An Interview with Professor John Marshall
In this interview, Prof. Marshall discussed both his work on 2RT and on microwave crosslinking as well as several other topics that will be of interest to ophthalmic researchers.
I would like to thank both Ms. Zang and Ophthalmology World Report for permission to reproduce the interview, which will appear beginning in the April 2011 issue of the magazine.
An Interview with Prof John Marshall: Sitting on the Edge of Technology
By: Lei Zang, Managing Editor of Ophthalmology World Report
He is absolutely a big fish. From excimer laser, to microwave refractive correction and keratoconus treatment, and the selective retina regeneration which is considered “the retinal rejuvenation”, and numerous other achievements in scientific research, Professor John Marshall, who by background is a physicist and pathologist, has brought so much to ophthalmology. Ophthalmology World Report spoke with Prof Marshall during Beijing APAO and he said, “I am simply lucky.”
We usually think it is the wavelength of a laser that makes the difference in terms of its effect. But in SLT and 2RT, it is a different case. Could you please explain this to us?
The first thing is, contrary to popular belief, wavelength is relatively unimportant. Providing the wavelength can get through to the target, it really doesn’t matter what wavelength you use. You can use wavelength anywhere between 400 to 1400 nm in the eyes. The thing that makes the difference in terms of specificity of reaction is the duration of the laser pulse. If you put in long wavelength with millisecond pulse duration, then as the energy is degraded into the tissue, it results in heating, and the heat spreads. So the bigger the spot, and the longer the pulse, more heat spreads and more damage you do to the tissue. By contrast, if you have a short pulse and you reach the point that the mechanism is no longer the heat, it is the state change of the tissue. Almost instantaneously the tissue goes from a solid state to a liquid or gas state. You can take the YAG-laser capsulotomy as an example, in which you pulse the holes on the capsule not by heating it but producing the microplasma, and so you get the state change in the tissue and get the explosion, and the hole.
In the trabecular meshwork, if you heat it up, the net result will be scaring. You just need to make holes in the trabecular meshwork instead of closing the holes with the scars. Dr Latina’s work (on SLT) showed if you put the very short pulse over a relatively large area, because there are only a small number of pigmented cells in the trabecular meshwork, the energy will be deposited in those separated pigmented cells. Those few cells will have chemical changes, they start to release enzymes and cytokines which recruit macrophages, and the macrophages will release more enzymes. The magic thing about SLT is the pulse duration. So the technology is to be selective in the few pigmented cells, and the very short pulse combines with the energy degradation only takes place in the small areas where the pigmented cells are involved.
Any wave between 400 and 1400 nm will be absorbed by the pigmented cells and be transmitted inside the eye. The shorter the wavelength, relatively more energy will be absorbed. But it doesn’t matter what wavelength it is in that wave band. If you have a tissue where the blood vessels are quite large then you can’t deposit the blue or green light in the tissue. But in the eye the blood vessels are so small, the percentage of the energy absorbed by the blood vessels is tiny comparing with the percentage absorbed by the melanin cells in the eye.
In the early textbooks it is partially correct that the shorter the wavelength the more energy will be absorbed. But in reality, in the practical level inside the eye, all the wavelengths will have the same effect on the retina, the only difference is, are they effective on the choroid behind the retina. Theory is only useful when it explains the practical results.
So if you want specific exquisite action on the tissue, change the pulse duration not the wavelength. It just so happens that it is very easy from the manufacturing standpoint to produce lasers of 532nm, which are green.
With 2RT what we’ve actually done is with the same principle, we use the short pulsed laser, 3 nanoseconds. Again it happens to be 532nm, but it doesn’t necessarily to be 532, it’s only because it is easy to make commercially reliable laser.
In trabecular meshwork you have dispersed a few pigmented cells. In the retina, all the epithelium cells are pigmented. We can’t select the tissue, on the contrary, the tissue selects the wavelength. You have to make the laser more selective. There are two key things, one is very short pulse, two is the discontinuous beam managing.
I am sure you have seen the laser pointer with speckle pattern, some points seem bright and some points seem dim. What we do now is in our laser beam, some bits are very bright and can make cells undergo change, and the rest of the beam is not as bright so the cells don’t undergo changes. We create the selective process by designing the beam of the laser. We make the very special beam, only certain points- 20 to 30um each- within the beam are enhanced and have enough energy to cause the changes. Even if we irradiate 400um, only 15~20% of the cells within the area are affected. So if you look at the laser beam the energy is distributed in a Gaussian pattern across the beam normally, or the squares pattern. In ours the energy is distributed in tiny areas. The beauty of 2RT is, these targeted pigmented epithelial cells will release the enzymes, creating the channels in the Bruch’s membrane so the fluids can get out, while the other epithelial cells will look after the rods and cones by providing the nutrients.
What are the applications of this concept of “selectivity” in other ophthalmic lasers?
I think this will be the norm in ophthalmology. Because currently every time you fire the laser, you kill the cells in the targeted area. We always say that’s the risk to benefit the retina, but do we really need to do so?
When lasers first started to be used for treating retina, the idea was to kill all the cells, the ganglion cells, the bipolar cells, the photoreceptor cells etc. The idea was if you destroy the ischemic retina, then you stop the factors which cause new vessels to grow. Then we thought, if it’s just ischemia, if we destroy just the photoreceptor cells, you can get the same effect. Then more recently we know that all the beneficial factors come from just destroying the pigmented epithelium, which means much less destruction to vision and much more preservation of the retina.
What can 2RT do?
The initial trials were done on DME. Part of this problem is when the fluids pass from the near retinal into the choroid through epithelium and get to the level of Bruch’s membrane which is hydrophobic, the fluids can’t get out. So if you “clean up” the Bruch’s membrane, then the fluid can go. The first trial was on diabetic retinopathy and 90% of the patients got better visual acuity. The next application is certainly going to be dry AMD*. But all those inheritive retinal diseases which affect Bruch’s membrane, like Sorsby’s dystrophy, any condition in which the fluid accumulates in the retina, or in which the photoreceptor cells are dying as a result of not getting the necessary metabolites, this laser will work for.
When you think of AMD, the most important risk factor is the age. For 60, 70 years, your retina may work well, even if you have bad genes. If you can remove or reduce the aging change, i.e., retinal rejuvenation, even if you have bad genes, the effect of the bad genes may not be seen until you are dead. So instead of the gene therapy, here you just change the space on the retina.
Please tell us about microwave in refractive correction and keratoconus treatment.
Having invented the method of the use of the excimer laser for reshaping the corneal surface (PRK), the thing I don’t like is people are now doing LASIK. Because when they cut the flap, 100% of the LASIK eyes are weak. I didn’t like that. So I thought, is there any way I can stop that happening? Then came the idea of microwave.
With microwave, we don’t cut or remove anything. You just change the shape of what’s there, and then it is as strong as it was before the surgery. The problem with microwave heat effect is you can only make it last for a short time. Then I asked, how can I make the heat effect there for a long time. We looked into the cross linking of collagen.
The cross linking classically takes one hour. So I thought, “is that science right?” When we looked into the science we found out people made a few mistakes in the thinking. In the classical cross linking, you soak the cornea with riboflavin for 30 minutes, then irradiate the cornea with 3mW for 30 minutes. What will happen if we put 30mW for 3 minutes, it’s the same amount of energy. It worked! Then let’s look at the cell biology for safety issue. There is no toxicity. So we designed a new microwave machine which has more power, presents the same energy but in a much shorter time. Now I can do that in 5 minutes! Then I said, well if it takes only 5 minutes like LASIK does, I can make the 100% weak LASIK eyes strong again.
Now let’s take a look at keratoconus. The doctor tells the patient, “I am sorry you have very bad cornea, and it’s going to get worse. If I cross link it, it stays where it is, but it’s still a bad cornea.” But with microwave, you restore a nearly perfect cornea, then with the flash cross-linkage, you have a stabilized good cornea.
So you use microwave to reshape the cornea, then use cross linking to fix it.
Yes. There are two things, the microwaves change the shape. The beauty of microwave shape change is it goes through the prolate cornea with different refractive power. The same as excimer laser. Before the LASIK surgery, you have to evaluate how much you should take away, of how big an area, for how many diopters. The parameters come up with the formula. Now with microwaves it is exactly the same procedure. How much microwave we have to apply, how deep and how big an area to get the given effect. We had gone through the experience with excimer, so it was a very much short learning curve with the microwave. In our early experiments in Istanbul, we showed the linear relationship between the microwave, the time, the size of the electrode in the diopter correction. So if the patient comes, you take the topography, you enter the topography and the refraction into the computer, it tells you what is going to do. We worked on the project for 4 years and it was moving very very quickly.
There are three parts for the microwave. You have a handheld device which is like the microkeratome vacuum ring, you put that on the cornea and lock it with vacuum. Then you put on a little device which has cross valves and you center and adjust, you lock out that centration. Then you switch on the microwave. Done. The beauty of that is this can be great effective in treating keratoconus because we can correct the optical defect caused by the cone without removing any tissue, without further weakening the tissue.
Finally you use flash cross linking to fix the cornea. We have done a lot of experiments and have reached the conclusion that the most of the corneal strength is on the upper 1/3. So we only need to change the first 1/3, i.e., 140-200um, of the cornea. You just need to soak the cornea with riboflavin for 3 minutes and irradiate with ultraviolet for 2 or 3 minutes.
So you think the microwave-quick cross linking technology can be applied in LASIK procedures?
100% of the LASIK eyes are weakened and that worries me. Any engineer will tell you, over the period of the time, the weakened structure will become more and more fatigued much more rapidly. By reducing the time for cross linking we can make 100% of the LASIK eyes stronger. We can do it in a time frame that surgeons don’t find unusual. The current cross linking takes one hour, we reduced it to 5 minutes, we could’ve reduced it even further but practically 5m is a good time for the procedure.
What we suggest now is if you do a LASIK procedure, you can then use the flash cross linkage to restore the integrity of the cornea, so you get rid of the real problem of LASIK. In LASIK, you weaken the cornea depending on how deep you cut. If you cut 80-90um flap, then you take away 10% of the strength, if you cut 140um, you take away 25~30% of the strength. LASIK removes 25~30% of the strength, while cross linking increases the strength by 400 times. So that way you shouldn't see any worrying complication of the LASIK in the future.
What do you see are the promising future technologies in ophthalmic laser?
I work very closely with LenSx. I did a lot of work with them on their femtosecond laser device. I think it has great future in the lens. Maybe you could change the elastic constant of the lens and adjust the lens for presbyopia.
The real thing you should look at, in my point of view, is that Schwind has created a new 355nm ultraviolet laser for cutting the flaps. I think it has more future than femtosecond for cutting the flap. It has very high photon energy compared with infrared, so instead of having a lot of photons to get a big plasma, with a few- much less- photons you can still get the plasma, but very small, so you can make much more refined cuts in the cornea, and you could perhaps do intrastromal corrections without lifting a flap. You don’t have to make the side cuts, so you keep a strong cornea. Now it is still used to cut the flap but I think it has the potential.
How did you transfer from a physicist to a professor in ophthalmology with extraordinary achievements?
I am very lucky. I am a physicist by background and I worked very early with some very good doctors, and I became a fellow of pathology, so I am also a pathologist. I am the honorary fellow of ophthalmology and honorary fellow of optometry because I made so many scientific contributions to so many fields, they adopted me like an “orphan child”.
From my PhD -- it was the very beginning of the lasers -- I was involved with laser safety working with World Health Organization, International Red Cross, every safety committee. And I wrote many of the codes of practice for safety, so my primary concern is always safety. I don’t want to endanger anybody. The first thing is safety, the second thing is efficacy. Is it safe? Does it work? Does it work well? Can we make it better and safe? All the time.
The biggest scientific advancements are always made when you apply one technology to another area. I have always sat on the edge of technology looking for opportunities, hence the excimer laser came from the work people were doing in the print industry. Printers were using excimer laser to make very fine plates for printing, then I thought, “wow, we can do it in the eye, then we could correct the refractive errors.” Always I think from one area to another.
I do a lot of science. Many clinicians see a problem, and think, “I am treating that problem then I don’t have to think about it anymore.” But I always think, how can I make it better, is there any other way doing that?
You always should be looking at the next technology cliff. I always think -- you know candles for lighting -- if I worked for a candle making company, what would I have thought when Edison came along with the electric light? The candle company might say “go away we make candles”, but in 2 or 3 years, the electric light went to everywhere! I always look into the next technology.
You have made so many achievements. Any advice to our readers?
I worked with two sorts of professors. There are some professors who think they are so good that they don’t want any competition, so they don’t have lots of bright people around them. The second sort of professors always want the challenge and new ideas.
I always want bright people to come and work with me, and challenge me. In my lab, what I say means nothing, the students should always ask why and always challenge everything I say. What I love is never to defend the science, but always look into the weaknesses. I tell all my students to look into the weaknesses. Because if you can’t find one, maybe this science is right. If you can find one, then that’s the future research. In my lab, everybody is on a first name basis, and anybody can ask anybody to defend what they say. Everyone has to know why he/she is doing the thing.
Always encourage young people to challenge you, never pretend you know everything. The young people are the future and their questions always cause me thinking. Dare always to question.
So to go back to your question, I have always been surrounded by smart people, young smart people, always.
What is the science behind 2RT?
Retinal Regeneration, 2RT (Ellex), is designed to treat a range of retinal diseases caused by a compromised retinal pigment epithelium (RPE) and Bruch’s membrane, the structures responsible for transporting the energy supply to, and removing the waste from, the retinal photoreceptors. 2RT stimulates a biological healing process that results in cellular regeneration, reversing these impaired transport mechanisms. Laboratory studies undertaken by Professor John Marshall, PhD, FRCPath, FRCOphth (Hon), at St. Thomas’ Hospital, London, UK, demonstrated that 2RT rejuvenates the entire transport mechanism of the retina and improves hydraulic conductivity of Bruch’s membrane.