[R-G] John Sulston on Patenting Human Genome

[Yoshie Furuhashi]

December 2002
NOBEL PRIZE FOR DISCOVERIES IN GENETICS
Heritage of humanity

The 2002 Nobel Prize in physiology or medicine was presented this 
month to John Sulston, Sydney Brenner and H Robert Horvitz for 
discoveries about the genetic regulation of organ development and 
programmed cell death. John Sulston is also a principal player in 
another remarkable scientific endeavour, the human genome project. 
The entire sequence of the genome will be made public next year, 
despite many obstructions because of greed over lucrative genetic 
patents.

by JOHN SULSTON *

ALTHOUGH the genome is the starting point for human life, we should 
view it as a source of possibility rather than as a constraint. Many 
fear that individuals' genetic information will be used against them, 
and these concerns should be taken seriously. Insurers are pushing 
for the right to use genetic test results in deciding whether or not 
to issue policies. If permitted by law, insurers and employers could 
make genetic testing a prerequisite for issuing policies or offering 
jobs. We should oppose such discrimination.

And since people continue to suffer from cancer, heart disease, 
senile dementia and other diseases, newspaper headlines such as 
"Miraculous gene code could eradicate all disease" will only lead to 
disappointment.

Still, our recently acquired genetic knowledge is enormously valuable 
to the twin fields of biology and medical research. That is why it is 
so important to complete a definitive version of the preliminary 
human genome sequence - the draft version's release was celebrated 
worldwide on 26 June 2000 - and to give researchers access to the 
data without delay. The sequence will be completed sometime next year 
and should become a permanent scientific archive and reference 
tool....

In all likelihood we will develop new drug treatments for 
hard-to-treat diseases over the next decade. For example, Mike 
Stratton's cancer team at the Sanger Centre is currently screening 
tumours to see how they differ genetically from normal tissues. In 
many cases it is still easier to kill a cell than to cure it. Genome 
information may help drugs find targets on cancer cells and destroy 
cells selectively, leading to fewer side-effects and better remission 
rates.

Genome sequencing is a major step forward for our knowledge of the 
human body at the molecular level. Yet we are only in the early 
stages. We still do not know what most of the genes look like, nor do 
we know when or where they are expressed as proteins. The genome by 
itself does not provide answers to any of these questions. 
Nevertheless, the information is available to everyone as a resource 
tool. The next step is to track down all the genes, determining their 
significance, their location and how their control signals work.

In November 1995 Stratton's team at the United Kingdom-based 
Institute of Cancer Research (ICR) found a mutation in one of their 
breast-cancer gene "families", apparently connected with the BRCA2 
gene. The region containing that gene had just been sequenced at the 
Sanger Institute, and within two weeks the ICR team had not only 
confirmed the discovery but found five more mutations. Stratton moved 
fast to publish the findings in the international weekly scientific 
journal Nature, keeping them secret from his colleagues until the 
last minute. But despite his efforts, some information reached 
Utah-based Myriad Genetics Inc in the United States, which then 
located the gene. Myriad's chief scientific officer, Mark Skolnick, 
then filed a patent application - on the day before the ICR paper was 
published.

With the threat of commercialisation looming, the ICR moved to patent 
the mutations it had discovered. At the same time, Myriad used its 
own patent applications to claim rights to the BRCA2 gene as well as 
to the entire BRCA1 gene, which Myriad's scientists were the first to 
clone. Myriad set up a commercial diagnostic laboratory, and once its 
patents were granted, the company threatened legal action against any 
other United States laboratory using either gene for breast cancer 
screening. This meant that Myriad had the only lab that could perform 
such screening, at a cost of nearly $2,500 per patient. The company 
also had the right to grant licences to other labs to carry out 
simpler procedures at a cost of $200 per test.

One of Myriad's tests focused on a mutation discovered by the ICR 
affecting the BRCA2 gene, commonly found among Ashkenazi Jews from 
central and eastern Europe. "The Ashkenazi A mutation was the 
framework for our original paper," says Professor Stratton. "Myriad 
is claiming a fee for a mutation that we discovered." As an Ashkenazi 
Jew, Stratton found this especially galling.

By claiming proprietary rights to the diagnostic tests for the two 
BRCA genes and charging for the tests, Myriad is adding to total 
health-care costs. Even worse, once scientists really understand how 
the BRCA1 and 2 mutations cause tumours to grow, they might be able 
to devise new therapies. But because of its patents, Myriad has 
exclusive marketing rights.

Throughout the formidable task of sequencing the human genome, we 
were faced with the question of research-related proprietary rights. 
Although the full impact of Myriad's aggressive approach was unclear 
in 1995, it was clear where a focus on commercial profit and patents 
would lead. What was needed was a commitment from the international 
sequencing community to make all genome information publicly 
available and not to parcel it out via individual deals between 
companies and researchers.

How to manage the data?

We decided to hold an international meeting to hammer out a strategy 
deciding who would do what, and how to manage the data. The UK 
selected Bermuda, close to the US, as the site of the meeting. This 
was our introduction to the world of international politics. The 
meeting was extremely constructive, since it was the first 
opportunity for researchers to compare notes freely. We were forced 
to work together because nobody at that time could complete the 
sequencing alone. Everyone arrived with pieces of paper stating their 
intentions to sequence a particular region of the genome, and during 
the meeting we resolved the overlapping claims.

At that time there was no mechanism for loading preliminary data into 
public databases, which were set up for finished data only. Even in 
raw form, the human genome sequence data obtained from our machines 
might prove useful to other researchers seeking to localise genes or 
to check hypotheses. As we had done with the nematode (1), we made 
all of our data available electronically from our own sites at the 
Sanger Institute, so that people could download information and do 
with it as they saw fit (2). We merely asked them to recognise that 
the data was preliminary and to acknowledge us as the source in any 
publications.

The principle of data availability had to be endorsed at the Bermuda 
meeting or else mutual trust would have been impossible. At first I 
thought it unlikely that everyone would come to an agreement. Several 
of those present, including Craig Venter of the Institute for Genomic 
Research (TIGR) (3), already had links to commercial organisations 
and might oppose the idea of giving everything away to the public, 
with nothing in return. But as I stood at the white board, scribbling 
away, erasing and rewriting, we eventually came up with a statement. 
The Wellcome Trust - a medical research charity and the Sanger 
Institute's main financial backer - still has a photo of that 
handwritten statement with its three bullet points:

* Automatic release of sequence assemblies larger than 1 kb 
(preferably within 24 hours).

* Immediate publication of finished annotated sequences.

* Aim to make the entire sequence freely available in the public 
domain for both research and development in order to maximise 
benefits to society.

While Bob Waterston of St Louis's Washington University and I were 
drafting the statement together with our colleagues, another 
colleague, Michael Morgan, was meeting with representatives from the 
funding agencies to secure support for our initiative. What I had 
written on the board, with minor modifications, became known as the 
Bermuda principles, and these have since served as the benchmark for 
publicly funded large-scale sequencing projects.

The principles of accessibility and on-the-spot release mean that 
anyone in the international biological community can use the data and 
ultimately turn them into new inventions that are eligible for 
patents. But when the raw sequence is released publicly, it will be 
unpatentable. It promised well that so many people came to share a 
vision of the genome sequence as the heritage of humanity, as stated 
in Article 1 of the universal declaration on the human genome and 
human rights, which emerged from Unesco's general conference in 1997.

The 20th century saw a split between the sciences and the humanities. 
Many no longer perceive science as a manifestation of culture. One 
reason is that science has become increasingly equated with 
technology; in many quarters technological development represents 
science's sole purpose. Scientists are encouraged to capitalise on 
their discoveries commercially, regardless of the social consequences.

A discovery, not an invention

The genome sequence is a discovery, not an invention. Like a mountain 
or a river, the genome is a natural phenomenon that existed, if not 
before us, then at least before we became aware of it. I believe that 
the Earth is part of the common good; it is better off not owned by 
anyone, even though we may fence off small parts of it. But if an 
area proves important because it is especially scenic or is home to 
some rare species, then it should be protected in the public interest.

To be sure, there will always be arguments concerning the balance 
between private and public lands and how they should be used. The 
human genome is an extreme example. We all carry our personal copies 
of the genome, and each portion of it is unique. You cannot say that 
you own a gene because you would then own one of my genes as well. 
And you cannot say that we can share our individual genes because we 
need every single one of our genes. A patent may not grant literal 
ownership of a gene but it does specifically bestow the right to 
prevent others from using that gene for commercial purposes.

Placing legal or proprietary restrictions on genes should be confined 
strictly to current applications or to inventive steps. Someone else 
may choose to work on another application and may thus need to have 
access to the same gene. Inventing human genes is impossible. So 
every discovery relating to genes - their sequence, functions and 
everything else - should be placed in the pre-competitive arena. 
After all, one goal of the patent process is to stimulate 
competition. The most valuable gene-related applications are often 
far removed from the first easy steps. So this is a matter of 
science, not just a matter of principle.

In March 2000 Maryland-based Human Genome Sciences Inc (HGSI), a 
company set up alongside TIGR in 1992, announced that it had been 
granted a patent on the CCR5 gene, which encodes a receptor on the 
surface of cells. When HGSI initially applied for its patent it did 
not know how this receptor functioned. While the patent was pending, 
a group of publicly funded researchers at the US National Institutes 
of Health (NIH) discovered that some people with CCR5 gene defects 
were resistant to infection with the AIDS virus (HIV). CCR5 appeared 
to be one of the gateways the virus uses to invade cells. As soon as 
they found out about the NIH discovery, HGSI confirmed the role of 
CCR5 through experiments and obtained the patent. HGSI asserted its 
proprietary rights to use the CCR5 gene for any purpose and then sold 
licences to several pharmaceutical companies to develop drugs and 
vaccines.

But who took the inventive step? Was it the company that made a lucky 
match with the right gene? Or was it the researchers who determined 
that HIV-resistant individuals had a defective gene?

William Haseltine, HGSI's chief executive officer, argues that 
patents stimulate progress in medical research, and that the CCR5 
patent may well lead to a new drug or vaccine for HIV. But a survey 
of researchers at US university labs found that many of them have 
been deterred from working on particular gene targets, fearing that 
they might have to pay hefty licence fees (or royalties) to companies 
or risk lawsuits (4).

The patent question

The US recently clarified its guidelines on granting gene patents to 
provide a somewhat tighter definition of utility - use must now be 
"substantial, specific and credible". But the guidelines still allow 
sequences to be patented since they can be used as probes to detect 
genes responsible for various diseases. The European patent 
directive, approved by the European parliament in 1998, states that a 
sequence or partial sequence of a gene is only eligible for a 
"composition of matter" patent when it can be replicated outside the 
human body (in vitro), for example copied in bacteria, as we do for 
human genome sequencing.

This argument has always seemed absurd to me. The essence of a gene 
is the information it provides - the sequence. Copying it into 
another format makes no difference. It is like taking a hardback book 
written by someone else, publishing it in paperback and then claiming 
authorship because the binding is different.

The number of applications for gene patents on humans and other 
organisms has now passed the half-million mark, and several thousand 
such patents have been granted. Nevertheless, the issue of gene 
patents remains complex and confused. The US Patent and Trademark 
Office (USPTO) still maintains that a gene discovery is patentable. 
Until the recent changes, the USPTO granted patents even for partial 
gene fragments whose only claimed utility was as gene probes. The 
European Patent Office remained unconvinced about gene patents until 
the European Union issued its 1998 biotechnology patent directive, 
which explicitly permitted the patenting of gene sequences. Several 
EU member states, including France, are opposed to the EU directive, 
while other EU members, such as the UK, maintain a more neo-liberal 
line on patenting so that their biotechnology industries remain 
competitive with those in the US.

I realised long ago that trying to reach an equitable solution using 
moral or even legal arguments was doomed to failure. The best way to 
prevent the sequence being carved up by private interests was to 
place it within the public domain so that, in patent office jargon, 
as much as possible became "prior art" and thus unpatentable by 
others. The international sequencing consortium, while working on the 
human genome project, succeeded in doing just that with respect to 
the raw sequence data. Now we are raising the bar by placing as much 
information as possible about the annotated gene sequence and gene 
function in the public domain.

Some have proposed drawing a patent line between life and non-life. 
While agreeing with the concerns, and with the urgent need for a 
value other than a commercial one to be placed on living things, I 
think there is no case for this particular line. Because the chasm 
that previously existed between the biological and the chemical is 
closing, such a distinction will not be sustainable. We should not be 
patenting whole life forms, such as transgenic mice or cotton plants 
- and not just because they are living organisms. A sounder reason is 
this: we did not invent these organisms, only the specific 
modification that made the mice susceptible to cancer or the cotton 
resistant to pests.

The future of biology is strongly tied to that of bioinformatics, a 
field of research that collects all sorts of biological data, tries 
to make sense of living organisms in their entirety and then makes 
predictions. If this data is freely accessible, bioinformatics will 
allow experimental biologists to complement the work of other 
researchers and to connect with them. If we wish to move forward with 
this fascinating endeavour, which will undoubtedly translate into 
medical advances, the basic data must be freely available for 
everyone to interpret, change and share, as in the open-source 
software movement. The situation is too complex for a piecemeal 
approach, with limited amounts of data released at a time and with a 
single entity holding the access keys.

The saga of the human genome project proves that publicly financed 
science is extremely effective because it is so intensely 
competitive. The project's success also refutes the widespread notion 
that only private industry is capable of carrying out large-scale 
research.



* Biological researcher and founding director of the Sanger 
Institute, based in Cambridge (UK). This article was adapted from 
John Sulston and Georgina Ferry's _The Common Thread: A Story of 
Science, Politics, Ethics, and the Human Genome_ (Bantam Press, 
London, 2002)

(1) Editor's note: By means of a microscope and cell-by-cell 
analysis, the author patiently observed the nematode Caenorhabditis 
elegans, measuring only one mm in length, throughout the various 
stages of its development. This was the first animal to be sequenced 
in its entirety.

(2) http://www.sanger.ac.uk/HGP/

(3) Editor's note: Craig Venter founded The Institute for Genomic 
Research (TIGR). He went on to launch Celera Genomics, whose stated 
goals were to decipher the entire human genome sequence and to patent 
the results. As a result of intense political pressure, the human 
genome project and Celera Genomics jointly announced on 26 June 2000 
that they had completed a draft version of the sequence.

(4) Anna Schissel, Jon Merz and Mildred Cho, "Survey confirms fears 
about licensing of genetic tests", _Nature_, vol 402, 1999, p~118.

Original text in English

<http://MondeDiplo.com/2002/12/15genome>
-- 
Yoshie

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