The Doctor Weighs In

By Dov Michaeli MD, Ph.D

Sunday, May 18, 2008.

Israel is a country of unrelenting tensions: between religious and secular, between left-leaning peaceniks and right wing uncompromising hawks, between rich and poor. These are universal tensions; we have them here as well. But here is one that is unique to the history of Israel: tension between those who saw Israel as a place of refuge and renewal of a nation, and those who saw it as a spiritual place, radiating enlightenment and reason to the rest of the world—the embodiment of the biblical “light unto the nations”.

The “practical” wing of Zionism was headed by young socialists from Eastern Europe like David Ben Gurion, who advocated the creation of “facts on the ground” in the form of collective farms (Kibbutzim), and industrial enterprises owned by the labor unions. They succeeded in creating an egalitarian society with all its wonderful attributes and inescapable shortcomings.

The “intellectual” wing of the Zionist movement was populated with thinkers, writers, and philosophers; they earned the disdain and ridicule of the socialist “doers”. But not all were hopeless dreamers. One of the leaders of “spiritual Zionism” as they were called, was a professor of Chemistry at Manchester University, Chaim Weizmann. As it often happens, being in the right place at the right time can change the course of history. Professor Weizmann devised a way to manufacture synthetic acetone on a large scale, and that discovery came at a time when the British were bogged down in the unwinnable trench warfare of WWI. To win they needed high explosives for the artillery, and to make the explosives they needed acetone. Weizmann gave it to them on a silver platter, and together with the development of the tank the battle in France took a decisive turn; Germany was quickly defeated. As the story goes, Weizmann was received by the British Prime Minister Lloyd George and was asked to name his reward. He asked for a national home for the Jews in Palestine. Apocryphal, to be sure, but a few months following that meeting, on November 2 1917, Lord Balfour, the Foreign Minister, issued a declaration of creating a national home for the Jews in Palestine. In 1948, when Israel was created, Chaim Weizmann was elected its first president. Weizmann did not retire to political life; he continued to head the research institute he established in Rehovot, later named after him, the Weizmann Institute of Science. This institute attracted some of the best scientific minds of the time, and it is still regarded as one of the prime scientific research institutes in the world. The fourth president of Israel, Ephraim Katzir, was also a professor, of biochemistry, at the Insitute. And he too continued to run his laboratory while serving his term (1973 - 1978).

The critical role of science in the birth of the state of Israel has not abated. In fact, it has grown immensely. Today, every large technology company has an R&D center in Israel. I traveled this morning north, from Tel Aviv to a place called Herzliya, and saw the campuses of Microsoft, IBM, Oracle, SAP, Hewlett-Packard, Google, to name a few.

A news item on the radio: Steve Ballmer, Microsoft’s CEO, opened today the company’s new R&D center in Herzliya, and stated that it was second in size to the one in the U.S, and in terms of size relative to the population it was the biggest.

And then there is the story of Intel. About 5 years ago Intel was on the ropes because its engineers in Silicon Valley developed faster and faster chips, at tremendous power consumption and heat generation. They were obsessed with more power, more speed, at any cost. Very much like Detroit and its power hungry machines. Consumers like Dell and Google turned  to the more economical products of AMD, and Intel saw its market share plunge. It was the Israeli Intel scientists in Haifa, who defied Intel HQ's testosterone-charged strategy and quietly developed the low power chipset, called Centrino, that saved Intel from self destruction. Another Israeli/Intel chip, code named Penryn, is the first eco-friendly  chipset--it does not contain lead and halogen - is due to be introduced later this year. Gordon Moore, the legendary co-founder of Intel, called it "the most revolutionary transistor development in the last 40 years".

Another index of scientific creativity and excellence: Israel, a country of 7 million people, is second to the U.S. in the number of technology and biotechnology companies trading on the NASDAQ.

Speaking of cars and green technology: Shai Agassi, an Israeli engineer and entrepreneur, is in the process of developing a plug-in electric car that will have a range of about 200 miles, go up to 90 miles an hour, and use off-the-shelf, readily available technology. Part of the business plan is to build battery charging stations throughout the country, where a car can pull in for charging up the battery, and where a change of battery will take less time than filling a tank of gasoline. The venture was started six months ago and the first cars will go on the market in 2009, and in 2010 will be marketed in Holland. This is lightening speed; just a change of model takes GM or Ford  a minimum of 3 years from design to maket.

Why can’t we do it?

Why is it that such a small country with virtually no natural resources can outdo us in creativity and entrepreneurship – what we call Yankee ingenuity? I think the answer lies in the attitude toward science in public policy. The legacy of Chaim Weizmann, its first president, lives on. Shimon Peres, Israel’s current president, convened last week a conference of hundreds (!) of scientists, engineers, architects, environmentalists, entrepreneurs, thinkers, philosophers, historians, from around the world (among them ten Nobel prize winners)– all grappling with and contributing to an overarching question: where should the country be in the next 60 years. This was not one of those ceremonial shows for public relations consumption; it was a serious endeavor at strategic planning. It lasted a full week; it will be published; and it will form the basis for the country’s blueprint for public policy. Today, Al Gore received one of Israel’s highest honors (the David Prize) for his environmental work. He, in turn, praised Israel for its extensive reforestation project and for its solar energy use. These events received wide coverage in the media; the news hour on channel 2 (the most popular) devoted over 15 minutes to coverage of the science-related events.

You can see my point: Israel did not declare war on science, it embraced it. Why can Israel resolve its ethical issues regarding stem cell research and move on to become one of most advanced centers in this field, while we are held captive by backward-looking troglodytes? Why can Israel, the birthplace of the Bible, accept the fact that the world was not created 5400 years ago and that evolution should be taught in school, while we have to fight off creationists and similar crackpots? Why can Israel see an opportunity in green technology while we are still arguing if global warming is real? Why can Israel have courses in computer science in middle and high school curricula while we are graduating students who can’t read and comprehend a simple sentence? Why can the Israeli president engage the world scientific community while our president does not know the name of his Science Adviser? Why can’t we think strategically and plan for the future? There are so many whys…

Our size and wealth will not help us in the long run; we won’t be able to buy our way out of this rut. Foreign scientists, engineers and entrepreneurs who once stayed here for the high salaries and  the unlimited opportunities are now leaving in great numbers for greener pastures. Remember the dinosaurs? When the earthshaking catastrophe happened they couldn’t adapt fast enough and became extinct. It was the small and agile mammals that survived and thrived.

Stay tuned.

By Dov Michaeli MD, Ph.D

While researching yesterday’s blog (“The Anatomy of an Exotic epidemic: When Science and Politics Collide”), my interest was piqued by an interesting article in the journal Nature by none other than Jared Diamond and his colleagues at UCLA. It examined the origins of 15 temperate and 10 tropical diseases.

Why is it important?

This question is not only of practical importance to physicians, and to all the rest of us as potential victims, but also of intellectual interest to historians and evolutionary biologists. Historians increasingly recognize that infectious diseases have had major effects on the course of history; for example, on the European conquest of Native Americans and Pacific Islanders, the inability of Europeans to conquer the Old World tropics for many centuries, the failure of Napoleon's invasion of Russia, and the failure of the French attempt to complete construction of a Panama Canal. Evolutionary biologists realize that infectious diseases, as a leading cause of human morbidity and mortality, have exerted important selective forces on our genomes.

But most important, it offers important clues as to what we can expect in the new world of urbanization, globalization and climatic change. As George Santayana said, and everybody loves to misquote: " Those who cannot remember the past are condemned to repeat it," (from Reason in Common Sense, the first volume of his Life of Reason).

The five stages of evolutionary development of a human infection.

There are 5 stages through which a pathogen evolves, from exclusively infecting animals (stage 1) to one infecting exclusively humans (stage 5).

Of the 25 diseases examined, 17 impose the heaviest world burdens today.Of the 17 diseases, 8 are temperate (hepatitis B, influenza A, measles, pertussis, rotavirus A, syphilis, tetanus and tuberculosis), and 9 are tropical (acquired immune deficiency syndrome (AIDS), Chagas' disease, cholera, dengue haemorrhagic fever, East and West African sleeping sicknesses, falciparum and vivax malarias, and visceral leishmaniasis). The remaining eight (temperate diphtheria, mumps, plague, rubella, smallpox, typhoid and typhus, plus tropical yellow fever) imposed heavy burdens in the past, although modern medicine and public health have either eradicated them (smallpox) or reduced their burden. Except for AIDS, dengue fever, and cholera, which have spread and attained global impact in modern times, most of these 25 diseases have been important for more than two centuries.

Differences between temperate and tropical diseases

Comparisons of these temperate and tropical diseases yield the following conclusions:

• A higher proportion of the diseases is transmitted by insect vectors in the tropics (8/10) than in the temperate zones (2/15).
• A higher proportion of the diseases conveys long-lasting immunity (11/15) in the temperate zones than in the tropics (2/10).
• Animal reservoirs are more frequent in the tropics (8/10) than in the temperate zones (3/15).
• Most of the temperate diseases (12/15) are acute rather than slow, chronic, or latent: the patient either dies or recovers within one to several weeks. Fewer of the tropical diseases are acute: 3/10 last for one or two weeks, 3/10 last for weeks to months or years, and 4/10 last for many months to decades.
• A higher proportion of the diseases belongs to Stage 5 (strictly confined to humans) in the temperate zones (10/15 or 11/15) than in the tropics (3/10). The paucity of Stage 2 and Stage 3 diseases (a total of only 5 such diseases) out of 25 major human diseases is noteworthy, because some Stage 2 and Stage 3 pathogens (such as anthrax and Ebola) are notoriously virulent.

The rise of agriculture starting 11,000 years ago played multiple roles in the evolution of animal pathogens into human pathogens. Those roles included both generation of the large human populations necessary for the evolution and persistence of human crowd diseases, and generation of large populations of domestic animals, with which farmers came into much closer and more frequent contact than hunter/gatherers had with wild animals.

It is interesting that fewer tropical than temperate pathogens originated from domestic animals. Why do temperate and tropical human diseases differ so markedly in their animal origins? Many tropical diseases (AIDS, dengue fever, vivax malaria, yellow fever) but only one temperate disease (hepatitis B) have wild non-human primate origins. This is because the vast majority of primate species is tropical rather than temperate. Conversely, few tropical but many temperate diseases arose from domestic animals, and this is because domestic animals live mainly in the temperate zones, and their concentration there before their introduction to the tropics was even more lop-sided.

So what can we expect in the future?

· As population densities grow, so will ‘crowd epidemics’.

· As globalization allows more people to move rapidly across geographic zones, more tropical diseases will appear in the the temperate regions.

· Immunization against tropical diseases will be difficult. An effective malaria vaccine has not been created despite decades of intensive efforts. HIV has frustrated the best minds in immunology and vaccinology.

· Warming climate trends will allow the migration of animal reservoirs and insect vectors of disease from the tropics to the temperate north.

· Most alarming: stage 2 and 3 pathogens, like Ebola, will migrate north and will undergo rapid evolution to stages 4 and 5 through genetic mutations that will allow them to become exclusively human diseases. This has already happened: HIV/AIDS is a case in point. Unfortunately, more is to come.

Postscript: One Day's News

The ending of this posting (written yestrday, March 24) bothered me a bit: am I being an alarmist? So my senses where heightened when I read the newspaper today. Here are 2 items:

1. An example of a pathogen undergoing mutations that allow it to "graduate" from stage 3 to stage 4.

Indonesia: Warnings on Failure to Contain Avian Flu and on Increased Risk of Deadly Mutation

 

By Dov Michaeli MD, Ph.D

In October of 2007 Julie Volberding, chief of the Centers for Disease Control and Prevention (CDC) was supposed to testify before a senate panel on the health consequences of global warming. At the last minute (literally the day before) White House political hacks prevented her from telling the story she intended to tell. This is not unusual: this administration has waged an undeclared war on Science, especially when the facts are inconvenient. So, in the interest of telling the unvarnished truth, here are a couple of examples of the effect of globalization and global warming on health.

The case of Bluetongue Disease

From the British New Scientist magazine:

Bluetongue is an animal virus, spread by tiny flies called midges – also called biting gnats, or no-see-ums. Scientists have been predicting for ages that insect-borne diseases would move north as global warming takes hold. They have predicted since at least 2002 that bluetongue could invade northern Europe and Britain . Those predictions have now come true.

Bluetongue infects ruminants – cattle, sheep, goats, deer, and the like – throughout Africa , southern Asia , and parts of Latin America . It does not infect humans. In most places that have it, livestock have evolved resistance to the virus, though it still takes a toll.

Sheep get much sicker with bluetongue than cattle; they develop fever, difficulty with breathing and swallowing, and swollen feet and faces. Sheep's tongues can turn blue if the swelling restricts circulation to the mouth, but despite the disease's name, this rarely happens. In non-resistant sheep, up to 80% of those infected can die.

How did it get to Europe ? First, the midge species that normally carries bluetongue in Africa and the Middle East has moved north into Europe , taking the virus with it. In 1998 just the southern tips of Spain , Italy and Portugal , and a few Greek islands, had bluetongue. Now the midge has carried five of the 24 known strains of the virus through much of Spain , Italy and Portugal , southern France and Greece , and across the Balkans.

Scientists warned that the disease might continue spreading past the most northerly point reached by the invading southern midge, because some midge species in northern Europe can also carry the virus.

But the virus had a second route into Europe . Bluetongue suddenly appeared in the Netherlands in August 2006, and rapidly spread to Belgium , Germany , France and Luxembourg, carried by local midges. The strain was completely different from the viruses in southern Europe – instead matching viruses from South Africa .

The outbreak was 6° of latitude farther north than bluetongue had ever been seen before, and there were hundreds of miles of uninfected territory between it and the affected southern regions. No one knows how it arrived. Midges like to breed in damp manure, and one notion is that manure with infected flies accompanied a horse shipped in by air.

Then the virus did something really new: it survived the winter, and broke out again in August 2007. It invaded eastern England, as scientists had predicted, probably in midges blown across the Channel from Belgium. So far, more than 1.8 million sheep have died across Europe . Unusually, the northern outbreak is also killing cattle.

What about us, humans?

Have you ever heard of Chikungunya disease? Me neither.

The mosquito-borne disease has caused massive outbreaks for at least half a century, but they all happened in developing countries in Asia and Africa. And although the virus causes severe rashes and joint pains, it never seemed to be fatal; many even called it "benign." Few researchers took an interest.

No longer. Things have changed in large part, researchers say, because chikungunya has finally struck a rich country. In 2005 and 2006, the virus caused a massive outbreak on La Réunion, an island twice the size of New York City 700 kilometers east of Madagascar --and a French département . Almost 40% of the population of 785,000 fell ill.

The big surprise of the outbreak at La Réunion was that the infamous Asian tiger mosquito, which is spreading fast across Europe and the United States, proved an excellent vector. This summer, Italy had a small Chikungunya outbreak, the first ever in Europe . There's no reason why the same couldn't happen elsewhere in Europe or in the United States .

Chikungunya--or "chik," as some scientists call it--belongs to the alphaviruses, a group that includes the Ross River virus in Australia and the viruses that cause eastern and western equine encephalitis, two serious diseases occurring in the United States . First isolated from a patient in Tanzania in 1953, the chik virus has surfaced occasionally since in countries across Africa, South Asia, and Southeast Asia . It causes high fevers, rash--sometimes with massive blisters--and excruciatingly painful swelling of the joints in fingers, wrists, and ankles.

The outbreak that hit La Réunion appears to have started in Kenya in 2004. It wasn't reported at the time, but in a paper published in 2007, researchers noted that the epidemic started in the coastal towns of Lamu and Mombasa, Kenya. Later, the virus appears to have gone on an island-hopping tour of the Indian Ocean, landing in Madagascar, the Comoro Islands , Mayotte --a much smaller French territory west of Madagascar -- Mauritius, and the Seychelles (see map). It reached India , where it hadn't been seen for 32 years, in December 2005, infecting an estimated 1.4 million people so far.

A more alarming finding is that the Asian tiger mosquito ( Aedes albopictus ) proved to be an efficient vector. Previously, a species called Ae. aegypti , which feeds on humans almost exclusively, was always the virus's main vector. Ae. albopictus , the predominant species on La Réunion, was considered a poor one, in part because it bites a wide variety of species. But recent studies have suggested why Ae. albopictus suddenly became a much better vehicle.

Between the first, small outbreak in early 2005 and the big one that started in December, the virus underwent a point-mutation change that altered a single amino acid in its envelope protein. Papers published last month by Anna- Bella Failloux of the Pasteur Institute in Paris and her colleagues and a team led by Stephen Higgs of the University of Texas Medical Branch in Galveston have shown that the change makes it much easier for the virus to reproduce in the mosquito's midgut. This leads to 100-fold higher virus concentrations in its salivary glands, which in turn increases the virus's chances of being transmitted during the next bite. Those findings strongly suggest that the mutation helped the virus adapt to the mosquito and "enhanced the epidemic,"

That's worrisome, because Ae. albopictus , originally from eastern Asia , has been spreading across the globe during the past 2 decades. The outbreak this summer in Italy --where Ae. albopictus is rampant--got started when a chikungunya patient from India traveled to a small village in the province of Ravenna . Such "imported" cases happen all the time: Mainland France had almost 800 in 2005 and 2006, and the United States 38. It's a matter of time before a patient kicks off a new outbreak in an unexpected place, Higgs says.

What can be done?

The usual remedies, such as drugs, vaccines, and chemical sprays to control the insect vectors, are notoriously difficult. Antiviral drugs are few and far between, and take many years to develop. Vaccines are likewise hard to develop. Both modalities are prone to development of resistance by the ever-mutating virus. And insecticides are notorious for their adverse effects on health, the environment, and the eventual development of resistance by the insect vector.

The inescapable fact though, is that we will have to confront the new reality. And no amount of muzzling scientists by ideological politicians who refuse to acknowledge reality will change it. There is precious little we can do about globalization. But global warming? All we need is political will, and signs of intelligent life in Washington .