinum level health insurance, even if Shkreli had not backed down on his decision to increase the price. I’m sure that those pitchforks would not be needed.

Shkreli’s failure was actually not of business logic, his plan was actually perfect on that side. He bought the drug that was in use for more than 60 years, there are no generic version of it and previous market holder had made virtually impossible to develop generic drugs. Poor and middle-class population is protected by the Federal law and Shkreli was to make money on perversely rich and AIDS infected population. Great plan. And it would have worked if Shkreli invested in one thing – marketing. His failure was not of business strategy, his plan flopped because he had lacked proper PR.

People brought pitchforks up because of overpriced medication that is mostly used by a very tiny percentage of AIDS infected population (that really is a niche of a niche on pharmaceutical market) but no one is bringing pitchforks to Apple headquarters for overpricing their technology. Moreover, for absolutely the same business strategy, Apple is applauded as the best tech company and it is currently ranked as world’s greatest company and the most profitable one. OK, that might be completely wrong example, iPhone or iPad are matter of luxury, not survival. Let’s try to find more suitable example.

Pricing of bread – in ideal world, ration of price of wheat to flour to bread is 1 : 2 : 3. First part of the equation adds up and ration of price of wheat to flour is about 1 : 2. Things completely break down in other part of the equation. Currently (in Europe), ration is 1 : 2 : 10. OK, let’s say that bakeries have many expenditures, they are bogged down by regulations just as anyone else and the ratio would be 1 : 2 : 5. Where are other 5 parts of the price? Pure extra profit. Where are the pitchforks? Why is there no public outcry for this example of profiteering?

The answer is simple – we are used to it. That is just the way things are and we live with that fact and for all of our lives, we are overpaying the commodity that is essential for all of our lives. Just as drugs are. If Shkreli had had a pinch of patience and good PR team behind him, he wouldn’t have raised anyone’s eyebrow.

Now, on to the other points that remained under the radar. Daraprim is on the World Health Organization Model list of Essential Medicines. Daraprim tablet cost in USA was $13.50 and nobody had had any problems with that fact. Nobody had mentioned the fact that the same drug in UK costs 13£ for 30 tablet pack – that is approximately 0.43£ (0.65$) per tablet, making Daraprim treatment around 2800% pricier in USA than in the rest of the world – BEFORE Turing Pharmaceuticals’ price increase. Even worse, there are various pyrimethamine tablets in India for the price of 0.08$ per tablet. Now, one could say that unregulated markets of India and southeast Asia where drugs could kill you just as they could cure you are not comparable to the market of USA, but markets of European Union are comparable to the market of USA. Difference in price of 2800% is unjustifiable. So why is there such a difference?

People and media are accusing capitalistic system and pharmaceutical industry as a whole, saying that drugs can’t be commodities. The problem is exactly lack of capitalism in this case. How could it be allowed that Daraprim – drug on WHO’s list of essential drugs – became commodity under monopoly of one company that closed the wholesale distribution of Daraprim and made it harder to obtain than the high quality crystal meth or cocaine on the street?! This situation is prime example of what happens when competition is stifled. This is not the story about greedy capitalist (although it is caused by one), this is story of failed system, system that became bogged down with unending sea of bureaucracy, system that actively discourages investment, competition and progress – system where it was non-profitable to develop generic version of a drug that was overpriced for 2800%. Just imagine, margin of 2800% was not enough to make a profit. That is the state of the legislation of pharmaceutical industry today, that is the amount of money the state takes for itself for every drug. And government of USA knew that and subsidized that drug, consciously overpaying each treatment for 2800%. I don’t know how you call that, but I call it cartelization – and that is not a sign of a healthy, capitalistic system, it is a sign of corrupt, bureaucratic (one could even say fascist) system.

And what was the reaction of politicians and policy makers? They want to regulate and dictate the price of drugs EVEN MORE! And what happened after those remarks? Whole sector of biotechnology fell and lost millions of dollars of worth in just one day.

At this point, I’m not worried about price of Daraprim treatment increase one bit – I’m more worried about politicians meddling in the affairs they are not qualified one bit, potentially destroying entire sectors of research in biology and chemistry that will improve all our lives. Every meddling of politicians in pharmaceutical industry resulted in destruction of entire companies and slowing down of research in certain areas for entire decades.

To conclude this post – yes, Martin Shkreli is a shortsighted, greedy man and Daraprim price increase is, to say the least, sickening. He will wreck havoc in this sector for a month or two and he will become history. I’m far more concerned about increase of the state legislation and start of the dictated economy, similar to fascist and communist economies, that will ultimately destroy years of research, years of hard work and the greatest victims of this event will be you and every one of us, all children, all men and all women. Innovation and progress cannot be dictated. We should keep hedge-fund managers out of pharmaceutical business, but we should not forget to keep out the politicians as well.

So, the question remains – why are drugs so expensive?

That will be the subject of my next blog post.

‘Till then,