Thank you Helmut, good morning everybody.
Indeed I use the academic freedom to change the title of my talk and to go to my old passion which is medicine.
I actually never got any formal training in chemistry, ever, neither did I get any formal training in biology.
I’m a simple physician, a surgeon as a matter of fact.
But then fell in love with science and what I’ll try to look with you today is to look at medicine but in different eyes.
We are going to look at medicine from the eyes of how drugs were developed.
How they are developed today and how we are going to use the power of science and mostly interdisciplinary science
in order to develop drugs in the future.
And then towards the end if time allows we shall go into some of the problems
that we are facing with the new technologies and platforms.
So we are into drug discovery and biomedical research in the 21st century.
And I divided it into kind of 3 revolutions.
And the first revolution was the revolution of the ‘30’s to the ‘60’s
where all clinical observation at times dated back to old times, was followed later on,
much later on by isolation of active ingredient and only last understanding the mechanism of action.
So it was kind of a serendipitous era.
And I want to bring you a few examples to this serendipitous era.
Aspirin, Aspirin is a wonderful drug, it’s probably the drug that is being consumed and used to these days in tonnes,
more than any other drug that has been ever produced.
And the story of Aspirin is extremely, extremely interesting.
We still don’t understand in full the effects of the drugs, the diseases that the drug effects
and the history goes back to Hippocrates.
And Hippocrates, the father of medicine, found that the barks and leaves of the willow tree have an effect on aches,
on pains and also can reduce pain.
It took many, many centuries for people to understand what's going on in these leaves and roots and barks of the willow tree.
Until Johann Buchner a German scientist from Munich University in the 19th century isolated a material from these barks
which is called salicin and showed that this may be the active drug, except that salicin was not soluble,
it was extremely bitter and people couldn’t use it.
It took another 8 years to the end of the 19th century, almost to the end of the 19th century
where a French scientist by the name of Charles Frédéric Gerhardt took the salicin and neutralised it by acetylating it
and made it a soluble drug that could be tolerated after being taken by people but then he dropped it completely.
He didn’t do anything with it.
And then it took this Jewish scientist that worked at the Bayer Company, Felix Hoffmann, to have his father,
being sick with arthritis, with inflammation of the joints to remember the old experiments of Charles Frédéric Gerhardt
in order to make a family experiment, maybe one of the first true clinical experiments.
So he took the salicin, acetylated it again, actually he reproduced the experiment of Gerhardt and gave it to his father
and his father was cured, the arthritis dissolved and disappeared.
Felix Hoffmann went back to Bayer and convinced them to produce the drug and the drug made Bayer what it is,
it’s a multi billion dollar selling drug that I’m not going, most of you are young here
but I’m sure that among the little bit older among you here, many use aspirin
and I can tell you that I use aspirin for many years now as a preventive drug and we still don’t know what's going on.
What's interesting about the drug is that it was introduced by Bayer in the late 19th century
and it was only in the ‘70’s that John Vane, who won the Nobel Prize in medicine in ’81,
discovered the mechanism of action of the drug, showing that it’s an inhibitor of synthesis of prostaglandins.
So aspirin is basically an anti-inflammatory drug and you can see here it’s an awfully simple molecule chemical,
it’s acetylsalicylic acid, that's what it is, everybody can make it in tones in the basement.
And it’s an excellent drug to relieve fever, people are using it to reduce fever
and people are using it as an anti-inflammatory drug.
You see here the patient with rheumatoid arthritis.
In the last 2 decades or 3 decades it was introduced as a wonderful drug to combat heart attacks
because it prevents aggregation of platelets and coagulation of blood in the coronary arteries that supply blood to the heart.
So it’s really an excellent drug for patients after myocardial infarction.
People claim that it can prevent coagulation even to patients that haven’t suffered yet a myocardial infarction.
And because it’s anti-inflammatory, it’s only recently that people discovered the anti-cancerous effect of aspirin.
Because it’s now known that chronic inflammation leads to cancer,
you can go through chronic inflammation of the bowel to chronic inflammatory disease of the bowel to crone disease,
all those chronic inflammatory states are ending up in many cases with malignant transformation.
So it’s anti-inflammatory, anti-pain, anti-cardiac, anti-cancer - it’s a magic drug.
People are using it all over the world as a preventive drug, it has side effects,
it leads in some cases to bleeding from the gastro intestinal tract.
But if we track back the history of aspirin it’s a wonderful story of complete serendipity.
It’s a story of centuries old piece of knowledge that goes back, dates back to Hippocrates,
that Felix Hoffmann with his sick father pulled out of the basement
and made it probably one of the drugs of the century, complete serendipity.
No planning, no designing, not knowing the proteome, not knowing the genome, not knowing anything, complete serendipity.
So we are still in the era of serendipity.
Let’s go to another one, to penicillin.
And penicillin was the first antibiotic, it’s really changed the life of people in the 20th century.
At the beginning of the 20th century people were living for 40, 50 years, they suffered every single small infection,
woman delivered in the delivery room or at home, soldiers in the battle field,
any scratch led to death, people suffered infections and died.
And it was again a serendipitous discovery by Sir Alexander Fleming who was a bacteriologist
and here you can see he grew this bacteria and he left on the desk by mistake,
completely by mistake a Petri dish open to the air and one spore of fungus,
penicillin fell on this spot and he came after a few days and he saw the penicillin grows.
But then he saw a halo, so bacteria couldn’t grow around this halo and he concluded that the penicillin,
the fungus secreted some anti-bacterial material.
He isolated the material and it turned to be the first antibiotic.
It turned out to be penicillin.
And after penicillin, penicillin brought with it knowledge that fungi do generate anti-bacterial materials
and it led to an enormous search for anti-bacterial materials and it truly switched the way that we are living,
it had huge influence on human health.
It is one of the major factors that led at the end of the 20th century to doubling of the life span
of people in western civilisations.
It opened up surgery, people were now not afraid anymore to take patients to the operating theatre,
to open them, to protect them with antibiotics.
Once they were infected there were many antibiotics to fight those infections
and I think that antibiotics is one of the greatest discoveries of this century.
Though now because of genomic resistance and changes in the bacterial world around us,
we are facing again reinvasion of pathogenic bacteria into our lives.
But no doubt this is one of the greatest discoveries.
Again, complete serendipity.
Nothing was planned, there was no knowledge at all that fungi can secrete antibiotics and all of a sudden it came into our lives.
And the same is true for many other.
Now we are entering the second revolution and the second revolution is a more planned revolution.
I would say it’s a brute force, high throughput screening of large library of chemical compounds.
What people are doing today, they have a purpose, they want to look for an anti-cancer drug, they don’t know anything,
which target they are going to hit, they take dish with cancerous cells, cultured cells
and they are screening hundreds and hundreds of thousands of compounds.
It’s kind of a fishing in a swamp, it’s a fishing expedition that there is no real idea behind it,
what we are going to hit but the idea is that one of hundreds of thousands of these compounds
will prevent the cancerous cells from dividing and this hit or several hits
that are coming from what we call chemical libraries will be taken further to animal experiments.
If they are successful in animal experiments they will be taken to phase 1 human experiments
to find out that they are not toxic and from there to sick patient to phase 2, to phase 3
and then at the end we shall make a drug.
So this is the way that we are working now.
I must admit that the era of serendipity hasn’t left us.
If you will look into one of the wonderful discoveries that also won the Nobel Prize in medicine a few years ago
to Barry Marshall and to Warren about the discovery of the cause of peptic ulcer which is a bacteria.
Peptic ulcer, it’s a wound in the stomach that is caused by the acidity,
was a disease that affected millions and millions of people all over the world.
And people didn’t know the reason for it.
people thought that it has to do with the state of mind and psychologists called it type A personality,
people that are tense and hard working and secrete lots of adrenalin and steroids are more prone
and sensitive to the disease while calm down people that are more relaxed, are less
and there were numerous drugs that were designed and planned against a peptic ulcer, like all kinds of milk to neutralise it.
And then surgeons were extremely busy, me myself, I remember myself as a surgeon,
were extremely busy in the operating theatre cutting stomachs, cutting the nerves that go to the stomach,
that lead to the secretion of the acid.
And all of a sudden in modern times Warren, an Australian pathologist from Perth looked at sections in the microscope
and found a spiral in the lesion, in the peptic ulcer and he suspected that the spiral is a bacteria, helicobacter pylori.
And then a physician that came to work with him, Barry Marshall was unable to,
did some animal experiments but the clinical and scientific community was dumb and deaf, they didn’t want to listen about it.
This is such a big disease that it cannot be caused by a simple bacteria,
that can be eradicated by a simple erythromycin dosage for 5 days.
So Barry Marshall had no choice but to infect himself, he drank the bacteria, developed an ulcer,
asked a colleague, gastroenterologist to put a camera into his stomach, to look and to see and to take pictures of the ulcer,
the ulcer was there, he drank antibiotics for 5 days, put the camera again, the ulcer was gone.
And one of the biggest epidemics in the 20th century,
mostly of western civilisation was almost completely eradicated by simple antibiotics.
So this is another story, a modern story of serendipity,
just to tell you that the era of serendipity has not disappeared completely.
But let’s go to the high throughput.
And in the high throughput I’ll bring you just one example and it’s a wonderful example,
this is a Japanese scientist by the name of Akira Endo who screened for anti-cholesterol synthesising drugs.
Why did he do it, he didn’t care about heart patients and cholesterol,
he cared about fungi and he realised that fungi are resistant to parasites.
And he thought that the fungi secrete some anti-cholesterol synthesising drug
so the parasite that infects the fungi cannot synthesise this cell wall.
And he screened different fungi for different anti-cholesterol synthesising drug and he found the statins.
Now what the statins are doing, the statin inhibit cholesterol synthesis at one point,
they inhibit the key regulatory glutaryl enzyme of cholesterol synthesis
which is called HMG or hydroxymethyl glutaryl coenzyme A reductase.
The fungi were forgotten, the parasite were forgotten and statin has become a $20 billion a year
selling drug to reduce the level of cholesterol in patients that suffer high cholesterol level
and suffer myocardial infraction or heart attack in the lay language.
So much so that recently there was a huge clinical experiment by the name of JUPITER
in which people tried statins on healthy patients but these healthy patients were prone
to be already sensitive to develop in the future heart attack, they had some marker which is called CRP or C-reactive protein.
And it turned out that it reduced the probability of suffering heart attack tremendously.
So this immediately increased the number of the patients that are taking statin.
A new experiment is going now, right now all over the world in which completely healthy patients are taking statin
and the prediction is that it will reduce completely,
it will reduce significantly the rate of heart attack in healthy patients that sometime in the future will develop heart attack.
Just to show you and here is the coronary artery with the cholesterol that accumulates,
that at the end occludes the lumen of the coronary space, doesn’t let blood flow into the heart and causes heart attack.
And what the statins are doing, they are reducing the amount of cholesterol and do not let it accumulate
and even regress already existing atheromatosis lesions.
Statins are being consumed now by millions and millions of people all over the world
and the prediction that the number will grow tremendously and here you can see the joke.
"I have an idea, let’s drug half of the population", and then it says "I have a better idea,
let’s get everyone to pay us for those drugs."
And then a third one says "I have the best idea, let’s call it a medicine."
So the idea will be that statins at the end will be added to, as food additive, like vitamins to our diet.
I mean that’s not going to happen probably but it’s just the prediction of what is going to happen with this drug.
Now again, like aspirin we don’t know what's going in with statins, it looks that statins are preventing Alzheimer,
they are preventing malignant transformation, there is a linkage between proteins
that carry cholesterol up or before in prevalence of Alzheimer disease,
I don’t want to go into this linkage but it looks that statins have a far long term and long distant effect
that we thought originally just on heart diseases which are large enough in the western population.
But it will go far beyond reducing the cholesterol level in the coronary arteries.
So this drug which is a huge block buster nowadays,
by the way the biosynthetic pathway also won the Nobel Prize to a wonderful scientist, to Mike Brown and Joe Goldstein in ’85.
So you see that understanding of mechanisms at the end leads to development of drug and vice versa.
So this is the story of statin and I call it the second revolution.
Now let’s go to the third revolution.
The third revolution is not going to be serendipitous at all and it’s going to be designed and planned.
And it’s the era of planning, understanding the mechanism first followed by targeted drug design.
We are going to understand exactly what's going on.
I’ll give you few example of what I mean and then we’ll go to the problems.
Well current medicine is awfully primitive, it’s one size fits all.
What is one size fits all.
A woman or a man walk to the clinic, the woman has, 2 women have a lump in their breast,
the 2 men have been diagnosed with prostate cancer, doesn’t matter, and it looks the same, all x-rays,
all imaging, MRI show that there are no metastasis in the bones for the men from the prostate or otherwise for the woman
and everything looks the same in the men, the 2 pairs are being treated with the same treatment.
Five years later, one woman is dead and one woman is completely disease-free.
The same for the men, one man with the prostate cancer sent metastasis to the bone and died in agony,
the other man is completely disease-free.
How come?
It means that the 2 women and the 2 men did not have the same disease.
We illused ourselves because we used the very primitive tools to think that they have the same disease.
What did we use, we used some imaging technology and we used the microscope, we asked the pathologist,
tell us what is this cancer, is it grade 1, grade 4,
how does it look but this is far away from what's really going in the cancerous cell.
It’s far away from understanding the mechanism, the signal transduction pathways.
We didn’t approach it all, we didn’t scratch even the surface of the diseases in doing the diagnoses.
We treated them the same.
But actually one of them was treated correctly and the other one was treated erroneously, wrongly
because we didn’t treat the disease.
What is the problem, the problem is again that we are one size fits all,
we have one treatment or one first line of defence and then a second line of defence
for what we think is the same disease but it’s not the same disease.
So here you have a group of patients with a certain disease, some of them will respond,
those will respond but those will not respond.
And the problem will be to sort out the responders from the non responders.
And we are doing it molecularly.
Here are 2 women, 1 woman has an oestrogen receptor in the breast tumour, you can see here,
it’s immunohistochemically stained and one woman doesn’t have it.
It will be a waste to treat this woman with Tamoxifen that is an anti-oestrogen receptor drug because she will not respond.
But it will be very wise to treat this woman with an anti-oestrogen receptor drug because she will respond,
this is called molecular diagnoses.
We are not just looking at the tumour, we are not just looking whether the tumour has sent metastasis.
But we are asking what is the difference between the 2 tumours molecularly.
And fit the treatment individually to one woman but not to the other.
The problem is, what we are going to do with this woman, this is the problem, what we are going to do with this woman?
And the story can go on and on and what is now being developed gradually is personalised medicine.
But we are seeing only the tip of the ice berg and the same is for Herceptin, it’s another antibody,
I will not go and bring you numerous examples, where we are designing drugs to causing proteins, to causing agents of tumours.
So Herceptin is an antibody, just one example, it’s an antibody that is targeted against HER2 which is an EGF receptor.
And the EGF receptor in this case is mutated and it signals to the cell all the time
and the cells divide in an uncontrolled manner.
We are taking the antibody, the antibody neutralises the receptor and leads it to internalisation into the cell
and to its destruction.
Now some woman will have the mutated receptor and some woman will not have the mutated receptor.
Those that have the mutated receptor should be treated with Herceptin
and those that don’t have the mutated receptor should not be treated with Herceptin.
And again we have to take a biopsy, we have to stain the biopsy, we have to do some PCR in order to amplify the tumour,
in order to diagnose the mutation and only then to decide on the treatment.
So again these 2 women that apparently look the same, should be diagnosed at the deepest molecular level.
Let’s leave this design and go further of what the future entails for us.
The markers that we have discovered so far are very few.
At the end we need to sequence the entire human genome of the diseased patient.
You will tell me well the human genome was sequenced already, we know all about it.
No you know nothing about it, it’s the human genome of one single person that walks on the face of earth that was sequenced.
And it took more than 10 years and more than $10 billion to do it.
The idea now is to sequence the human genome of each and every one of us if necessary and we’ll come to the problems in a minute.
But how this is possible, it takes 10 years and $10 million, who can afford it.
Well novel technologies can afford it.
And we are driving now to a point and I apologise that you cannot see here,
but it says here to drive down the cost of sequencing to $1,000 for genome.
We are now already at $10,000 per genome, so the genome in each and every one of us can be sequenced by $10,000.
Within 5 years it will be $1,000 and more than that it will take about 15 minutes.
The computer technology, the informatics will enable to use now sequencing of each and every genome like an MRI,
like a CAT scan, like a simple biochemical test that is going on in the lab.
Now what this will give us, if we take the human genome of a disease patient or of the tumour itself
and of a healthy tissue, we’ll be able to compare the 2 and to identify all the mutations in the disease tissue.
Now this is not a drug yet, the road is extremely long but once we identify the targets like the oestrogen receptor,
like the EGF receptor that I pointed out, there will be many more targets and this many more targets will be sequenced.
The 3 dimensional structure will be determined and people will be able to design,
to chemically design drugs by planning that will fit into the active site and inhibit it,
like we are inhibiting today other targets in the body.
So this will be the era of design, that will require a lot of interdisciplinary efforts
between protein structural biologists, between synthetic chemists, between designers, between computer scientists,
we are moving now into an era of design that one single person from one single discipline will not be able to do it anymore.
Now so we are moving into interdisciplinarity, I hope to tell you about it a bit later, maybe in the afternoon
but I just want to conclude with the problems that we are facing.
Everything looks ideal, the road map looks like it’s taking us to the solution and indeed it does take us to the solution.
But there are many roadblocks, one roadblock is that many diseases, metabolic, psychiatric or multigenic, we are not,
you know we are going to identify several genes and they are going to interplay between one another,
how we are going to sort them out.
And which role each plays and in the hierarchy who is first, that will be worth to inhibit
and who is the second and the third that inhibiting them will be less worthy.
Malignancies are characterised by genomic instability.
We attack the malignancy from the door, it will come from the window,
we attack it from the window it will come from the ceiling.
We attack it from the ceiling it will penetrate from the floor.
You know targets are changing all the time, the cancerous cell is extremely clever and extremely wise and it escape,
it evades all the time therapy.
It doesn’t want to be treated, it has a target to attack, to divide and to evade treatment.
So even if we describe and we identify new targets, it’s not certain that we’ll be able to really nail them down.
Human experimentation is complicated, I don’t want,
maybe in the afternoon to tell you about hormone replacement therapy for women after menopause
or what the stents that enlarge the lumen of the coronary arteries,
what revolution they brought and how the pendulum move from left to right with stenting the coronary arteries.
But we need to do at the end human experimentation and they bring us very surprising result,
far away from the result that we are getting in the lab.
Like a faithful animal models, neuro-degeneration, metabolic diseases, malignancies.
The huge research into malignancies didn’t yield the real revolution that we are expecting,
so much because a mouse is not a human being at the end.
The cost of developing new drugs, companies will not go to develop new drugs for the Third World,
this is an extremely difficult problem because they are not going to make the money that they are expecting to make.
But the last one is the one that I want to touch in my last 2 minutes.
And that’s bioethical problem of availability of genetic information.
Science is wonderful but there are human beings behind, there are societies behind,
there are cultures behind, there are histories behind and languages and variability among people.
And we should all not only respect but admire this variability of the society that we are living in.
Now think about it, that in the future we are going to know what are the genes that will lead to psychiatric diseases,
to depression, to schizophrenia, to heart diseases, to malignancies.
And we shall be able to issue an ID card to an embryo before it even saw the light of the sun.
Think about the risks and the huge dangerous potential in this information.
Who is going to use this information, my government in recruiting me to the army
when the government would like to have only the best soldiers?
My employer that wants to have only the most intelligent fellow or woman working for him.
But that’s ok, let’s say that we shall be able to protect the information in a deep buried 30 metres under the ground vault
that have 1 metre thick stainless steel wall.
What about ourselves, do we want to know the information or don’t we want to know the information.
You will say well I don’t care, I don’t want to know the information, whatever happens to me happens to me.
I will give you an example that you do want to know the information.
Or if you don’t want to know the information you will be forced to know the information
and I will give you just one example and I’ll finish with that.
A woman got a breast cancer and it was discovered that she has a sensitive gene that causes breast cancer
and it’s called BRCA1 which happens to be an element of the ubiquitin system that we discovered in the past.
I don’t want to go into it.
But bearing the mutated BRCA1 gene carries with it a risk of 80% of getting breast cancer
and a high chance of getting ovarian cancer.
So the woman says fine, I’ll take the tumour out and my ovaries out,
will she tell her daughter that the daughter is at risk, the daughter is a 21-year-old college woman, beautiful lady.
And the daughter will have a choice in her life, whether to make preventive mastectomy or not.
But then it’s again in the family.
But let’s say that the daughter is now dating a nice fellow and she is going to marry him,
will she tell her fiancé that she, the one that he fell in love with, has a risk of 80% of getting breast cancer.
What are the problems behind, the moral problems behind?
And so on and so forth.
And there are many, many examples.
So you see that this woman, who all of a sudden while bathing felt that she has a lump in her left breast or right breast,
all of a sudden faces a problem that goes much beyond her own tumours.
It goes to her daughter and it goes to her grandchildren and it goes to the faith of the fiancé
and the whole family is all of a sudden engaged in an unbelievable piece of information that they have to handle.
And it goes on and on.
All I wanted to tell you, it was my view of the revolution in medicine but we are in it, there is no choice,
but also to throw a word of caution that this is not just science in the test tube, there are human beings behind it.
Thank you very much.
(applause).