Your genes cannot be patented, but it is too early to celebrate

The US Supreme Court came down with its ruling on the Myriad case. Maybe somewhat expected, the Supreme Court ruled that as genes are considered “naturally occurring,” they are not patent eligible. This is not surprising, although quite a relief at least (a good thing). The idea of a company being able to patent genes in us is simply quite disturbing.

However, I think it is too early to celebrate. The judge, interestingly, stated that as complementary DNA (cDNA) are not naturally occurring, they will be patent eligible. According to Justice Thomas in the opinion of the court:

cDNA is not a “product of nature,” so it is patent eligible under §101. cDNA does not present the same obstacles to patentability as naturally occurring, isolated DNA segments. Its creation results in an exons-only molecule, which is not naturally occurring. Its order of the exons may be dictated by nature, but the lab technician unquestionably creates something new when introns are removed from a DNA sequence to make cDNA.

This, to me, feels like a very awkward decision based on my understanding of biochemistry (I do have a biochemistry degree after all!). In your cell, many processes are involved in going from the genetic code in your genome to a final protein product that will be made. This process is known as the central dogma. The DNA code is first transcribed into mRNA (“transcription”), the mRNA goes through a few additional steps (adding the 5′ cap and the poly-A tail, and “splicing” – during which parts of the mRNA called “introns” are removed), and then based on this mRNA sequence, an amino acid chain is made (“translation”). This amino acid chain goes through more modifications and eventually becomes a protein. Here is a quick video about the splicing process (please watch it before reading on if you are not familiar with the central dogma):

To generate a cDNA,  an enzyme called the reverse transcriptase is used to produce the cDNA based on the sequence of the spliced mRNA (here is an infographic on making a cDNA library). This means that the cDNA contains the genetic code in your genome, except with the introns already removed (this is likely a simplification of the process, because I am sure there are exceptions, but for majority of the time this is the case).

So let’s come back to this “cDNA being patent eligible” business. Because I am not an expert in the different types of patents, I am hoping to cover the different situations I can think of – none of which sit well with me.

Situation 1: cDNA essentially contains your genetic code (well, sort of, then we probably need to define what your “gene” really means – with the introns? without the introns? complementary to the mRNA sequence?). So to allow patents for the information on cDNA doesn’t seem too different from allowing patents for your gene…at least in my opinion.

Situation 2: A few have mentioned that the judge was pointing to a “method patent,” which also seems weird to me. The technique used to generate cDNA has been around for a few decades (HT Mark Hoofnagle for mentioning this in his blog post). So, the technique itself is definitely not novel.

Situation 3: If the judge was suggesting a “method patent” for the act of technicians from Myriad generating cDNA of BRCA1 and BRCA2, then does this mean that any of us with enough knowledge of how to use reverse transcriptase, with access to equipment, and a source of mRNA, can walk into a biochemistry lab to generate cDNA and patent the “method”? (if so, we probably all should start doing this…)

Situation 4: Research labs often isolate cDNAs for many purposes, or prepare cDNA libraries. If a specific cDNA is patented, does it mean that researchers will then need to pay the company a licensing fee in order to continue isolating the said cDNA or cDNA libraries? Will it be considered that they infringed on the patent?

It was, however, noted in the court opinion that:

This case, it is important to note, does not involve method claims, patents on new applications of knowledge about the BRCA1 and BRCA2 genes, or the patentability of DNA in which the order of the naturally occurring nucleotides has been altered.

This means there was no actual ruling about whether cDNA should be patented (yet). This case, therefore, is not the end of the patent discussion for genes – companies are already moving toward working with cDNA and there will likely be more discussions and court cases about cDNA down the road.

According to the Daily Beast:

…a cDNA patent would still have to show that its invention is “non-obvious,” says Matthew Dowd, the lawyer who filed an amicus brief on behalf of James Watson, who won a Nobel Prize for his co-discovery of the structure of DNA. “If you have human genes you almost necessarily have cDNA,” says Dowd. “Down road will be battles over whether cDNA is non-obvious.”

This brings up another issue that is burning to be discussed – how do we provide companies with enough financial incentives for investment in innovation, without prohibiting others from accessing the innovation? From this case, to the patent wars between Apple, Google, and Samsung, to the lack of drug development for rare diseases (mostly as a result of the lack of financial incentives), a bigger discussion will probably need to happen as to how we can create win-win situations. Otherwise, we will continue chase the patent tail, and fill up the pockets of corporate lawyers.

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Note: I would like to thank Joyce and Jone for our discussions on this topic. I am really just brushing the surface here – Joyce provided me with a much more extensive reading list (which I unfortunately didn’t finish – sorry Joyce!)

• US Supreme Court seems unconvinced of human gene patent legality by Liat Clark for Wired.co.uk. April 16, 2013
• Background/History – Myriad Genetics: In the eye of the policy storm by E. Richard Gold, and Julia Carbone. April 1, 2013
• For those who love legal documents – Association for Molecular Pathology v. Myriad Genetics, Inc. (2013) by Kevin E. Noonan. June 13, 2013 (not the one that Joyce sent me, but an update after the ruling was out

(updated June 14 at 4pm) Joyce also wrote about this for her first blog post – if you enjoy some additional technical/legal details you will likely enjoy it.

Note 2: I met Andrea, a graduate student in Biology (Genetics), on twitter. She is collecting links about this ruling on her blog “Appetite for Awesome.” Go check it out!

Note 3: This whole patent discussion reminds me of Kevin O’Leary! If you watch Dragon’s Den or Shark Tank, you would know what I am talking about 😛 Apparently he also had some opinions about this (and I’m absolutely not surprised by his standpoint):

Note 4: No, I am not an american citizen, but at the same time rulings like this set precedence…so of course I am gonna write about it 😛

I have a headache reading about ENCODE: moving into the realm of “big science”

I spent the past few days reading about ENCODE: the ENCyclopedia Of DNA Elements, which is generating a lot of fuzz right now – why does reading about it give me a headache? What is ENCODE? This is a great chance to talk about this “big science” project, and to learn how communication of scientific results can become a mess…

The genome is a collection of genetic codes, based on which an organism (like us) gets the traits and features the organism has. These traits and features come from many processes within the cell – the codes are transcribed and translated to become chains of amino acids, which are then modified to become proteins, which are then transported to where they need to be, and essentially become the building blocks for an organism. Now, after the Human Genome Project, we have an idea what the long sequence of codes looks like – 3164.7 million chemical nucleotide bases, each is represented by a letter of A, T, C, or G. This is massive! If we were to print this out letter by letter, apparently we can fill two hundred 500-page telephone directories. The ENCODE project (420 scientists, 32 labs around the world) aims to go a step further. It says on its project website:

The goal of ENCODE is to build a comprehensive parts list of functional elements in the human genome, including elements that act at the protein and RNA levels, and regulatory elements that control cells and circumstances in which a gene is active.

This is an important step, because simply knowing the codes does not tell us what they really do. But how do you start building a comprehensive list when you have 3164.7 million nucleotide bases to go through? In general, the ENCODE approach is this – let’s imagine that you are doing online shopping at ebay, which has lots and lots (and lots!) of products. Some are useful, working products, and some are not. You want to get a clock, but looking for it one after another is simply taking too long, so instead you look for specific “features” – something with gears, a circular face with numbers 1 to 12 on it, with hour/minute hands, and so on.

This is actually a pretty smart approach. In their 2012 paper, the ENCODE team looked for 4 features: regions of transcription, transcription factor association, chromatin structure, and histone modification, because these are elements that likely matter if we are to search for something specific (like, a clock) later on.

So what’s the problem? It mostly comes down to one word – “function.”

In ENCODE’s news release, they stated that

[…], researchers linked more than 80 percent of the human genome sequence to a specific biological function and mapped more than 4 million regulatory regions where proteins specifically interact with the DNA.

The news release further stated that “most of the human genome is involved in the complex molecular choreography required for converting genetic information into living cells and organisms.”

This sent a shock wave throughout much of the science community. From what we learnt about DNA and human genome so far, we know that a large proportion of the sequence is not “functional” – doesn’t code for a protein and doesn’t seem to have specific purposes in the cell. It is what we called “junk DNA” (terrible term, because not having immediate functions doesn’t mean that it should be thrown out – so many scientists avoid the term). 80%  is much, much higher than what was expected by most scientists. This discovery by ENCODE was picked up immediately by media, marked as “an overturn of the junk DNA theory” *cringe*. A new breakthrough in the field! – or is it?

Just because it has a gear doesn’t mean it is something “functional” (image by Catherinette Rings Steampunk)

You might have figured out what doesn’t seem quite right here. What ENCODE identified were “functional elements” – elements that suggest the possibility for biological functions. Just like not all products with gears are actually “functional” (it could be a clock, a broken watch, some “as seen on TV” product, a bag of random mechanical parts, or a craft project glued together by your 4 year old nephew), identification of functional elements does not equate to actual biological functions in your cell. And having functional elements does not confirm involvement in critical cellular pathways or association with important functions in the cell.

After the immediate media hype, other scientists expressed concerns (to say it lightly), but it was too late (read A Genome-Sized Media Failure by Michael White). This also leads to a very recent, rather aggressive paper by Graur et al refuting the claims by the ENCODE project. This whole thing is now very messy (that’s why I was having a headache) 😦  I won’t elaborate much further, but if you want to know more about this – see Further Reading.

The funny thing is, ENCODE could have been more specific, could have chosen a less controversial term –  like “specific biochemical activity” as suggested by PZ Myers, or perhaps “ability to bind to cellular factors.” If they did not attempt to over-reach the claim,  the focus would have remained on the amazingly huge amount of information that ENCODE provides, which can now be analyzed by scientists around the world to enable us to know more about our genome and how it works.

The ENCODE experience is probably good for science (I didn’t say it is going to be a pleasant one…). We now have this enthusiasm/obssession about big science, that there is so much pressure to get the “next breakthrough” out, to create the next hype. But we should really come back to the objectives of these big science projects – for ENCODE, it is about building an informative genome database for scientists – and disseminate well-supported information to the public and media with adequate explanations.

And, scientists or not, we should remain curious yet inquisitive about “breakthrough” discoveries in the future 🙂

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Postscript 1: This reminds me of the OPERA discovery about neutrinos travelling faster than the speed of light – which was found out later to be the result of equipment/calculation errors. Even though in the end this went down not so nicely, at least they right out stated that they were not sure what was going on, and invited everyone to help figure out whether this was a true discovery or an error (In fact, this sparked a lot of good public discussion about particle physics, which was awesome). I gave the OPERA team kudos for that.

Postscript 2: While I am a little sympathetic about the situation ENCODE is in, I don’t have much good to say about ENCODE’s public promo video below. Neither the Human Genome Project, nor ENCODE, is a shortcut to drug discoveries and treatments for rare diseases. They are however critical  steps toward the understanding of how our genome works. It will take a lot more efforts in the future to tease out specifics – and the video seems to convey the message the ENCODE is much closer than Human Genome Project in finding cures for diseases (it isn’t…we don’t even know where the end is…)

Further Reading

• So I take it you aren’t happy with ENCODE… by Josh Witten
• ENCODE says what? by Sean Eddy
• A coverage by the Guardian Scientists attacked over claim that ‘junk DNA’ is vital to life
• ENCODE gets a public reaming, and the ENCODE Delusion by PZ Myers
• Ewan Birney (ENCODE lead coordinator) and Chris Ponting from Oxford on BCC radio
• Ed Yong’s exhausting summary ENCODE: the rough guide to the human genome
• Nature Journal’s ENCODE Project Explorer
• PLoS paper: A User’s Guide to the Encyclopedia of DNA Elements (ENCODE)