A microbe fighter at 90

Twenty years after his retirement, Prof. Nathan Citri has invented an ingenious kit to fight back against bacterial resistance.

By
April 8, 2012 03:27
PROF. NATHAN CITRI

PROF. NATHAN CITRI 370. (photo credit: Judy Siegel-Itzkovich)

 
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Retired university professors typically rest on their laurels after many years of teaching and research and take it easy. Not so for Hebrew University Faculty of Medicine emeritus professor Nathan Citri. Two decades after his retirement, the veteran microbiology expert has developed a novel kit enabling speedy detection of multidrugand extremely antibiotics-resistant “superbugs” and providing instant guidelines for patients’ appropriate treatment in hospitals.

His invention will improve patient care, save lives, shorten hospital stays and significantly reduce healthcare costs around the world, according to Yissum, HU’s research and development company, which recently signed a licensing agreement for commercializing the kits with BioConnections, a microbiology company in the UK.

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The Polish-born Citri, who marks his 91st birthday this month, was in March one of 27 HU researchers to be honored in a permanent photo exhibition on the Mount Scopus campus’s Innovators’ Way.

“I hardly dealt with bacteria until the last two or three years,” Citri told The Jerusalem Post in an interview in his apartment in Jerusalem’s retirement residence Nofim.

“Twenty years after I went on pension, I became a microbe hunter,” he said with some irony. It was 80 years ago that he first read the classic book Microbe Hunters by US microbiologist and author Paul de Kruif – which remains a bestseller – which piqued his interest in science and has remained high on lists of recommended science texts.

After finding little interest in the kit idea among Israeli pharmaceutical and medical supply companies, he went to London and met Prof. David Livermore, an expert in medical microbiology at the University of East Anglia who is also a senior authority on antibiotic resistance at England’s Health Protection Agency. “He is the world’s opinion leader on this subject. He immediately understood exactly what I was talking about,” said Citri. “He was on his way from Japan to chair a conference on antibiotics resistance in the US and we met when he stopped in London.” The deal with BioConnections was the result.

Today, antibiotics against streptococci or syphilis, for example, still work, but not those against a growing number of bacteria.



In antibiotic resistance, the microorganism is able to survive exposure to an antibiotic. If people who have a viral infection unnecessarily take antibiotics meant for fighting bacteria, or if antibiotics are otherwise overused, stronger bacteria will evolve. As a spontaneous or induced genetic mutation in bacteria may make them resistant to common antibiotics, genes that confer resistance can be transferred between bacteria in a horizontal fashion by conjugation, transduction or transformation. Exposure to antibiotics then selects for the antibiotic resistant trait.

“Bacteria are the great survivors; humanity is a short episode. We have to learn from them,” Citri warns.

As pharmaceutical companies don’t find it financially worthwhile to develop new antibiotics, doctors’ weapons against increasingly resistant bacteria have been reduced, which could mean deaths. Thus the handful of most powerful antibiotics that remain in the physicians’ armory have to be saved to fight the pathogens in patients who really need them. That is exactly why Citri’s kit is such a boon. “It will help prevent the spread of bacteria. In 15 minutes, the result shown by my kit will tell doctors whether to isolate the patient and what antibiotics are appropriate.

Using the conventional technology, doctors have to wait for days to get an answer from the lab, during which the number of resistant bacteria multiplies many times over.”

The World Health Organization recently called on medical institutions around the world to stop giving antibiotics when there was no evidence that they were needed and effective. In fact, antibiotic resistance was the theme for World Health Day last year.

“When the first antibiotics were introduced in the 1940s, they were hailed as ‘wonder drugs,’ the miracles of modern medicine,” said WHO director-general Dr. Margaret Chan. “With hospitals now the hotbeds for highly resistant pathogens, the world is on the brink of losing these miracle cures. The speed with which these drugs are being lost far outpaces the development of replacement drugs.

“In the US alone, antibiotic-resistant infections are responsible for eight million additional hospital stays annually and for the consequent bed-to-bed spread of resistance, taking a toll of $20 billion per year in excess healthcare costs and $35 billion a year in societal costs.”

“But until my kits become widely available,” commented Citri, “there is no way to implement this recommendation fast enough because the physician doesn’t know whether using the antibiotic is justified or not. Humanity is facing the end of the antibiotic era – and it’s our own fault!” The unique identification kits are based on a chemical reaction that directly tests for the presence of the antibiotic-destroying enzymes called beta-lactamases, which are found in all multidrug-resistant bacteria. The kits enable direct and precise recognition of bacterial resistance to all members of the beta-lactam family, which include penicillins, cephalosporins and carbapenems.

The kits are modular, disposable arrays of spots impregnated with several types of antibiotics. The exact combination can be easily varied according to need. Unprocessed samples of any specimen to be tested (such as blood or urine) are placed directly on the array spots, which are then covered by a lid containing a dark indicator dye. If the sample contains bacteria that can destroy the antibiotic impregnated in a particular spot, the dark indicator dye facing that spot becomes lighter, exposing the antibiotic resistance within minutes.

The modular kits will thus alert doctors to the presence of multi-drug-resistant (MDR) or extremely drug-resistant (XDR) bacteria, warn which antibiotics will be futile and indeed wrong to use and inform which, if any, still constitute a treatment option. Thus, for the first time, evidence-based guidance for appropriate treatment can be made available without delay. Furthermore, treatment efficacy can be easily assessed by real-time monitoring.

The kits not only detect the presence of bacteria resistant to antibiotics, but also offer immediate information on the type of antibiotic that may still be of use.

At present, antibiotic resistance assays used in the lab are indirect and consume precious days of testing. Citri’s approach of using enzyme identification kits enables a direct visualization of the activity of betalactamase, the resistance conferring enzyme. The information on the presence and activity spectrum of the enzyme is received within minutes, and enables evidence- based treatment.

Ken Denton, CEO of BioConnections, said: “We are very excited with this new partnership. The first kits are in the last stages of development, and we hope it will reach the market within months. In parallel, we have applied for a CE mark for marketing of the kits in Europe.”

“We are pleased to collaborate with Bio- Connections for the commercialization of this invention,” said Yissum CEO Yaacov Michlin. “Drug-resistant gut bacteria present the most alarming, imminent threat to our ability to control infectious diseases. In order to contain its spread, a case of multidrug resistance should be promptly isolated and treated with the one or two last-resort drugs that may still work. However, currently available techniques for identifying drug-resistant bacteria are slow or hardly accessible, and evidence-based decisions are delayed for days. Prof. Citri’s invention... is an extremely important step in our fight against antibiotic resistance and one that will not only greatly improve patient care, but will also save billions of dollars in healthcare expenses related to antibiotic resistant bacteria.”

CITRI NEVER intended to become a scientist, but to be a farmer in a kibbutz. It was the Holocaust – to which he lost most of his family – that persuaded him otherwise.

He was born with the name Natan Cytrynowski on April 21, 1921, in Lodz. His father, Yechiel, was a Hebraist, Zionist and painter and worked as a Hebrew teacher in the Yavne private Hebrew coed high school in the Polish city. Later he became principal of the school. Coming from a hassidic family, Yechiel rebelled against haredi life and was the only member of his family who became a Zionist. His Russian-born mother, Genia, taught Hebrew language and literature in high schools for girls. Natan and his younger sister Miriam were thus raised in a Hebrew-speaking home where Zionism and moving to the Jewish homeland were pervasive ideas.

When a Youth Aliya emissary arrived in Lodz in 1936 to rescue Jewish children, Natan insisted on going the following year to Palestine, with the family planning to join him as soon as possible. “I was the only one to survive. I owe everything to [Youth Aliya] founder Henrietta Szold. Youth Aliya was one of the greatest accomplishments by humanity.”

In 1939, Yechiel traveled to Palestine to look for work and try to get entry for himself and his family. He was offered an excellent position and went to bring his wife and daughter, but they did not make it out of Europe in time.

As World War II broke out, the three moved to Warsaw, where they were forced into the ghetto. Genia died in 1942; Yechiel was transported to Treblinka, where he met his death; and Miriam, who slapped a Nazi officer in Auschwitz, was shot by him and killed on the spot.

Natan went to study at Ben-Shemen (now-President Shimon Peres was two years younger and “apparently doesn’t remember me”). Then he volunteered for the British Army in 1942 and remained until 1946.

“My father had drawn a scroll for the opening of the Hebrew University back in the ’20s. I was less than four years old when I saw him doing it. By accident, I pushed his finger,” Citri recalled. The scroll was sent to Jerusalem for the opening. When Natan was an IDF commander at Mount Scopus during the War of Independence, he found scrolls on the floor of the shelled library. “I looked for his scroll and found it; I identified it by the centerpiece – the dome of the library – and found the place where I had pushed his finger. He hadn’t changed it.”

For a while Citri kept his original name in the hope of being identified by Holocaust survivor relatives, but then, when no one was found, he shortened it.

Finally out of uniform, Citri remembered the call of Labor Zionist leader Berl Katznelson to fill the ranks of Jewish intellectuals lost in the Holocaust. Instead of becoming a farmer, he decided to be an academic at the Hebrew University. “But I lacked a matriculation certificate. Without it, I had to be tested in eight subjects. I studied for weeks round the clock and passed. I was accepted to study bacteriology, but studied general science and then parasitology instead.”

With his first wife, Citri had a son – “a brilliant neurobiologist who was killed in 1995 in an accident,” and a daughter, who is a social worker at Hadassah University Medical Center. His second wife, Naomi, gave birth to a son, who is now completing work at Stanford University in California and is coming to work at HU’s natural sciences faculty soon.

Since Naomi died of illness last year, his book- and test-tube filled apartment in Nofim is shared by Lorena, a Filipina caregiver.

Citri has six granddaughters and three great-grandchildren.

He notes sadly that the children and grandchildren of many in the elder residence live abroad. “In Israel, when I do something, I can see the blessings. I can make a contribution. In the US, what I do would not make a difference,” he concluded.

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