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And we will go live to the small intestine

A tiny pill developed by an Israeli company in Mikneam fulfills Isaac Asimov's vision. It is equipped with a tiny color video camera, flash, watch batteries, a tiny transmitter and an antenna and allows scanning and photographing the mysteries of the body and its diseases from the inside. You just have to swallow, and stick to the screen

By Amira Segev

The photo pill of Givan Imaging
The photo pill of Givan Imaging

This is no longer surprising: what was considered science fiction in the not-so-distant past is today an almost self-evident technological reality. Isaac Asimov's microscopic submarine in his "Fantastic Voyage", which was injected into a person's blood system to destroy a clot before it reached the brain and was excreted in a tear, and its sister, in the film "A Day in the Trap", which conducts chases between the various body systems, are valid scientific targets today. When the field of biomedical research and development in Israel is today in second place in the world after the United States in the number of companies active in it, it is only natural that the latest invention originates from an Israeli mind and its (partial) American execution.

This is a pill made by the company "Givan Imaging" in Mikneam, named: M2A, one centimeter in diameter and 2.6 cm long, and it is equipped with a tiny color video camera, a flash, wrist watch batteries, a tiny transmitter and an antenna. Its stated goal is to scan the small intestine, which existing techniques, including X-ray and CT, fail to document what is happening in it. But in fact she takes pictures of everything, until the batteries run out. The subject swallows the pill, continues his normal routine, and expels it naturally. The video camera in the pill records 8-6 hours of its natural course in the digestive tract, and transmits the images to a receiver the size of a Walkman that is tied to the subject's waist.

The film is processed using a special software, rapid, which is also a development of the company, and projected onto a computer screen, alongside a computerized recording that records the exact location in the intestine of each image, when at any stage you can freeze each image and enlarge it, on the same screen. The edited film, the whole or a clip of the suspicious segments only, will be sent via e-mail to the attending physician for diagnosis and treatment, and will assist the surgeon in locating the exact location where he will need to operate.

In the first stage, the pill is supposed to replace the scanning test using the endoscope - a tube about two meters long into which an optical fiber is threaded - which is inserted into the small intestine through the subject's mouth or nose, a test that is very difficult to pass without a smear injection. Among the twenty or so patents already registered by the company are not only those that make up the current development, but also the components of the next steps whose development has not yet begun. In the future, the heads of the company hope and estimate, the developments of the pill will not only replace the nightmare of examination using the endoscope and gastroscope (insertion of a tube through the anus into the lower part of the digestive system and large intestine), but also, like them, they will be able to take samples from suspicious areas and treat the problems they find.

Modern medicine today is almost as interested in the patient as in the disease from which he suffers and strives to develop less traumatic tests. The gastroenterological examinations are among the most intrusive and horrible, but in the spirit of concern for the patient's well-being, tiny cameras like the M2A will probably be invented in the future to replace, for example, the x-ray of the uterus, a clearly unpleasant process, or the painful lumbar puncture aimed at examining the bone marrow. These cameras will wander through the bloodstream or between the lymph nodes, open adhesions, locate turbidity and take a sample from it, and there are endless other possibilities.

In an experiment conducted by the "Diversity Imaging" people on animals, their pill shoots small charges into the wall of the intestine so that it contracts and pushes it further. The possibility that in the future the charge you will shoot will be a chemotherapy drug or a laser beam seems just as logical. "There is no limit to the possibilities," says Dr. Arkady Glukovsky, Vice President of "Diversity Imaging" for research and development. "Science has long been non-fiction".

A pill for $300

An atmosphere of celebration reigns in the company's offices in Kneam. This was probably the atmosphere in Mirabilis or Chromatis when it became clear that their technologies were going to be sold for huge sums. Rashya has just returned from San Diego, from the world's largest gastro exhibition, where their invention was a big hit. They do not elaborate on proposals to sell the technology they developed - based on an invention by Dr. Gabriel Idan, a former missile scientist from Raf'el. As long as they haven't exhausted the entire range of future possibilities of the invention, they say, there's no way they'll let someone take it from them, even at an astronomical price.

Approval by the FDA, the American Food and Drug Administration, to start clinical trials of the pill in humans is expected soon, as well as approval by the Israeli Ministry of Health. "I assume we will receive the approvals by the end of the year," says Dr. Gabi Maron, CEO and president of the company. "To date, twenty healthy volunteers have tried the pill, including me and others in the company. All reported easy ingestion and unproblematic excretion. You just don't feel anything." All volunteers who swallowed the pill were interested. Why didn't you allow me to take it, for a trial?

"You're not the only one who asked. We have many requests, from journalists, investors, but we prefer to get all the approvals first and, of course, give it to such people, so that when it comes out it will be under our control." Are you afraid that someone will swallow the pill here and spit it out at competitors in Tokyo for example?

"Something like that. Yes. And it doesn't matter that only 'interested parties' tried the pill. After all, if we create a product that cannot be swallowed easily, we are only deceiving ourselves." You can use it over and over again, right? After all, even the coating is indestructible.

"I don't think so. The parts really remain intact inside and whoever wants to can dig in the feces and extract them, but the selling price of the pill, around $300, is low enough, so I don't think anyone will bother."

Maron refuses to talk about the profit component of the quoted price. "Certainly the production costs will be less than $300, otherwise I don't have a product. From the responses I have received so far from doctors around the world, this is a reasonable price and even lower than that."

missile technology

Five years ago, Dr. Gabriel Idan, head of the Rafael missile array, went on a sabbatical in Boston and met Prof. Eitan Scafe, a gastroenterologist from Assaf Harofeh Hospital. The friendship between the two, and Scapa's explanations about the digestive system and the difficulties in diagnostic tests in its intricacies, ignited Idan, who, in order to first understand the existing horror, underwent a colonoscopy himself. Together with his team at Raphael, he designed a small missile-like pill at the end of an optical eye that captures and transmits the image - an application of missile technology to transmit an image in real time. He registered a patent through Raphael for both the idea of ​​the pill and the optical method; Today the patent is fully owned by Givan Imaging.

Rafael, which is a trusted unit of the Ministry of Defense, does not have a mandate to enter private businesses, except through RDC (Rafael Development Corporation, which is owned by the state) and Gal Ram, a government company that owns shares in RDC. si. The idea behind the establishment of these subsidiaries is to trade Raphael's technologies through them. Since Raphael was unable to promote the project, Idan turned to Maron, a Doctor of Business Administration, former VP at Interfarm and former CEO of Aflitech, a company that developed and marketed endoscopy video cameras.

"It seemed to me at the time an interesting idea with far too many technological risks," says Maron. "But at the beginning of '97, when the patent was approved in the United States, the technology also advanced, especially the cmos technology, which is an innovative method for producing video cameras, and the idea started to grab me. I went to RDC, prepared a business plan and started raising money." And there were also comments along the lines of crazy people get off the roof?

"Not far from it. There were many who thought it was not applicable. Rafael's CEO himself, Giora Shelgi, said that he does not believe that from a technological point of view it is feasible. But he agreed to go for it. 'Do you think it's possible?' He said, 'Then we will see you.' But usually people immediately went for it. Discount Investments, for example, and RDC, who gave the initial investment."

For six months, says Maron, he recruited an initial team of consultants, "including Gabi Idan, who is now in Japan and serves as chief scientist at another company that is developing another of his inventions, XNUMXD video. While writing the business proposal it expanded beyond the basic idea of ​​a pill, to a platform on which it would be possible to do many more things. I started presenting the plan to quite a few people, including goals, ways to achieve them, medicine, science, technology, how much money is needed for each stage, what are the timetables for implementation, what are the expected sales and what is the estimated profit." Is there a public relations system before approaching investors?

"I guess usually yes. There was no need here. Know that these are ideas that come from a good house. But it became clear to me that it is not enough that an investor is willing to put money, the question is at what price. Venture capital fund managers in Israel have an attitude that an investment in a company that starts on the basis of a future product, will be in exchange for half of its shares based on a company value of two million dollars. This is the answer we received from all of them and it seems to us far too much. At the end of a not long process, we managed to interest a very large American company, Thermo Electron, which is its first investment in Israel, which initially invested according to a company value of six million dollars. During '98 we started recruiting the development team to realize the project. The ten people of that time are today close to forty. Today we are recruiting people, in order to double the number of staff members."

An unpleasant moment in Princeton

"The heart of the invention is two chips, the sensor and the transmitter, and both were developed especially for our company," says Dov Avni, a graduate of Rafael, where he managed a camera development project for the needs of the IDF and other entities. "Over the years, Gabi Idan would occasionally ask me, 'Well, is there already technology?' And I would tell him 'no'. Towards '98 it became clear to me from articles that there is already a way to minimize a camera. The technology also existed ten years earlier, but not for civilian use and not in a size that would allow us to use it for our needs."

Their first step was to write the technical specifications of the system. "We started looking for manufacturers who would be able to make the product according to our specifications. We traveled all over the United States, demanding two basically impossible things: size and amount of energy. In terms of energy, this sensor takes 1 milliamp, which is very, very low. And in addition, it was necessary, in the language of ordinary mortals, to find a way to photograph a dark courtyard from a lighted room through a window, without the camera being reflected in it and only it being captured in the photograph. This solution is also our patent, by the way."

If raising the initial funding went relatively easily, the development of the components encountered difficulties and mainly lack of trust. "We did market surveys," Avni says, "and we started moving between the companies and it wasn't easy. We arrived, for example, at a very famous American research institute in Philadelphia, at Princeton University, and after we explained to them for two hours what it was all about, some Jewish doctor of microelectronics stood up and said, 'You have no chance. Physically, at a body temperature of 37 degrees, you will get garbage'. It was an unpleasant moment, but we decided, despite his assertion, to bet."

Avni checked and found that the doctor was wrong. "In theory, he was right, but in practice, with a certain production method, it is possible to reach a situation where even at a temperature of 37 degrees, we will not only get garbage. And today we really get some garbage. Five percent."

Even in the American company "Photobit", he says, they were treated with great suspicion. "Their senior team came from the American research institute JPL, which developed sensors in our example for military purposes. They founded a start-up company to realize this technology, which is based on digital technology - and not analog as in the usual cameras, which wastes energy. Every week they receive offers to develop chips and they didn't believe in the idea. Chip manufacturers don't make money from development but from selling quantities, and it didn't help that we said, 'We'll buy the quantities from you.' In short, we came and went back and in the end, after another whole morning of swans, I got fed up and said about it, let's get out of here. 'Wait until after lunch,' he told me. "Today we sign with them." and so it was".

After they signed and drank to life, one of the CEOs told Avni: "What motivated me to go for it is the fact that my father died a month ago from small intestine cancer that was not diagnosed in time." Avni, who worked for some time at Alcint developing CT and saw images on the most sophisticated CT available, knew what the American CEO was talking about. "On CT you simply don't see anything, just a lace, and when you already see something it's usually too late."

PhD in every way

After the signing, a stressful development period began that lasted four months, "a lot of setbacks and problems and situations of not getting in, not reaching the power, not reaching the performance, decisions and compromises of the moment, because we set schedules. At the beginning of '99 the first chips arrived and it didn't work as it should, with the main problem being the same garbage that the scientist from Princeton talked about. We found that the external radiation interferes with one of the legs of the sensor. It took a month to find a way to protect her using electronics, and we succeeded."

Then the minimization process began. "What can I tell you, we did a doctorate on every thread. In August we will start producing pilots and everything, I hope, will run. Pasadena-based Photobit manufactured the sensor. The design of the transmitter was done in Israel, by the IC-Com company, and here too it is an amazing success. The miniaturization and design of the lens was done by an Israeli specialist in optics, Dr. Hanoch Kislo, who works with us, and the entire product will be produced in Israel, without human contact, using only robots."

The promotional film produced for the gastro exhibition in the United States features two global gastro experts who joined the medical team: Prof. Paul Swain from the Royal Hospital in London and Prof. Blair Lewis from the "Mount Sinai" School of Medicine in New York. In the film, the two talk about a whole world of unknown information that will be revealed to doctors in the future, thanks to the continued development of the pill. "Their standing openly next to the product is in itself a very strong statement in the world of medicine," says Maron. But they have shares in the company, don't they?

"It's really not their motive. Although I offered them a few options, it is more important for them that their name is not attached to something that will turn out to be nonsense. If there is a doctor who owns 80% of the company, one can be suspicious. But when it comes to a few percentiles, it's another matter. The fact is that since the endoscope, which was invented 15 years ago, there has been no such progress. There is enthusiasm all over the world, from patients and doctors. It was important to us that they be enthusiastic."

I understand that they are mostly enthusiastic about the fact that you can finally see what is happening in the small intestine and less about the suffering that is saved for the subject.

"This is true".

"When Professor Lewis, in the promotional film, says that we are about to discover information that could only be dreamed of," says Dr. Arkady Glukovski, "he means, for example, discovering parameters for the duration of the digestive process in each person, and later learning what is normal. Along with the film that is projected on the computer screen, you also receive information about the structure of the patient's digestive tract movement through a time graph that is projected at the bottom of the screen, that is, how long the pill stayed in the stomach and how long in the small intestine, which will save additional tests that are done today."
like what?

"The subject is given a meal marked with a special substance and a series of X-rays are taken for him, for an entire day, to see how long it takes for it to pass through the digestive system. And this is a side effect of our pill, the whole purpose of which is to allow the doctor to be given more and more information at once. The camera is able, for example, to see a polyp in the small intestine when it is less than a tenth of a millimeter in size and to restore its shape by rewinding the film, to see its shape and exact location also in perspective, that is, in a video sequence, and this cannot be done with endoscopy. And a polyp that is smaller than five millimeters is difficult to identify on an X-ray."

The camera shoots twice a second. A polyp that is less than a tenth of a millimeter won't be missed between flashes?

"No, because the camera takes pictures while moving, which also means depth. distance. She takes pictures of practically everything multiple times, so there is no need for her to take pictures all the time. More frames, it requires more energy, the batteries will run out faster, and the shooting duration will be shorter."

How did you determine the size of the pill?

"With the help of cooperation with doctors. The goal was for it to be large enough to contain the electronics and small enough to be easily swallowed, easily emitted and easily pass through the system. All natural medicine is based on pills of this size. The goal was for the patient not to feel that he was being examined."

Can the camera detect lymphoma, for example? Injury to the lining cells of the intestine? Inflammatory process?

"Yes. In principle, everything that is seen - the camera will see."
And will she replace the endoscope?

"Not at this stage, because unlike the endoscope we do not have the ability to treat."
What about a colonoscopy?

"It may be in the future. Colon imaging also requires preparation to empty it, it is much wider and requires another technology that I believe can be developed on the basis of this platform. We have ideas and patents in the direction of a capsule in all places in the digestive system."

Why not a laser or X-ray of nearby organs through the intestinal walls?

"It's not a bad idea to continue. Thanks".

The intestines are not exactly a clean environment whereas the photography is so clean and clear. How is it that the lens does not get dirty and does not become cloudy?

"The fluids in the intestine are mostly transparent. The bowel movement that moves the pill involves the bowel touching it, which also cleans the lens, which is very smooth, so nothing sticks to it."
Doesn't it happen that the pill comes out and it turns out that she didn't take any pictures?

"just no".
There are doctors who say that with the endoscope it is possible to both take a biopsy and give spot treatment. You solved the problem of photographing the small intestine, but all the other parts can be reached and treated with other means, so why do you need your pill?

"The endoscopic examination is terrible. The patient convulses, suffocates. Not to mention that out of fear people do not come to the examination. So beyond the well-being of the patient, which is one of the most important goals for us, it is about life and death."
How long does it take from when you swallow the pill until the doctor gets the bowel picture?

"Could be within ten hours."
So for emergency room medicine the pill will not be used.

"No. But you have to take into account that it takes an average of three months from the moment the doctor determines that you need a test until it is carried out. This is about swallowing a pill and that's it."
What about radiation hazards?

"The radiation of the pill is a thousand times less than the amount allowed according to the safety standard. Three times less, for example, than the remote control of the car."

business confidentiality

Dr. Gabi Maron does not expect any bureaucratic glitches, certainly not negative answers from the FDA or the Israeli Ministry of Health. The construction of the factory where the pill will be produced is almost complete and the website that the company opened is flooded with inquiries from patients. The company "Diversity Imaging" has already hired the services of the large American company "Lehman Brothers" as exclusive bankers. Rumors about the private offering that the company is planning, as a test phase before the offering on the New York or Paris Stock Exchange, spread quickly in the business community. The hysterical demand to take part in it was answered in the negative. The heads of the company refuse to specify what amounts they will raise from the public and when, nor how much the project has cost so far.
Was there any stage where you feared that you would not be able to pick up the project?

"Absolutely not," says Maron.
And there are people who will eat their hearts out for not agreeing to join?

"The research institute from Princeton, for example. But in the end almost all those we approached responded. And besides, there's nothing else to eat your heart out about. We haven't succeeded yet."
*

The road is still long

"I think this is a very interesting and important development," says Prof. Yaron Niv, chairman of the Israeli Association for Gastroenterology and Liver Diseases, "but it is still in the very early stages, it has not yet been approved by the FDA, and we have only seen it in exhibitions so far. And so I cautiously say that I hope it will really prove itself, but at the moment there is still not enough data. It will never replace the endoscopes, whose purpose is mainly therapeutic, not just diagnostic, and its importance will be mainly for those six to seven meters of small intestine that are currently difficult to visualize endoscopically. There is only one device, called an enteroscope, which fulfills the role of imaging the small intestine, but not perfectly, so the role of the pill will be mainly for that area that is hidden from our eyes, and of course the union wishes all the best for success." The idea that the pill might in the future be able to shoot medicine doesn't intrigue you?

"Most drugs work systemically and not locally, they are absorbed through the mucosa and pass into the blood system and from there to the target, so that the local activity of a drug has its importance in its place, but that is not the main message, which is mainly visual, and first of all they have to prove themselves in this section."

Prof. Niv, like other doctors in his field, refuses to address the reluctance of patients from endoscope examinations of any kind. "We do not do unnecessary actions. Therefore, the discomfort of the tests is irrelevant, and it can be minimized if there is a good relationship between the doctor and the patient and he is given an exhaustive and reassuring explanation. The discomfort with the tests is mainly due to the patients' irrational fear of the unknown."

"A camera in a pill can reach places we have difficulty reaching," said Dr. James Frakes, president of the American Gastrointestinal Endoscopy Association, to the New York Times after seeing a demonstration of the M2A in San Diego. Although Dr. Freix claims that the images produced by the pill are not of the quality that can be achieved using the latest generation of endoscopes, he describes the display as a landmark: "The invention demonstrates that it is indeed possible to do this and there is no limit to the possibilities."

* Appeared in Haaretz newspaper, 6/7/2000, the knowledge site was part of the IOL portal until the end of 2002

3 תגובות

  1. The pill is very good but for example in my case it shows a disease that I don't have at all. It doesn't solve all the problems...don't get your hopes up

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