Showing posts with label Pathos. Show all posts
Showing posts with label Pathos. Show all posts

Saturday, 21 February 2015

Comrade Wolf

  • Товарищ волк знает, кого кушать. Кушает, и никого не слушает, и слушать, судя по всему, не собирается.
  • Translation: Comrade wolf knows who to eat. He eats without listening to anybody and it seems he is not ever going to listen.
    • On the U.S., whose military budget is 25 times bigger than Russia's; annual presidential address to the Federal Senate, 10 May 2006

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May 10, 2006,

Marble Hall, the Kremlin, Moscow

Annual Address to the Federal Assembly

PRESIDENT VLADIMIR PUTIN: Distinguished members of the Federal Assembly,

Citizens of Russia,

The addresses of the last years have set out our main socio-economic policy priorities for the coming decade. Our efforts today focus precisely on the areas that directly determine the quality of life for our citizens. We are carrying out national projects in the areas of healthcare, education, agriculture and housing construction. As you know, the problems in these areas have accumulated not just over a period of years but over entire decades. These are very sensitive issues for people’s lives. We have had to build up considerable strength and resources in order to finally be able to address these problems and focus our efforts on resolving them.

A number of laws were passed in order to implement the proposals set out in the Annual Address for last year (2005). These were laws designed to improve our political system, in particular, the law on the Public Chamber, the law on parliamentary investigations and the law giving the party winning the majority in regional elections the right to take part in the process of selecting the regional governor. We likewise adopted a decision that improves relations between the federal, regional and local authorities.

In other words, we have concentrated over these last years on ironing out the imbalances that had arisen in our system of state organisation and in the social sphere. 

Now, as we plan the continued development of our state and political system, we must also take into account the current situation in society. In this respect I note what has become a characteristic feature of our country’s political life, namely, low levels of public trust in some of the institutions of state power and in big business. The reasons for this situation are understandable.

The changes of the early 1990s were a time of great hopes for millions of people, but neither the authorities nor business fulfilled these hopes. Moreover, some members of these groups pursued their own personal enrichment in a way such as had never been seen before in our country’s history, at the expense of the majority of our citizens and in disregard for the norms of law and morality.

“In the working out of a great national program which seeks the primary good of the greater number, it is true that the toes of some people are being stepped on and are going to be stepped on. But these toes belong to the comparative few who seek to retain or to gain position or riches or both by some short cut which is harmful to the greater good.”

These are fine words and it is a pity that it was not I who thought them up. It was Franklin Delano Roosevelt, the President of the United States of America, in 1934.

These words were spoken as the country was emerging from the great depression. Many countries have faced similar problems, just as we are today, and many have found worthy ways to overcome them.

At the foundation of these solutions was a clear understanding that the state’s authority should not be based on excessive permissiveness, but on the ability to pass just and fair laws and firmly ensure their enforcement.

We will continue, of course, to work on raising the prestige of the civil service, and we will continue to support Russian business. But be it a businessman with a billion-dollar fortune or a civil servant of any rank, they all must know that the state will not turn a blind eye to their doings if they attempt to gain illegal profit out of creating special relations with each other.

I make this point now because, despite all the efforts we have made, we have still not yet managed to remove one of the greatest obstacles facing our development, that of corruption. It is my view that social responsibility must lie at the foundation of the work of civil servants and business, and they must understand that the source of Russia’s wellbeing and prosperity is the people of this country.

It is the state’s duty to ensure that this principle is reflected in deed and not just in word. I believe that this is one of the priority tasks we face today and that we cannot resolve this task unless we ensure the rights and liberties of our citizens, organise the state itself effectively and develop democracy and civil society.

We have spoken on many occasions of the need to achieve high economic growth as an absolute priority for our country. The annual address for 2003 set for the first time the goal of doubling gross domestic product within a decade. The calculation is not hard to make: to achieve this goal our economy needs to grow at a rate of just over seven percent a year.

On the surface we look to be keeping to our objectives and have had average economic growth of around seven percent for the past three years, but I want to stress that if we do not address certain issues, do not improve our basic macroeconomic indicators, do not ensure the necessary level of economic freedom, do not create equal conditions for competition and do not strengthen property rights, we will be unlikely to achieve our stated economic goals within the set deadline.  

We have already begun taking concrete steps to change the structure of our economy and, as we have discussed a great deal, to give it a more innovative quality. I think that the government is moving in the right direction in this regard but I would like to make the following points. 

First, state investment is necessary, of course, but it is not the only means of achieving our objectives. Second, it is not the volume of investment that is important so much as an ability to choose the right priorities while at the same time ensuring that we continue following the responsible economic policy we set five years ago. 

After a long period during which we ran a budget deficit and faced sharp fluctuations of the rouble’s exchange rate, the situation today is changing dramatically. We must maintain this financial stability that has been achieved as one of the basic conditions for increasing people’s trust in the state and for encouraging entrepreneurs to invest money in business development.

Today’s situation allows us to make a calmer and more sober assessment of the threats that Russia encounters as part of the world system, threats that represent a danger for our internal development and for our country’s international interests.

We can make a more detailed examination of our place in the world economy. In a context of intensive competition, scientific and technological advantages are the defining factors for a country’s economic development. Unfortunately, a large part of the technological equipment used by Russian industry today lags not just years but decades behind the most advanced technology the world can offer. Even allowing for the climate conditions in Russia, our energy use is many times less efficient than that of our direct competitors.

Yes, we know that this is the legacy of the way our economy and our industry developed during the Soviet period, but it is not enough just to know. We have to take concrete steps to change the situation. We must take serious measures to encourage investment in production infrastructure and innovative development while at the same time maintaining the financial stability we have achieved. Russia must realise its full potential in high-tech sectors such as modern energy technology, transport and communications, space and aircraft building. Our country must become a major exporter of intellectual services.

Of course, we hope for increased entrepreneurial initiative in all sectors of the economy and we will ensure all the necessary conditions for this to happen. But a real leap forward in the areas that I just mentioned, all areas in which our country has traditionally been strong, gives us the opportunity to use them as an engine for growth. This is a real opportunity to change the structure of our entire economy and establish for ourselves a worthy place in the international division of labour.

We already feel confident in the mining and extraction sector. Our companies in this sector are very competitive. Gazprom, for example, has just become the third biggest company in the world in terms of capitalisation, while at the same time maintaining quite low tariffs for Russian consumers. This result did not just come about all on its own, but is the result of carefully planned action by the state.

But we cannot pat ourselves on the back and stop here. We need to put in place the conditions for more rapid technological modernisation in the energy sector. We need to develop modern refining and processing facilities, build up our transport capacity and develop new and promising markets. And in doing all of this we need to ensure both our own internal development needs and fulfil all of our obligations to our traditional partners. 

We must also take steps to develop nuclear energy, a nuclear energy sector based on safe, new-generation reactors. We need to consolidate Russia’s position on the world markets for nuclear energy sector technology and equipment and make full use here of our knowledge, experience, advanced technology, and of course, international cooperation. Restructuring in the nuclear energy industry itself also aims at enabling us to achieve these goals. We must, of course, also focus work on promising new directions in energy – hydrogen and thermonuclear energy.

We must also take action to make our energy consumption radically more efficient. This demand is not just a whim for a country rich in energy resources, but is an issue for our competitiveness in the context of integration into the world economy. It is an issue of the environmental security and quality of life for our people.

I believe that only in this way can we ensure that Russia maintains a leading and stable position on energy markets in the long term. And in this way, Russia will be able to play a positive part in forming a common European energy strategy. 

Our country has an advantageous geographical location and we must make use of this factor to realise our potential in the very promising area of modern transport and communications. The key decision in this respect is comprehensive and interlinked development of all types of transport and communications.

I note in this regard that concession mechanisms create new opportunities for carrying out such projects, and we should start making use of them very soon.  

The reorganisation of important sectors such as aircraft- and shipbuilding has been dragging on for an unjustifiably long time. The government must take rapid steps to finally complete work on establishing holdings in these sectors.

It is also extremely important for us to make the right choices in our development priorities for the space industry. We must not forget that the development of outer space is Russia’s protective shield, gives us the possibility of detecting global natural cataclysms at an early stage and is a testing ground for new materials and technology. These and other objectives all require considerable investment to modernise facilities producing equipment for the space industry and to develop the infrastructure on the ground.

Russia has the potential to become one of the leaders in the field of nanotechnology. This sector represents one of the most promising directions for energy conservation and for developing new elements, medical technology and robotics. I believe we must take rapid steps to draw up and adopt an effective programme in this field.

I hope too that the implementation of the government’s and the Russian Academy of Sciences’ joint plans to modernise the science sector will not be no more than a formality but will bring genuine results and provide our country’s economy with promising new scientific developments. 

Overall, what we need today is an innovative environment that will get new knowledge flowing. To do this we need to create the necessary infrastructure: technology incubators, technology parks, venture funds, investment funds. We are already doing this. We need to establish favourable tax conditions for financing innovative activities.

I believe too that the state should also facilitate the purchase of modern technology abroad. In this respect we have also taken some steps, first of all, of course, in order to modernise priority branches of industry. In this respect I ask you to analyse the possibilities for channelling resources into the capital of the financial institutions involved in leasing, lending and providing insurance for these types of contracts.

Reliable protection of intellectual property rights remains an essential condition for developing new technology. We must guarantee the protection of copyright within our country – this is also our duty to our foreign partners. And we must also ensure greater protection for the interests of Russian copyright holders abroad.

Dear colleagues,

Russia today needs unhindered access for its goods on international markets. We consider this an issue of more rational participation in the international division of labour and a question of making full use of the benefits offered by integration into the world economy. It is precisely for this reason that we are continuing our negotiations on accession to the World Trade Organisation based only on conditions that fully take into consideration Russia’s economic interests.

It is clear today that our economy is already more open than the economies of many of the members of this esteemed organisation. The negotiations on Russia’s accession to the WTO must not become a bargaining chip on issues that have nothing to do with this organisation’s activities. 

In my address for 2003 I set the goal of making the rouble convertible. An outline of the steps to take was set out and I must say that these steps are being taken. I propose today that we speed up the removal of the remaining restrictions and complete this work by July 1 of this year.

But making the rouble genuinely convertible depends in great part on its attractiveness as an instrument for settlements and savings. In this respect we still have a great deal of work to do. In particular, the rouble must become a more universal means for carrying out international settlements and should gradually expand its zone of influence. 

To this end we need to organise markets on Russian territory for trading oil, gas and other goods, markets that carry out their transactions in roubles. Our goods are traded on world markets, but why are they not traded here in Russia? The government should speed up work on settling these issues.

As I said before, our growing economic possibilities have enabled us to allocate additional money to the social sphere – investment in our people’s prosperity and in Russia’s future.

The goal of the Affordable Housing project, for example, is to lower interest rates on mortgage loans over a period of two years and almost triple the total mortgage loans made, bringing them to a total of 260 billion roubles.

Another of our national projects allocates considerable resources to the development of agriculture. Work has already begun on programmes to build housing for young higher education graduates in rural areas. We are also developing a system for making loans available to co-operative retailers, small individual land cultivation and large-scale agricultural production enterprises. We are facilitating the purchase of the new technology and high-quality agricultural equipment that is so essential for our rural areas.

Now for a few words on the aims and measures set out in the Education national project. Russia needs a competitive education system otherwise we will end up facing the real threat of having our quality of education not measure up to modern demands. Above all, we need to support the higher education establishments that are carrying out innovative programmes, including by buying the latest Russian and foreign-made equipment and technology.

The government must bring order to the curriculum of vocatonal education schools. This is something that should be done through work together with the business community and social services sector, for whom these institutions are training specialists in the first place.

We need to create a system of objective and independent external control over the quality of the education received, and we need to engage in broad-based and open dialogue with the public to establish an objective rating of universities.   

We should not be afraid to expand the financial independence of education institutions, including schools, at the same time raising their responsibility for the quality of every aspect of the learning process and for the final result. 

I support our business community’s initiative of financing major universities through special development funds and through the formation of an education loans system. In this respect we need to look at improving the legislation in order to create incentives for such spending and ensure the necessary guarantees. I deliberately have not used the term state guarantees, but there must be guarantees of some kind, and the government can organise this work and put in place the required mechanisms.

Our fourth national project has been started in the area of healthcare and is aimed at improving primary healthcare and prevention and at improving access to high-tech medical services. I want to emphasise at the same time that the money allocated to the national projects accounts for only around 5-7 percent of total state spending in these sectors.

The government and the regional and local authorities must work systematically together on modernising these four sectors and making more effective use of the considerable resources that we already have. If properly organised, all of this work should improve the quality of service in healthcare and education and also make it possible to considerably increase wages for all groups working in these sectors, not only those who are receiving additional payments as part of the priority projects.

Furthermore, starting this year, a large part of the federal budget spending will be focused on the final result. The regional authorities also must begin this work. I deliberately draw the regional authorities’ attention to this point. The government has already taken the first steps in this direction but in the regions nothing is happening.

We must also continue the process of devolution of powers. In particular, the regions should be given part of the investment funds from the federal budget, which are essentially already being used today to finance municipal powers.

It is high time to stop overseeing the construction of schools, bathhouses and sewerage systems from Moscow.

And now for the most important matter. What is most important for our country? The Defence Ministry knows what is most important. Indeed, what I want to talk about is love, women, children. I want to talk about the family, about the most acute problem facing our country today – the demographic problem.

The economic and social development issues our country faces today are closely interlinked to one simple question: who we are doing this all for? You know that our country’s population is declining by an average of almost 700,000 people a year. We have raised this issue on many occasions but have for the most part done very little to address it. Resolving this problem requires us to take the following steps.

First, we need to lower the death rate. Second, we need an effective migration policy. And third, we need to increase the birth rate.

The government just recently adopted a programme for improving road safety. Adopting a programme is easy, now we need to implement it. I take this opportunity to draw the government’s attention to delays and unjustified red tape involved in carrying out these kinds of tasks. I spoke about this issue in last year’s address, and the programme has only just now been prepared.

I am certain that other issues raised in last year’s address are also not always being resolved in the way they should be.

We are taking measures to prevent the import and production of bootleg alcohol. The national Healthcare project is rightly focusing on the detection, prevention and treatment of cardiovascular disease and other illnesses that are high causes of death among our population.

Regarding migration policy, our priority remains to attract our compatriots from abroad. In this regard we need to encourage skilled migration to our country, encourage educated and law-abiding people to come to Russia. People coming to our country must treat our culture and national traditions with respect.

But no amount of migration will resolve our demographic problems if we do not also put in place the conditions and incentives for encouraging the birth rate to rise here in our own country. We cannot resolve this problem unless we adopt effective support programmes for mothers, children and families. 

Even the small increase in the birth rate and the drop in infant mortality we have seen of late are not so much the result of concerted effort in this area as of the general improvement in the country’s socio-economic outlook. It is good to see this improvement, but it is not enough. 

The work we have carried out on social projects over these last years has laid a good base, including for resolving the demographic problem, but it is still inadmissibly insufficient, and you know why. The situation in this area is critical. 

Distinguished members of the Federal Assembly, you will soon begin work on the budget for 2007, the year of elections to the State Duma. Understandably, the budget adoption process will be determined in large part by your desire to do as much as you can for your voters. But if we really want to do something useful and necessary for our citizens, I propose that you lay aside political ambitions and don’t disperse resources, and that we concentrate on resolving the most vital problems the country faces, one of which is the demographic problem, or, as Solzhenitsyn put it, the issue of ‘conserving the people’ in the broad sense. All the more so as there is public consensus that we must first of all address this key problem affecting our country.

I am sure that if you do this you will reap the gratitude of millions of mothers, young families and all the people of our country.

What am I talking about specifically? I propose a programme to encourage childbirth. In particular, I propose measures to support young families and support women who decide to give birth and raise children. Our aim should be at the least to encourage families to have a second child.

What stops young families, women, from making such a decision today, especially when we’re talking of having a second or third child? The answers are well known. They include low incomes, inadequate housing conditions, doubts as to their own ability to ensure the child a decent level of healthcare and education, and – let’s be honest – sometimes doubts as to whether they will even be able to feed the child. 

Women planning to have a child face the choice of either giving birth and losing their jobs, or not giving birth. This is a very difficult choice. The programme to encourage childbirth should include a whole series of administrative, financial and social support measures for young families. All of these measures are equally important but nothing will bring results unless the necessary material support is provided.

What should we be doing today? I think that we need to significantly increase the childcare benefits for children under the age of one-and-a-half.

Last year we increased this benefit from 500 roubles to 700 roubles. I know that many deputies actively supported this decision. I propose that we increase the childcare benefit for the first child from 700 roubles to 1,500 roubles a month, and that we increase the benefit for the second child to 3,000 roubles a month.

Women who had jobs but then take maternity leave and child care leave until it is one-and-a-half should receive from the state not less than 40 percent of their previous wage. We realise that we will have to set an upper threshold from which this sum is counted. I hope that the government will work together with the deputies to set this threshold. Whatever the case, the total benefit should not be lower than what a woman who did not previously work would receive, that is to say, 1,500 roubles and 3,000 roubles respectively.

Another problem is getting women back into the workforce again. In this respect I propose introducing compensation for the expenses families pay for pre-school childcare. Compensation for the first child would come to 20 percent of expenses, for the second 50 percent, and for the third 70 percent of the average amount the parents actually pay for the pre-school childcare facility.

I draw your attention to the fact that I said that compensation would be for the expenses the parents actually pay and not for the costs for the childcare facility. The regional leaders understand what I am talking about. It is up to the regional and local authorities to ensure that there are enough kindergartens and nurseries to cover demand.

We also need to work together with the regions to develop a programme providing financial incentives for placing orphans and children whose parents are unable to care for them in family care. We currently have some 200,000 children living in children’s homes and orphanages. In reality the number of orphans is far higher, but around 200,000 of them are in children’s homes. It seems to me that foreigners are adopting more of our children than we ourselves are. I propose that we double the benefit paid to guardians or foster parents of children and make it at least 4,000 roubles a month. I also propose considerably increasing the wage paid to foster parents from 1,000-1,500 roubles a month to 2,500 roubles a month. And we should also increase the one-off payment made to families taking in children, regardless of the form chosen for placing the child with a family, to 8,000 roubles, that is, equal to the one-off payment made for giving birth to a child.

I instruct the government to work together with the regions to create a mechanism that will make it possible to reduce the number of children in institutions. We likewise need to take care of the health of future mothers and newborn babies and bring down the infant mortality and disability rates.

I propose that we increase the value of the childbirth certificates that were introduced last year and have worked well so far. I propose that we increase their value from 2,000 roubles to 3,000 roubles for pregnancy centres and from 5,000 roubles to 7,000 roubles for maternity homes.   

This additional money should be used for buying the necessary medicines for women and providing a higher quality of medical services. This must take into account the views of the patients themselves, the women, and I stress this point. We need to develop such a mechanism. This is not difficult to do. 

We also need to move rapidly to adopt a programme to create a network of perinatal centres and ensure that maternity homes have all the necessary equipment, special transport and other technology they need.

Finally, and most effective in my view, is a measure to ensure material support. I think that the state has a duty to help women who have given birth to a second child and end up out of the workplace for a long time, losing their skills. I think that, unfortunately, women in this situation often end up in a dependent and frankly even degraded position within the family. We should not be shy about discussing these issues openly and we must do so if we want to resolve these problems. If the state is genuinely interested in increasing the birth rate, it must support women who decide to have a second child. The state should provide such women with an initial maternity capital that will raise their social status and help to resolve future problems. Mothers could make use of this capital in different ways: put it towards improving their housing situation, for example, by investing it in buying a house, making use of a mortgage loan or other loan scheme once the child is three years old, or putting it towards the children’s education, or, if they wish, putting it into the individual account part of their own old-age pension.   

Experts say that these kinds of state support measures should total at least 250,000 roubles, and this sum should be indexed to annual inflation, of course.

The question arises of what to do with the families who already have at least two children. This is an important question and I am sure that the deputies will come to a carefully thought-through decision in this respect.

Of course, carrying out all of these plans will require a lot of work and an immense amount of money. I ask you to work out the obligations the state would increasingly bear in this case over the years and give the programme a timeframe of at least 10 years at the end of which the state can decide on future action depending on the economic and demographic situation in the country.

Finally, the money needed to begin implementing these measures should be allocated in the budget for next year. This mechanism should be launched starting on January 1, 2007. I also ask you to work together with the government on the implementation procedures for carrying out this programme I have proposed.

Concluding on this subject, I note that we cannot resolve the problem of the low birth rate without changing the attitudes within our society to families and family values. Academician Likhachev once wrote that “love for one’s homeland, for one’s country, starts with love for one’s family”. We need to restore these time-honoured values of love and care for family and home.

While concentrating on raising the birth rate and supporting young families, we must also not forget about the older generation. These are people who have devoted their entire lives to their country, who laboured for their country and who, if necessary, rose to its defence. We must do all that we can to ensure them a decent life.

As you know, we have raised pensions on a number of occasions over recent years, and ahead of the planned timeframe. Next year we will again raise pensions by almost 20 percent overall. The state is allocating considerable money to providing social benefits and guarantees for pensioners and veterans. We need to continue our programme for providing state-funded housing for pensioners and veterans, including through using additional funds that are part of the Affordable Housing project. I ask you to continue focusing on this work as a key priority. 

Distinguished deputies and members of the Federation Council,

In order to calmly and confidently resolve all the issues I have mentioned, issues of peaceful life, we need convincing responses to the national security threats that we face. The world is changing rapidly and a large number of new problems have arisen, problems that our country has found itself facing. These threats are less predictable than before and just how dangerous they are has not yet been fully gauged and realised. Overall, we see that conflict zones are expanding in the world and, what is especially dangerous is that they are spreading into the area of our vital interests.

The terrorist threat remains very real. Local conflicts remain a fertile breeding ground for terrorists, a source of their arms and a field upon which they can test their strength in practice. These conflicts often arise on ethnic grounds, often with inter-religious conflict thrown in, which is artificially fomented and manipulated by extremists of all shades.

I know that there are those out there who would like to see Russia become so mired in these problems that it will not be able to resolve its own problems and achieve full development. 

The proliferation of weapons of mass destruction also represents a serious danger. If these weapons were to fall into the hands of terrorists, and they pursue this aim, the consequences would be simply disastrous.

I stress that we unambiguously support strengthening the non-proliferation regime, without any exceptions, on the basis of international law. We know that strong-arm methods rarely achieve the desired result and that their consequences can even be more terrible than the original threat. 

I would like to raise another important issue today. Disarmament was an important part of international politics for decades. Our country made an immense contribution to maintaining strategic stability in the world. But with the acute threat of international terrorism now on everyone’s minds the key disarmament issues are all but off the international agenda, and yet it is too early to speak of an end to the arms race.

What’s more, the arms race has entered a new spiral today with the achievement of new levels of technology that raise the danger of the emergence of a whole arsenal of so-called destabilising weapons.

There are still no clear guarantees that weapons, including nuclear weapons, will not be deployed in outer space. There is the potential threat of the creation and proliferation of small capacity nuclear charges. Furthermore, the media and expert circles are already discussing plans to use intercontinental ballistic missiles to carry non-nuclear warheads. The launch of such a missile could provoke an inappropriate response from one of the nuclear powers, could provoke a full-scale counterattack using strategic nuclear forces.

And meanwhile far from everyone in the world has abandoned the old bloc mentality and the prejudices inherited from the era of global confrontation despite the great changes that have taken place. This is also a great hindrance in working together to find suitable responses to the common problems we face.

Taking into account all of the above, Russia’s military and foreign policy doctrines must also provide responses to the issues of today, namely, how to work together with our partners in current conditions, to fight effectively not just terrorism but also the proliferation of nuclear, chemical and bacteriological weapons, how to settle the local conflicts in the world today and how to overcome the other new challenges we face. Finally, we need to make very clear that the key responsibility for countering all of these threats and ensuring global security will lie with the world’s leading powers, the countries that possess nuclear weapons and powerful levers of military and political influence. This is why the issue of modernising Russia’s Armed Forces is extremely important today and is of such concern to Russian society.

The addresses of recent years have all dealt with various national security problems. Today I want to look more closely at the current state of the Russian Armed Forces and their development prospects. 

These days  we are honouring our veterans and congratulating them on Victory Day. One of the biggest lessons of World War II is the importance of maintaining the combat readiness of the armed forces. I point out that our defence spending as a share of GDP is comparable or slightly less than in the other nuclear powers, France or Britain, for example. In terms of absolute figures, and we all know that in the end it is absolute figures that count, our defence spending is half that of the countries I mentioned, and bears no comparison at all with the defence spending figures in the United States. Their defence budget in absolute figures is almost 25 times bigger than Russia’s. This is what in defence is referred to as ‘their home – their fortress’. And good on them, I say. Well done!

But this means that we also need to build our home and make it strong and well protected. We see, after all, what is going on in the world. The wolf knows who to eat, as the saying goes. It knows who to eat and is not about to listen to anyone, it seems.

How quickly all the pathos of the need to fight for human rights and democracy is laid aside the moment the need to realise one’s own interests comes to the fore. In the name of one’s own interests everything is possible, it turns out, and there are no limits. But though we realise the full seriousness of this problem, we must not repeat the mistakes of the Soviet Union, the mistakes of the Cold War era, neither in politics nor in defence strategy. We must not resolve our defence issues at the expense of economic and social development. This is a dead end road that ultimately leaves a country’s reserves exhausted. There is no future in it.

Of course, the question arises whether we can reliably ensure our security in a situation of such disparity with the other leading powers. Of course we can, and I will say how now. I propose that we look at this issue in more detail.

A few years ago the structure of the country’s armed forces was not in keeping with the reality of today’s situation. The armed forces were no longer receiving any modern equipment. Not a single new ship was built between 1996 and 2000 and only 40 new items of military equipment were commissioned by the armed forces. The troops carried out military exercises on maps, only on maps, the navy never left the docks and the air force never got to fly. When the need arose to counter a large-scale attack by international terrorists in the North Caucasus in 1999, the problems in the armed forces became painfully evident.

I remember very clearly a conversation I had with the chief of General Staff at that time. He is probably present here today. In order to effectively repel the terrorists we needed to put together a group of at least 65,000 men, but the combat ready units in the entire army came to only 55,000 men, and they were scattered throughout the entire country. Our armed forces came to a total of 1,400,000 men but there wasn’t enough men to fight. This is how  kids who had never seen combat before were sent in to fight. I will not forget this ever. And it is our task today to make sure that this never happens again. 

The situation in the armed forces today has changed dramatically. We have created a modern structure for the armed forces and the different units are now receiving modern, new arms and equipment, arms and equipment that will form the basis of our defence through to 2020. This year saw the start of mass defence equipment procurement for the Defence Ministry’s needs. 

Naval shipbuilding has got underway again and we are now building new vessels of practically all types. The Russian Navy will soon commission two new nuclear submarines carrying strategic weapons. They will be equipped with the new Bulava missile system, which together with the Topol-M system will form the backbone of our strategic deterrent force. I emphasise that these are the first nuclear submarines to be completed in modern Russia. We had not built a single vessel of this type since 1990.  

Five Strategic Missile regiments have already received silo-based Topol-M missiles, and one of our missile divisions will also receive the mobile version of the Topol-M system this year. 

Another important indicator over recent years is that intensive combat and operational training is being conducted among the troops. Dozens of field exercises and long-distance sea voyages have been organised. One just finished today.

The result of these changes has been to boost combat spirit and improve the morale of soldiers and officers. We know examples of what it is no exaggeration to call mass heroism among military servicemen and law enforcement personnel.

The changes in the structure of the military budget are also an indicator of change. Defence spending has increased from year to year. An ever greater share of this money is going precisely into improving the quality of the armed forces. Over the coming years we must reach the goal of having at least half of the defence budget being spent on development. Every budget rouble must be spent carefully and for the designated purpose.

I have long since raised the issue of the need to establish a unified procurement and supply system for arms, military equipment and rear support. The government must settle this issue by the end of the year and complete this work and then establish a federal civilian agency with the according powers. I very much hope that this will also have a positive impact on overcoming corruption in the armed forces.

Now I would like to name the main demands regarding the missions our armed forces must be ready fulfil. Over the next five years we will have to significantly increase  the number of  modern long range aircraft, submarines and launch systems in our strategic nuclear forces.

Work is already underway today on creating unique high-precision weapons systems and manoeuvrable combat units that will have an unpredictable flight trajectory for the potential opponent. Along with the means for overcoming anti-missile defences that we already have, these new types of arms will enable us to maintain what is definitely one of the most important guarantees of lasting peace, namely, the strategic balance of forces.

We must take into account the plans and development vectors of other countries’ armed forces, and we must keep ourselves informed on promising developments, but we should not go after quantity and simply throw our money to the wind. Our responses must be based on intellectual superiority. They will be asymmetrical, not as costly, but they will unquestionably make our nuclear triad more reliable and effective.

Modern Russia needs an army that has every possibility for making an adequate response to all the modern threats we face. We need armed forces able to simultaneously fight in global, regional and -  if necessary - also in several local conflicts. We need armed forces that guarantee Russia’s security and territorial integrity no matter what the scenario.

Another important demand is that the armed forces be professional and mobile. I particularly note that we have made the necessary personnel cutbacks over the last five years. The process of bringing the size of the armed forces down to an optimum 1 million servicemen will not require further special cutbacks but will be reached as officers who have served their time take their retirement. This scaling down will be achieved only through cutting back the bureaucratic apparatus. The combat units will not be affected by any more cutbacks.

Changes will also be made to the military command system and the mobilisation system will be improved. By 2008, professional servicemen should account for two thirds of the armed forces. All of this will enable us to reduce compulsory military service to one year. 

Once the permanently combat-ready units are all manned by contract servicemen, we must also, starting 2009, begin filling posts for sergeants, master sergeants, and for above-water craft crews on principle of contract service.

The armed forces units stationed in Chechnya are all manned by contract servicemen. As from January 1, 2007, the Interior Ministry troops in Chechnya will also all be contract servicemen. In other words, we will no longer use conscript servicemen at all in anti-terrorist operations.

By 2011 our general purpose forces should include around 600 permanently combat-ready units. A much larger number of such units will be created in fighter plane units and military aviation, in the air defence forces, communications, radio-electronic reconnaissance and electronic warfare units. If need be, we will be able to quickly put into place mobile and self-sufficient units in any potentially dangerous area. Professionally trained units and permanently combat-ready units will form the backbone of these forces. 

Service in the Russian Armed Forces should be modern and genuinely prestigious. People serving their motherland should have a high social and material status and benefit from solid social guarantees.

By 2010 we should have definitively resolved the issue of permanent housing for servicemen and by 2012 we should have resolved the issue of service housing.

We also plan a number of wage rises for the military over the coming years. At the same time we are developing the healthcare and insurance system for servicemen. Finally, the issue of increasing discipline among the troops is an equally important task. The political problems of the transition period and the lack of funding meant that the army was essentially just taking what it could get to fulfil its personnel needs, and this also led to worse conditions of service and a drop in the level of combat preparedness. 

A huge number of young men of conscript age today suffer from chronic diseases and have problems with drinking, smoking and sometimes drugs as well. I think that in our schools we need not just to educate our young people but also see to their physical and patriotic development. We need to restore the system of pre-conscription military training and help develop military sports. The government should adopt the appropriate programme in this area.

The regional authorities should not just be seriously concerned with meeting conscription figures but are also responsible for ensuring that the recruits satisfy quality requirements, and they should carry out preparatory work in close contact with the armed forces themselves.

Administrative measures alone are not enough to really change the situation. We need to realise that the armed forces are part of ourselves, part of our society, and that service in their ranks is of immense importance for the country and for the entire Russian people.

Reflecting on the basic principles on which the Russian state should be built, the well known Russian thinker Ivan Ilyin said that the calling of soldier is a high and honourable title and that the soldier “represents the national unity of the people, the will of the Russian state, strength and honour”. We must always be ready to repel potential aggression from outside and to counter international terrorist attack. We must be able to respond to attempts from any quarters to put foreign policy pressure on Russia, including with the aim of strengthening one’s own position at our expense. 

We also need to make clear that the stronger our armed forces are, the lesser the temptation for anyone to put such pressure on us, no matter under what pretext this is done.

Dear colleagues,

Russia’s modern foreign policy is based on the principles of pragmatism, predictability and the supremacy of international law. I would like to say a few words today about the state of relations and prospects for cooperation with our main partners, and above all, about relations with our nearest neighbours, with the countries of the CIS. 

The debate on the very need for and future of the Commonwealth of Independent States still continues to this day and we all have an interest in working on reform of the CIS.

The CIS clearly helped us to get through the period of putting in place partnership relations between the newly formed young states without any great losses and played a positive part in containing regional conflicts in the post-Soviet area.  

I stress that it was Russia that helped defuse the tension in many of these conflicts. We will continue to carry out our peacekeeping mission in all responsibility.

The CIS experience has also given rise to several productive economic cooperation initiatives. The Union State with Belarus, the Eurasian Economic Community and the Common Economic Space are all developing in parallel today, based on the shared interests of the partners involved. Together we are resolving the problems that no one else will settle for us. We see in practice that multilateral partnership enables us to do this at much less cost and far more effectively.

The CIS has provided a good basis for the formation of the Collective Security Treaty Organisation that brings together countries genuinely interested in close military and political cooperation.  

Finally, without diminishing the importance of the other aspects of reform in any way, I note the particularly promising project of strengthening our common humanitarian space, which has not just a rich historical and human foundation but now offers new social and economic opportunities. Throughout the CIS a difficult but active search for optimum cooperation models is underway. Russia states clearly and firmly that the end result we want from this search is the creation of an optimum economic system that would ensure the effective development of each of its participants. 

I repeat that our relations with our closest neighbours were and remain a most important part of the Russian Federation’s foreign policy.

I would like to say a few words briefly about our cooperation with our other partners.

Our biggest partner is the European Union. Our ongoing dialogue with the EU creates favourable conditions for mutually beneficial economic ties and for developing scientific, cultural, educational and other exchanges. Our joint work on implementing the concept of the common spaces is an important part of the development of Europe as a whole.

Of great importance for us and for the entire international system are our relations with the United States of America, with the People’s Republic of China, with India, and also with the fast-growing countries of the Asia-Pacific Region, Latin America and Africa. We are willing to take new steps to expand the areas and framework of our cooperation with these countries, increase cooperation in ensuring global and regional security, develop mutual trade and investment and expand cultural and educational ties.

I wish to stress that at this time of globalisation when a new international architecture is in the process of formation, the role of the United Nations Organisation has taken on new importance. This is the most representative and universal international forum and it remains the backbone of the modern world order. It is clear that the foundations of this global organisation were laid during an entirely different era and that reform is indisputably necessary.

Russia, which is taking an active part in this work, sees two points of being of principle importance.

First, reform should make the UN’s work more effective. Second, reform should have the broad support of a maximum number of the UN’s member states. Without consensus in the UN it will be very difficult to ensure harmony in the world. The UN system should be the regulator that enables us to work together to draw up a new code of behaviour in the international arena, a code of behaviour that meets the challenges of our times and that we are so in need of today in this globalising world.

Distinguished members of the Federal Assembly,

Citizens of Russia,

In conclusion I would like to say once more that today’s address, like previous addresses, sets out the basic directions of our domestic and foreign policy for the coming decades. They are designed for the long term and are not dictated by fluctuations of the moment. 

Previous addresses have focused on construction of our political system, improving the state power system and local self-government, have examined in detail the modernisation of our social sphere and have set new economic goals.

Today I have set out our vision of what place we want to hold in the international division of labour and the new architecture of international relations. I have also examined in detail what we can do to resolve the complex demographic problem we face and to develop our armed forces.

The steps proposed are very concrete. Russia has immense development opportunities and huge potential that we need to put to full use in order to better the lives of our people.

Without question we realise the full scale of the work at hand. I am sure that we will be up to the task.

Thank you for your attention.

Wednesday, 5 February 2014

Kary Mullis, 1993 Nobel Lecture

The Nobel Prize in Chemistry 1993
Kary B. Mullis, Michael Smith

Nobel Lecture

Nobel Lecture, December 8, 1993


The Polymerase Chain Reaction

In 1944 Erwin Schroedinger, stimulated intellectually by Max Delbrück, published a little book called What is Life? It was an inspiration to the first of the molecular biologists, and has been, along with Delbrück himself, credited for directing the research during the next decade that solved the mystery of how "like begat like."

Max was awarded this Prize in 1969, and rejoicing in it, he also lamented that the work for which he was honored before all the peoples of the world was not something which he felt he could share with more than a handful.Samuel Beckett's contributions in literature, being honored at the same time, seemed to Max somehow universally accessible to anyone. But not his. In his lecture here Max imagined his imprisonment in an ivory tower of science.

"The books of the great scientists," he said, "are gathering dust on the shelves of learned libraries. And rightly so. The scientist addresses an infinitesimal audience of fellow composers. His message is not devoid of universality but it's universality is disembodied and anonymous. While the artist's communication is linked forever with it's original form, that of the scientist is modified, amplified, fused with the ideas and results of others, and melts into the stream of knowledge and ideas which forms our culture. The scientist has in common with the artist only this: that he can find no better retreat from the world than his work and also no stronger link with his world than his work."

Well, I like to listen to the wisdom of Max Delbrück. Like my other historical hero, Richard Feynman, who also passed through here, Max had a way of seeing directly into the core of things and clarifying it for the rest of us.

But I am not convinced with Max that the joy of scientific creation must remain completely mysterious and unexplainable, locked away from all but a few esoterically informed colleagues. I lean toward Feynman in this matter. I think Feynman would have said, if you can understand it, you can explain it.

So I'm going to try to explain how it was that I invented the polymerase chain reaction. There's a bit of it that will not easily translate into normal language. If that part weren't of some interest to more than a handful of people here, I would just leave it out. What I will do instead is let you know when we get to that and also when we are done with it. Don't trouble yourself over it. It's esoteric and not crucial. I think you can understand what it felt like to invent PCR without following the details.

In 1953, when Jim Watson and Francis Crick published the structure of DNA, Schroedinger's little book and I were eight years old. I was too young to notice that mankind had finally understood how it might be that "like begat like." The book had been reprinted three times. I was living in Columbia S.C., where no one noticed that we didn't have a copy. But my home was a few blocks away from an undeveloped wooded area with a creek, possums, racoons, poisonous snakes, dragons, and a railroad track. We didn't need a copy. It was a wilderness for me and my brothers, an unknown and unregimented place to grow up. And if we got bored of the earth, we could descend into the network of storm drains under the city. We learned our way around that dark, subterranean labyrinth. It always frightened us. And we always loved it.

By the time Watson and Crick were being honored here in Stockholm in 1962, I had been designing rockets with my adolescent companions for three years. For fuel, we discovered that a mixture of potassium nitrate and sugar could be very carefully melted over a charcoal stove and poured into a metal tube in a particular way with remarkable results. The tube grew larger with our successive experiments until it was about four feet long. My mother grew more cautious and often her head would appear out of an upstairs window and she would say things that were not encouraging. The sugar was reluctantly furnished from her own kitchen, and the potassium nitrate we purchased from the local druggist.

Back then in South Carolina young boys seeking chemicals were not immediately suspect. We could even buy dynamite fuse from the hardware with no questions asked. This was good, because we were spared from early extinction on one occasion when our rocket exploded on the launch pad, by the very reliable, slowly burning dynamite fuses we could employ, coupled with our ability to run like the wind once the fuse had been lit. Our fuses were in fact much improved over those which Alfred Nobel must have used when he was frightening his own mother. In one of our last experiments before we became so interested in the maturing young women around us that we would not think deeply about rocket fuels for another ten years, we blasted a frog a mile into the air and got him back alive. In another, we inadvertently frightened an airline pilot, who was preparing to land a DC-3 at Columbia airport. Our mistake.

At Dreher High School, we were allowed free, unsupervised access to the chemistry lab. We spent many an afternoon there tinkering. No one got hurt and no lawsuits resulted. They wouldn't let us in there now. Today, we would be thought of as a menace to society. If I'm not mistaken, Alfred Nobel for a time was not allowed to practice his black art on Swedish soil. Sweden, of course, was then and still is a bit ahead of the United States in these matters.

I never tired of tinkering in labs. During the summer breaks from Georgia Tech, Al Montgomery and I built an organic synthesis lab in an old chicken house on the edge of town where we made research chemicals to sell. Most of them were noxious or either explosive. No one else wanted to make them, somebody wanted them, and so their production became our domain. We suffered no boredom and no boss. We made enough money to buy new equipment. Max Gergel, who ran Columbia Organic Chemicals Company, and who was an unusually nice man, encouraged us and bought most of our products, which he resold. There were no government regulators to stifle our fledgling efforts, and it was a golden age, but we didn't notice it. We learned a lot of organic chemistry.

By the time I left Georgia Tech for graduate school in biochemistry at the University of California at Berkeley, the genetic code had been solved. DNA did not yet interest me. I was excited by molecules. DNA before PCR was long and stringy, not really molecular at all. Six years in the biochemistry department didn't change my mind about DNA, but six years of Berkeley changed my mind about almost everything else.

I was in the laboratory of Joe Neilands who provided his graduate students with a place to work and very few rules. I'm not even sure that Joe knew any rules except the high moral ground of social responsibility and tolerance. Not knowing that the department did have rules, I took astrophysics courses instead of molecular biology, which I figured I could learn from my molecular biologist friends. I published my first scientific paper in Nature, in 1968. It was a sophomoric astrophysical hypothesis called "The Cosmological Significance of Time Reversal." I think Nature is still embarrassed about publishing it, but it was immensely useful to me when it came time for my qualifying examination. The committee would decide whether or not I would be allowed to take a Ph. D, without having taken molecular biology. And my paper inNature, helped them to justify a "yes." In retrospect, the membership of that committee is intriguing.

Don Glaser, who received this Prize in physics in 1960 at age 34, would later be one of the founders of Cetus Corporation, where I was working when I invented PCR. Henry Rapaport, who discovered psoralens would be the scientific advisor to my department at Cetus, and would co-author two patents with me. Alan Wilson, now sadly passed away, would be the first researcher outside of Cetus to employ PCR. And Dan Koshland would be the editor of Science when my first PCR paper was rejected from that journal and also the editor when PCR was three years later proclaimed Molecule of the Year. I passed. None of us, I think, as we walked out of that room, had any conscious inkling of the way things would turn out among us.

In Berkeley it was a time of social upheaval and Joe Neilands was the perfect mentor to see his people through it with grace. We laughed a lot over tea at four every afternoon around a teakwood table that Joe had brought from home and oiled once a month. Our lab had an ambience that was special. I decided to become a neurochemist. Joe was the master of microbial iron transport molecules. It wasn't done like that in most labs, where the head of the lab would prefer that you help advance his career by elaborating on some of his work. Not so with Neilands. As long as I wrote a thesis and got a degree, he didn't care what else I did, and I stayed in his lab happily, following my own curiosity even if it carried me into music courses, for as long as Joe thought we could get away with it. The department was paying me a monthly stipend from the NIH, and eventually, Joe knew, I would have to leave.

After six years I headed east with a Ph. D. and confidence in my education. My wife of a few months went to Kansas to go to medical school and I followed her there. That was 1972.

I had made no professional plans that would work in Kansas, so I decided to become a writer. I discovered pretty quickly that I was far too young. I didn't know anything yet about tragedy, and my characters were flat. I didn't know how to describe a mean spririt in terms someone else could believe.

So I had to get a job as a scientist. I found one at the medical school working with two pediatric cardiologists and a pathologist. It was a very fortunate accident. For one thing pediatricians are always the nicest doctors, and for another thing these doctors were very special: Leone Mattioli, whose wife could cook, Agostino Molteni and Richard Zakheim. For two years I did medical research, learned how to appreciate Old World values from two Italians and a New York Jew, and learned human biology for the first time.

Marriage over, I returned to Berkeley, working for a time in a restaurant and then at the University of California at San Francisco killing rats for their brains. I saw Max Delbrück talk, but I don't think I understood the significance of who he was, nor was I influenced to go into molecular biology by him. I was working on the enkephalins.

But then there was a seminar describing the synthesis and cloning of a gene for somatostatin. That impressed me. For the first time I realized that significant pieces of DNA could be synthesized chemically and that they were likely to be very exciting. I started studying DNA synthesis in the library. And I started looking for a job making DNA molecules.

Cetus hired me in the fall of 1979. I worked long hours and enjoyed it immensely. DNA synthesis was much more fun than killing rats, and the San Francisco Bay Area was a good place to be doing it. There were a number of biotechnology companies and several academic groups working on improving the synthesis methods for DNA. Within two years, there was a machine in my lab from Biosearch of San Rafael, California, turning out oligonucleotides much faster than the molecular biologists at Cetus could use them. I started playing with the oligonucleotides to find out what they could do.

The lab next door to me was run by Henry Erlich and was working on methods for detecting point mutations. We had made a number of oligonucleotides for them. I started thinking about their problem and proposed an idea of my own which they ended up calling oligomer restriction. It worked as long as the target sequence was fairly concentrated, like a site on a purified plasmid, but it didn't work if the site was relatively rare, like a single copy gene in human DNA.

I apologize to those of you who just got lost, but I do have to say a few things now that are going to be difficult. I will get back to the story in a few minutes.

The oligomer restriction method also relied on the fact that the target of interest contained a restriction site polymorphism, which kept it from being universally applicable to just any point mutation. I started thinking about doing some experiments wherein an oligonucleotide hybridized to a specific site could be extended by DNA polymerase in the presence of only dideoxynucleoside triphosphates. I reasoned that if one of the dideoxynucleoside triphosphates in each of four aliquots of a reaction was radioactive then a analysis of the aliquots on a gel could indicate which of the dideozynucleoside triphosphates had added to the hybridized oligonucleotide and therefore which base was adjacent to the three prime end of the oligonucleotide. It would be like doing Sanger sequencing at a single base pair.

On human DNA, it would not have worked because the oligonucleotide would not have specifically bound to a single site. On a DNA as complex as human DNA it would have bound to hundreds or thousands of sites depending on the sequence involved and the conditions used. What I needed to make this work was some method of raising the relative concentration of the specific site of interest. What I needed was PCR, but I had not considered that possibility. I knew the difference numerically between five thousand base pairs as in a plasmid and three billion base pairs as in the human genome, but somehow it didn't strike me as sharply as it should have. My ignorance served me well. I kept on thinking about my experiment without realizing that it would never work. And it turned into PCR.

One Friday night I was driving, as was my custom, from Berkeley up to Mendocino where I had a cabin far away from everything off in the woods. My girlfriend, Jennifer Barnett, was asleep. I was thinking. Since oligonucleotides were not that hard to make anymore, wouldn't it be simple enough to put two of them into the reaction instead of only one such that one of them would bind to the upper strand and the other to the lower strand with their three prime ends adjacent to the opposing bases of the base pair in question. If one were made longer than the other then their single base extension products could be separated on a gel from each other and one could act as a control for the other. I was going to have to separate them on a gel anyway from the large excess of radioactive nucleosidetriphosphate. What I would hope to see is that one of them would pick up one radioactive nucleotide and the other would pick up its complement. Other combinations would indicate that something had gone wrong. It was not a perfect control, but it would not require a lot of effort. It was about to lead me to PCR.

I liked the idea of a control that was nearly free in terms of cost and effort. And also, it would help use up the oligonucleotides that my lab could now make faster than they could be used.

As I drove through the mountains that night, the stalks of the California buckeyes heavily in blossom leaned over into the road. The air was moist and cool and filled with their heady aroma.

Encouraged by my progress on the thought experiment I continued to think about it and about things that could possibly go wrong. What if there were deoxynucleoside triphosphates in the DNA sample, for instance? What would happen? What would happen, I reasoned, is that one or more of them would be added to the oligonucleotide by the polymerase prior to the termination of chain elongation by addition of the dideoxynucleoside triphosphate, and it could easily be the wrong dideoxynucleoside triphosphate and it surely would result in an extension product that would be the wrong size, and the results would be spurious. It would not do. I needed a way to insure that the sample was free from contamination from deoxynucleoside triphosphates. I could treat the sample before the extension reaction with bacterial alkaline phosphatase. The enzyme would degrade any triphosphates present down to nucleosides which would not interfere with the main reaction, but then I would need to "deactivate the phosphatase before adding the dideoxynucleoside triphosphates and everyone knew at that time that BAP, as we called it, was not irreversibly denaturable by heat. The reason we knew this was that the renaturation of heat denatured BAP had been demonstrated in classic experiments that had shown that a protein's shape was dictated by it's sequence. In the classical experiments the renaturation had been performed in a buffer containing lots of zinc. What had not occurred to me or apparently many others was that BAP could be irreversibly denatured if zinc was omitted from the buffer, and that zinc was not necessary in the buffer if the enzyme was only going to be used for a short time and had its own tightly bound zinc to begin with. There was a product on the market at the time called matBAP wherein the enzyme was attached to an insoluble matrix which could be filtered out of a solution after it had been used. The product sold because people were of the impression that you could not irreversibly denature BAP. We'd all heard about, but not read, the classic papers.

This says something about the arbitrary way that many scientific facts get established, but for this story, it's only importance is that, had I known then that BAP could be heat denatured irreversibly, I may have missed PCR. As it was, I decided against using BAP, and tried to think of another way to get rid of deoxynucleoside triphosphates. How about this, I thought? What if I leave out the radioactive dideoxynucleoside triphosphates, mix the DNA sample with the oligonucleotides, drop in the polymerase and wait? The polymerase should use up all the deoxynucleoside triphosphates by adding them to the hybridized oligonucleotides. After this was complete I could heat the mixture, causing the extended oligonucleotides to be removed from the target, then cool the mixture allowing new, unextended oligonucleotides to hybridize. The extended oligonucleotides would be far outnum- bered by the vast excess of unextended oligonucleotides and therefore would not rehybridize to the target to any great extent. Then I would add the dideoxynucleoside triphosphate mixtures, and another aliquot of polymerase. And now things would work.

But what if the oligonucleotides in the original extension reaction had been extended so far they could now hybridize to unextended oligonucleotides of the opposite polarity in this second round. The sequence which they had been extended into would permit that. What would happen?

EUREKA!!!! The result would be exactly the same only the signal strength would be doubled.

EUREKA again!!!! I could do it intentionally, adding my own deoxynucleoside triphosphates, which were quite soluble in water and legal in California.

And again, EUREKA!!!! I could do it over and over again. Every time I did it I would double the signal. For those of you who got lost, we're back! I stopped the car at mile marker 46,7 on Highway 128. In the glove compartment I found some paper and a pen. I confirmed that two to the tenth power was about a thousand and that two to the twentieth power was about a million, and that two to the thirtieth power was around a billion, close to the number of base pairs in the human genome. Once I had cycled this reaction thirty times I would be able to the sequence of a sample with an immense signal and almost no background.

Jennifer wanted to get moving. I drove on down the road. In about a mile it occurred to me that the oligonucleotides could be placed at some arbitrary distance from each other, not just flanking a base pair and that I could make an arbitrarily large number of copies of any sequence I chose and what's more, most of the copies after a few cycles would be the same size. That size would be up to me. They would look like restriction fragments on a gel. I stopped the car again.

"Dear Thor!," I exclaimed. I had solved the most annoying problems in DNA chemistry in a single lightening bolt. Abundance and distinction. With two oligonucleotides, DNA polymerase, and the four nucleosidetriphosphates I could make as much of a DNA sequence as I wanted and I could make it on a fragment of a specific size that I could distinguish easily. Somehow, I thought, it had to be an illusion. Otherwise it would change DNA chemistry forever. Otherwise it would make me famous. It was too easy. Someone else would have done it and I would surely have heard of it. We would be doing it all the time. What was I failing to see? "Jennifer, wake up. I've thought of something incredible."

She wouldn't wake up. I had thought of incredible things before that somehow lost some of their sheen in the light of day. This one could wait till morning. But I didn't sleep that night. We got to my cabin and I starting drawing little diagrams on every horizontal surface that would take pen, pencil or crayon until dawn, when with the aid of a last bottle of good Mendocino county cabernet, I settled into a perplexed semiconsciousness.

Afternoon came, including new bottles of celebratory red fluids from Jack's Valley Store, but I was still puzzled, alternating between being absolutely pleased with my good luck and clever brain, and being mildly annoyed at myself and Jennifer Barnett, for not seeing the flaw that must have been there. I had no phone at the cabin and there were no other biochemists besides Jennifer and me in Anderson Valley. The conundrum which lingered throughout the week-end and created an unprecedented desire in me to return to work early was compelling. If the cyclic reactions which by now were symbolized in various ways all over the cabin really worked, why had I never heard of them being used? If they had been used, I surely would have heard about it and so would everybody else including Jennifer, who was presently sunning herself by the pond taking no interest in the explosions that were rocking my brain.

Why wouldn't these reactions work?

Monday morning I was in the library. The moment of truth. By afternoon it was clear. For whatever reasons, there was nothing in the abstracted literature about succeeding or failing to amplify DNA by the repeated reciprocal extension of two primers hybridized to the separate strands of a particular DNA sequence. By the end of the week I had talked to enough molecular biologists to know that I wasn't missing anything really obvious. No one could recall such a process ever being tried.

However, shocking to me, not one of my friends or colleagues would get excited over the potential for such a process. True. I was always having wild ideas, and this one maybe looked no different than last week's. But it WAS different. There was not a single unknown in the scheme. Every step involved had been done already. Everyone agreed that you could extend a primer on a DNA template, everyone knew you could melt double stranded DNA. Everyone agreed that what you could do once, you could do again. Most people didn't like to do things over and over, me in particular. If I had to do a calculation twice, I preferred to write a program instead. But no one thought it was impossible. It could be done, and there was always automation. The result on paper was so obviously fantastic, that even I had little irrational lapses of faith that it would really work in a tube, and most everyone who could take a moment to talk about it with me, felt compelled to come up with some reason why it wouldn't work. It was not easy in that post-cloning, pre-PCR year to accept the fact that you could have all the DNA you wanted. And that it would be easy.

I had a directory full of untested ideas in the computer. I opened a new file and named this one polymerase chain reaction. I didn't immediately try an experiment, but all summer I kept talking to people in and out of the company. I described the concept around August at an in-house seminar. Every Cetus scientist had to give a talk twice a year. But no one had to listen. Most of the talks were dry descriptions of labor performed and most of the scientists left early without comment.

One or two technicians were interested, and on the days when she still loved me, Jennifer, thought it might work. On the increasingly numerous days when she hated me, my ideas and I suffered her scorn together.

I continued to talk about it, and by late summer had a plan to amplify a 400-bp fragment from Human Nerve Growth Factor, which Genentech had cloned and published in Nature. I would start from whole human placental DNA from Sigma. taking a chance that the cDNA sequence had derived from a single exon. No need for a cDNA library. No colonies, no nothing. It would be dramatic. I would shoot for the moon. Primers were easy to come by in my lab, which made oligonucleotides for the whole company. I entered the sequences I wanted into the computer and moved them to the front of the waiting list.

My friend Ron Cook, who had founded Biosearch, and produced the first successful commercial DNA synthesis machine, was the only person I remember during that summer who shared my enthusiasm for the reaction. He knew it would be good for the oligonucleotide business. Maybe that's why he believed it. Or maybe he's a rational chemist with an intact brain. He's one of my best friends now, so I have to disqualify myself from claiming any really objective judgement regarding him. Perhaps I should have followed his advice, but then things would have worked out differently and I probably wouldn't be here on the beach in La Jolla writing this, which I enjoy. Maybe I would be rich in Tahiti. He suggested one night at his house that since no one at Cetus had taken it seriously, I should resign my job, wait a little while, make it work, write a patent, and get rich. By rich he wasn't imagining $300000000. Maybe one or two. The famous chemist Albert Hofmann was at Ron's that night. He had invented LSD in 1943. At the time he didn't realize what he had done. It only dawned on him slowly, and then things worked their way out over the years like no one would have ever predicted, or could have controlled by forethought and reason.

I responded weakly to Ron's suggestion. I had already described the idea at Cetus, and if it turned out to be commercially successful they would have lawyers after me forever. Ron was not sure that Cetus had rights on my ideas unless they were directly related to my duties. I wasn't sure about the law, but I was pretty happy working at Cetus and assumed innocently that if the reaction worked big time I would be amply rewarded by my employer.

The subject of PCR was not yet party conversation, even among biochemists, and it quickly dropped. Albert being there was much more interesting, even to me. He had given a fine talk that afternoon at Biosearch.

Anyhow, my problems with Jennifer were not getting any better. That night was no exception to the trend. I drove home alone feeling sad and unsettled, not in the mood for leaving my job, or any big change in what was left of stability in my life. PCR seemed distant and very small compared to our very empty house.

In September I did my first experiment. I like to try the easiest possibilities first. So one night I put human DNA and the nerve growth factor primers in a little screw-cap tube with an O-ring and a purple top. I boiled for a few minutes, cooled, added about 10 units of DNA polymerase, closed the tube and left it at 37°. It was exactly midnight on the ninth of September. I poured a cold Becks into a 400-ml beaker and contemplated my notebook for a few minutes before leaving the lab.

Driving home I figured that the primers would be extended right away, and I hoped that at some finite rate the extension products would come unwound from their templates, be primed and re-copied, and so forth. I did not relish the idea of heating, cooling, adding polymerase over and over again, and held this for a last resort method of accomplishing the chain reaction. I was thinking of DNA:DNA interactions as being reversible with all the ramifications thereof. I wasn't concerned about the absolute rate of dissociation, because I didn't care how long the reaction took as long as nobody had to do anything. I assumed there would always be some finite concentration of single strands, which would be available for priming by a relatively high concentration of primer with pseudo-first order kinetics.

For a reaction with the potential which I dreamed of for this one, especially in light of the absence of anything else that could do the same thing, time was only a very secondary consideration. Would it work at all was important. The next most important thing was, would it be easy to do? Then came time.

At noon the next day I went to the lab to take a 12-hour sample. There was no sign by ethidium bromide of any 400-bp bands. I could have waited another hundred years as I had no idea what the absolute rates might be. But I succumbed slowly to the notion that I couldn't escape much longer the unpleasant prospect of cycling the reaction between single stranded temperatures and double stranded temperatures. This also meant adding the thermally unstable polymerase after every cycle.

For three months I did sporadic experiments while my life at home and in the lab with Jennifer was crumbling. It was slow going. Finally, I retreated from the idea of starting with human DNA, I wasn't even absolutely sure that the Genentech sequence from Nature that I was using was from a single exon. I settled on a target of more modest proportions, a short fragment from pBR322, a purified plasmid. The first successful experiment happened on December 16th. I remember the date. It was the birthday of Cynthia, my former wife from Kansas City, who had encouraged me to write fiction and bore us two fine sons. I had strayed from Cynthia eventually to spend two tumultuous years with Jennifer. When I was sad for any other reason, I would also grieve for Cynthia. There is a general place in your brain, I think, reserved for "melancholy of relationships past." It grows and prospers as life progresses, forcing you finally, against your grain, to listen to country music.

And now as December threatened Christmas, Jennifer, that crazy, wonderful woman chemist, had dramatically left our house, the lab, headed to New York and her mother, for reasons that seemed to have everything to do with me but which I couldn't fathom. I was beginning to learn tragedy. It differs a great deal from pathos, which you can learn from books. Tragedy is personal. It would add strength to my character and depth someday to my writing. Just right then, I would have preferred a warm friend to cook with. Hold the tragedy lessons. December is a rotten month to be studying your love life from a distance.

I celebrated my victory with Fred Faloona, a young mathematician and a wizard of many talents whom I had hired as a technician. Fred had helped me that afternoon set up this first successful PCR reaction, and I stopped by his house on the way home. As he had learned all the biochemistry he knew directly from me he wasn't certain whether or not to believe me when I informed him that we had just changed the rules in molecular biology. "Okay, Doc, if you say so." He knew I was more concerned with my life than with those cute little purple-topped tubes.

In Berkeley it drizzles in the winter. Avocados ripen at odd times and the tree in Fred's front yard was wet and sagging from a load of fruit. I was sagging as I walked out to my little silver Honda Civic, which never failed to start. Neither Fred, empty Becks bottles, nor the sweet smell of the dawn of the age of PCR could replace Jenny. I was lonesome.

From Nobel Lectures, Chemistry 1991-1995, Editor Bo G. Malmström, World Scientific Publishing Co., Singapore, 1997


Copyright © The Nobel Foundation 1993

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