Dr. Allen Roses
-President and Worldwide Director, Genetic Directorate, Glaxo Wellcome Inc.
NEW GENETICS: DISCOVERING INNOVATIVE MEDICINES FOR THE 21 ST CENTURY
Chairman: Robert J. Dechert
President, The Empire Club of Canada
Head Table Guests
David McFadden, QC, Partner, Smith Lyons and a Director, The Empire: Club of
Canada; Julian Kirk-Elleker, OAC Student, Ursula Franklin Academy; Rabbi Baruch
Frydman-Kohl, Senior Rabbi, Beth Tzedec Congregation; Dr. Heather Monroe-Blum,
Vice-President, Research and International Relations, University of Toronto;
Dr. David B. Shindler, President and CEO, Milestone Media Corporation; Dr.
Manuel Buchwald, Chief of Research and Director, Sick Children's Institute; Ken
Shaw, National Editor, CFTO Television and a Director, The Empire Club of
Canada; Dr. Alan Bernstein, Director, Samuel Lunenfeldt Research Institute,
University of Toronto; Dr. Michael Levy, Senior Vice-President, Research and
Development, Glaxo Wellcome Inc.; Dr. Bruce Archibald, Assistant Deputy
Minister, Ministry of Science and Technology; and Paul N. Lucas, President and
CEO, Glaxo Wellcome Inc.
Introduction by Robert J. Dechert
Ladies and gentlemen, many of you will recall that a little more than a year
ago the Chairman of Glaxo Wellcome Inc., Sir Richard Sykes, in his address to
the Empire Club, described his company's involvement in the Human Genome
Project and the many benefits that humankind could expect from genetic
Hardly a week passes without the announcement of the discovery of a gene
linked to one of medical science's most perplexing diseases. With each new
discovery comes the hope that those susceptible to a particular disease can be
identified, treated and with the development of gene therapy potentially even
We are very privileged to have with us today one of the world's leading
experts on genetic research.
Before joining Glaxo Wellcome in 1998, Dr. Allen Roses was associated with
Duke University for more than 20 years as a senior research scientist. He was
Chief of the Division of Neurology from 1977 to 1997, Director of the Joseph
and Kathleen Bryan Alzheimer's Disease Research Centre from 1984 to 1997 and
the Director of the Centre for Human Genetics from 1996 to 1997.
Dr. Roses was one of the first clinical neurologists to apply molecular
genetic strategies to neurological diseases. During the early years of
recombinant DNA research, Dr. Roses initiated several pioneering studies. His
laboratory reported the chromosomal location for more than 15 diseases,
including Lou Gehrig's disease. A multi-disciplinary team of Duke University
geneticists led by Dr. Roses discovered a susceptibility gene which lowers the
age of onset and increases the risk of Alzheimer's disease.
For his contribution to genetic research, Dr. Roses has received numerous
prestigious awards including the Metropolitan-Life Award for Alzheimer's
disease research and the American Academy of Neurology Potamkin Award for
Alzheimer's disease research.
Dr. Roses is currently a member of the Glaxo Wellcome Research and
Development Executive Committee and heads the Genetic Directorate. His current
research involves genetic strategies for susceptibility gene discovery with
respect to Alzheimer's disease and other neurological diseases.
Ladies and gentlemen, please help me in welcoming Dr. Allen Roses to the
podium of The Empire Club of Canada.
Thank you very much. It is an honour to be here. It is not often that I try
to explain genetics to a primarily non-scientific audience.
What I would like to try to do today is explain some of the things that are
going to happen in medicine in the next five to 10 years. Our primary customer
is the patient and the most important part of our work is getting the right
medicine to the right patient at the right time for an appropriate cost.
At Glaxo Wellcome I have had the opportunity to see things in a very
different manner than I did when I was at the university for 27 years. The
opportunity to actually affect medicine development and affect the way
government and industry can work together to improve medicine development has
been maximised by my being at Glaxo Wellcome.
Many of you probably read a couple of weeks ago (and maybe didn't quite
understand its significance) an announcement about the SNP consortium which is
a group that has as its founding members the Wellcome Trust, the largest
charity in Great Britain for medical causes, and 10 contributing pharmaceutical
companies sponsoring research in four genome centres to make a map that would
be useful for pharmacogenetic purposes. I am going to explain more about that
but it is probably the first time that companies that compete at the end
product have declared that certain things like the human genome belong in the
public domain. The human genome is not private property and we should treat it
in an ethical way in order to be able to get the right drugs for the right
One of the things you should know about the pharmaceutical industry (which I
learned when I came into the industry and didn't really realise when I was an
academic, even a seasoned academic) is that of 100 molecules that
go into development only 10 come out and of those 10 only three are
profitable. Of those three only one pays for all of them. There is a
blockbuster mentality in the industry and it is a real one because only by
maintaining that output can an industry survive.
One of the things that genetics can do is find out what underlying genes are
responsible for some of the diseases that we get; not cause a disease but give
a propensity or a susceptibility for it.
Most of the genetics work that you have been hearing about or reading about
in the newspapers for the past 20 years has identified genes causing monogenic
diseases like cystic fibrosis or Huntington's disease. Most of the people who
have these mutations actually get the disease sometime in their life.
There are a number of other genes called susceptibility genes. With these
you don't necessarily get the disease but have more susceptibility or less
susceptibility for the disease depending on which gene flavour you inherit from
your father or your mother. Multiple genes contribute to the actual development
of these diseases.
This is a different kind of genetics but lay people understand it much
better than scientists or physicians. We know cancer runs in some families. We
know Alzheimer's disease and heart disease runs in some families. These are not
monogenic-inherited diseases but some families have a greater susceptibility
for these diseases.
With the genome project sequencing the whole genome, we now have a chance to
study the hundred thousand plus genes that are there. As a company we are
interested in the 30 or 50 genes that are most likely to help us find targets
that we can screen to develop medicines related to certain diseases. Rather
than try to own the whole human genome we're trying to hasten the time taken to
find what those particular genes are and work on them for disease targeting. At
the present time targets are basically like hypotheses were at the university.
People believe in them but their beliefs could be wrong. They can have great
arguments for them but many of those arguments can be fairy tales. If we can
get genetically relevant targets we can get a better hit rate and from that hit
rate get more drugs that are going to help in more diseases.
In order to do that Glaxo Wellcome started a programme which is I think the
only one in the industry. We took half the genetics budget and decided to place
it in academia. We didn't think that companies should be owning DNA from
people. We didn't think that companies should have access, direct access, to
Mrs. Smith's medical record. There was a type of research that could be done in
universities that we needed to be able to access but we didn't need to have the
data sitting in the company. We formed what are called genetic networks, Glaxo
Wellcome genetic networks.
We have three components to these networks. We got together the best
academics worldwide that had an interest in accessing patients and their
families. We got together a few laboratories set up as screening laboratories
to do all the DNA screening for the networks. We took about 10 of the 15 people
in the world who are really super at genetic epidemiology and made them
non-exclusive consultants to do these projects for us. We provided support and
we provided money to get this done, to centralise some of the things and to
make sure that everybody was relatively happy and that all academic demands
that ought to be in the system were adhered to.
From my point of view it's the perfect system that I would've wanted if I
were still at Duke University. I have access to my own data. I have access to
my own DNA. I can do anything I want with it except do a linkage study. The
linkage study is what the company will do with this to narrow down the place on
the human genome where the genes for a particular disease are found. We're
using something called a SNP map. A SNP map is basically a single nucleotide
polymorph, a variation, something that we can experimentally tell apart. This
third generation genetic mapping promises a means of targeting the right
medicine to the right patient, truly individualising treatment.
The big problem that people have once they get linkage information is they
don't know how to narrow it down with current techniques. They use the
candidate gene approach. They pick a gene. They think it is important and make
up all the reasons in the world why they think it's important. They submit a
grant, get paid for it, study the gene and it's not the gene. Or even worse
they report it as the gene and somebody or a bunch of people say it isn't. Most
of the reports you've read for instance about Alzheimer's disease recently are
from genes that have not been confirmed and confirmation is the name of the
Once we get these linkage areas using a very fine, very dense map, we can
find a small area that is easier to work with to find genes. We've done that.
I'm not going to tell you about that but it works.
A SNP map is like a fingerprint or a profile. Using a SNP map you can
measure people who have some sort of clinical response and compare them to
people who don't get the clinical response and start targetting medicines. What
do I mean by that?
There are really two things to look for--effective drugs and adverse events.
We do about 20 per cent of our clinical studies here in Canada. It's a very
important part of what we do. We had 20-per-cent responders in a phase 2 study,
an early study where we just looked for response. One hundred people responded
and 400 people didn't respond, We can take the DNA of each of those two groups,
do a profile, compare the profile and see if we can get specific regions mapped
in the people who responded so we can abstract those regions into a much
smaller test and be able to pick out people who are most likely to respond to
the medicine. Then when we do our clinical trials we would not subject as many
people to the medicine. The trials would be smaller, faster and cheaper.
That's going to require some proof of concept and what. we're doing in proof
of concept is something totally different. Other companies are doing the same
thing. We have a drug that is an incredibly good anti-convulsant for epilepsy.
We've got a problem with that drug; not a big problem but a small type of
problem that keeps a very good drug from being a blockbuster. As a neurologist
I can tell you that that drug is probably the best drug for certain forms of
epilepsy that are commonly found in the population with fewer side effects than
many of the other drugs. It is commonly used but why isn't it the blockbuster
that everybody uses right off the bat?
It is because about 2 per cent of patients get an itchy skin rash. If you're
a doctor and you see a lot of people with epilepsy you certainly don't want 2
per cent of them calling on the phone questioning what kind of doctor you are
because they've got this itchy skin rash. The drug gets used in a dose
escalation by experts but it doesn't necessarily get used by the general
doctors who don't want to get involved in dose escalation or don't want to hear
that they are not a good doctor for giving someone a rash. What are we going to
Using the 100 people who got the skin rash and the 200 people who took the
drug but didn't get the skin rash, a SNP map from the SNP consortium is
obtained and can be used to determine the profile of people who get the skin
rash. From a blood sample it can be determined that you are not going to get
the skin rash and can take the drug. You avoid dose escalation, you avoid the
nasty telephone calls in the middle of the night, and you become a happy user
of a very good and otherwise safe drug.
The consortium is working to develop and make the SNP map freely available.
We will have a SNP map that's useful in less than two years. We are developing
ways of reading the map in order to construct profiles. If we can bring
individualised medicine, customised medicine, safely and efficaciously to the
population the pharmaceutical industry is doing something good and I'm very
very happy that Glaxo Wellcome is at the head of that movement.
Thank you very much.
The appreciation of the meeting was expressed by Ken Shaw, National Editor,
CFTO Television and a Director, The Empire Club of Canada.