Thursday, December 29, 2005

Scientific Fraud

The New York Times is now reporting that the human cloning result of Hwang Woo Suk was completely fabricated. His two Science papers in 2004 and 2005 rocked the scientific community and put South Korea at the forefront of stem cell research. He had planned to open cloning centers around the world to provide research labs with various embryonic stem cell lines. Now, he has been completely disgraced and the field has been set back somewhat.

I think this is an example of how giving unlimited resources to a single individual can lead to bad results. The Korean government gave Hwang almost 40 million dollars since 1998 in hopes of garnering the nation's first Noble prize. He must have felt tremendous pressure to succeed.

I can envision a scenario that led to the fraud. His lab probably had preliminary results that seemed to work but they then couldn't reproduce it. Hwang likely felt frustrated but confident that the method would eventually work so he decided to proceed with publication so they wouldn't get scooped. Maybe he rationalized that there would be little harm to embellish some data to get the news out earlier. In the meantime he would get it to work reliably. He may even have gotten away with it if the papers didn't have as large an impact which led to greater scrutiny of the work.

Sometimes throwing money at a problem does pan out. Examples include the Manhattan project and the Apollo moon mission. In these cases, there was a talented and motivated team focused on the task. There was a sense of urgency but there was also an imperative to be correct. People were checking other people's work because making an error had dire consequences. The participants weren't thinking about future riches or fame. While it is true that Oppenheimer became a household name, he certainly didn't put pressure on the team to succeed so he could become rich and famous. What he did do was assemble the greatest minds of the time.

Will a Manhattan type effort work in biology? I'm not so sure because there is still a lot of basic science to discover. We don't really know what must be done to cure diabetes, malaria or cancer. I think the best thing to do now is to have many labs pursue many different paths. We may even want to divide the money out more evenly than it is now. Someone should do a study to see if it is more cost effective to fund a few big labs or many small labs. I'm betting on the latter.

Tuesday, December 20, 2005

Life Will Go On

At this moment, we are undergoing a massive loss of species on par with the six great extinctions of history such as the most recent one 65 million years ago and the Great Dying of 250 million years ago. Being a good existentialist, I agree that we should do all we can to prevent loss of biodiversity even if the effort is likely to be futile. However, a part of me is secure that life will go on regardless of what happens now. Each great extinction is always followed by a flowering of new life. It was only because of the demise of the dinosaurs were mammals able to rise. I agree that it is a major cause of concern as to whether we will survive this extinction but on the long time scale all species eventually go extinct.

Ironically, one reason for my optimism is the large amount of garbage we dump into the environment. The toxicity of a waste product implies that it is bioreactive and hence could be exploited. Remember that oxygen was once an environmental toxin that forced major changes to life on earth. The extra methane and carbon dioxide we currently spew into the atmosphere could likewise be utilized. I'm sure new species of life will be found in garbage dumps sometime in the future.

There are already some signs of adaptation to the modern world even by large animals. For example, deer are now doing so well in cities and suburbs that some communities need to cull them. New York City has several pairs of thriving peregrine falcons. Some fear that beautiful species like orchids, parrots, and sea otters will disappear leaving behind only drab scavengers like cockroaches, coyotes, crows and rats. I think we need to give life more credit. I don't think beauty is necessarily correlated with fragility. Also, our standards of beauty have been shaped by our environment. As the environment changes, so too will our brains and hence what we consider beautiful. Barring a catastrophic event like a nearby supernova or a complete loss of atmosphere, I think we can be fairly certain that life will continue to flourish on earth in spite of what we do.

Saturday, December 03, 2005

Observations of a Dad

When a baby is born, she immediately has a set of reflexes - like rooting for a nipple, crying, grasping, and sleeping. These reflexes are hardwired into the brain and get triggered by certain sensory cues. Hunger and discomfort trigger crying, stroking of the face sets off rooting, and putting something in her hand initiates grasping.

What makes a baby fussy or easy going is coded in the thresholds that trigger the reflexes and shuts them off. Some babies can tolerate a large amount of discomfort before they cry and transition from an active state into sleep quickly. These are easy babies. In fussy babies, the discomfort thresholds may be very low and small perturbations can trigger crying. Most babies are somewhere in between - fussy in some aspects, impervious in others.

The multiple thresholds are set at birth and in essence define the initial personality of a baby. There is probably a genetic component but I bet most are set entirely randomly. After the baby is born, neural plasticity can shift these settings. So depending on how the parents react to the baby, thresholds could be moved up or down.

An entire book industry has sprouted in an attempt to educate parents on how to train their baby to be an easy going one. However, I doubt there will ever be a surefire method. The different sensory and reflex modalities probably interact in a highly nonlinear fashion. So trying to make a baby less sensitive to one thing could make them more sensitive to something else. Personally, I think we should just enjoy our babies the way they are. But then again, I think my baby is pretty easy, even if she stays up all night.

Monday, November 21, 2005

Life with Baby

Time stands still, time rushes forward.

A day is gone and what has happened?

Change her diaper, feed her, make a trip to the doctor, go get food, do the laundry, do some more laundry, make another trip to the doctor.

Did I miss a day? When did I last sleep?

Yet, when she opens her bright wide eyes and sneaks a peak, my heart melts.

When she cracks a wry smile, I just want to hold her close.

What if she could be like this forever, so tiny in my hands, so beautiful?

She waves her arms about and alights one gently on her cheek.

She is my one joy, my being, my life.

She is my baby.

Wednesday, November 09, 2005

Why vote?

In last Sunday's New York Times magazine, the economists that brought us Freakonomics argued that a rational individual should abstain from voting. According to them, virtually no election is decided by a single vote so the cost for voting is never compensated by any payoff. Their conclusion of why we (or some of us) actually do vote is because of the social esteem gained by being seen voting by our peers. They predict that internet voting may actually reduce voter turnout because we would no longer get this social payoff.

It seems to me that using social prestige as the basis for selecting a leader is a shaky way to maintain a democracy. The real intent of an election is to determine which candidate is favoured by the majority of the populace. For the most part, our current method accomplishes this task (insert your favourite Florida 2000 joke here) although it has two main problems.

The first is that making everyone vote to determine who is preferred is wasteful. In statistics, this is known as an overpowered experimental design. We only need to sample a fraction of the population to obtain an estimate of the election result. The error on the estimate scales with the square root of the sample size. In an election, when enough people have voted so that the error in the estimated result is less then the eventual margin, additional polling won't give you any new information. This is why a single vote doesn't matter.

In a practical sense, this is already what we do because only a fraction of the population votes. However, the fraction that votes is not guaranteed to be a representative sample of the population. Any bias in how the sample is selected will bias the estimate. This leads to the second problem with elections. In a close election, who shows up to vote could skew the results. One facet of election strategy is to enhance the turnout of your voters and suppress that of your opponent's. This never seemed very democratic to me.

If we really wanted to elect leaders based on what the true majority wishes then an election is not the optimal method. What we really should be doing is to scientifically select a sample of the population to vote. Of course deciding on how to choose this sample will never be perfect. There will also be some misrepresentation (like underrepresentation of homeless people) but I think we can certainly do better than what we have now. If we wanted to be really efficient we could even use a bootstrap method to estimate the error compared to the estimated margin of victory on the fly. Now, I'd like to see some brave politician suggest this scheme.

Friday, November 04, 2005

Dark Genome

Cosmologists are very troubled by the fact that they can't account for (depending on whom you ask) 90% to 99% of the mass and energy of the universe. The nature of this "Dark Matter" is the most pressing problem of their field. However, biologists don't seem nearly as perturbed by the fact that the purpose of a similar fraction of the mammalian genome is completely unknown. They are so unconcerned that only a small fraction of the genome is in the genes that code for proteins that much of the non-coding region is simply called junk DNA.

It has always perplexed me why most of our DNA would be junk. I can't believe that 90% of the DNA has no use whatsoever. It would seem much more likely that this so-called junk DNA is necessary for genetic regulation. After all, the main reason I am different from another person is not in the differences in the proteins I carry but in how and when they are expressed. Darwin himself recognized that much of the variation in nature must be due to regulation.

A very nice paper by Peter Andolfatto in the October 20 issue of Nature shows that in the fruit fly between 40% to 70% of the DNA nucleotides situated between genes are under selection pressure by evolution. He showed this in a very clever way. He analyzed the DNA of two species of Drosophila - D. melanogaster and D. simulans and looked at the level of polymorphism (differences within a species) and divergence (differences between species) in the genome. As a control he looked at synonymous sites (region in the coding region of DNA where a change in the nucleotide does not change the amino acid it codes for because of redundancies in the nucleotide triplet code).

Andolfatto found that the rate of mutation in non-coding regions is slightly lower than in synonymous sites indicating these sites have undergone negative selection pressure. Additionally, he found that the divergence rate in selected sites was increased relative to the polymorphism indicating that they also experience positive selection pressure. In other words, most mutations in these regions are deleterious and thus are selected against but every once in a while a nucleotide substitution confers some advantage and this is selected for. The bottom line is that these non-coding regions are crucial for the survival of the organism.

What these non-coding regions are for is unknown. The current dogma says that gene expression is controlled by sets of transcription factors that act on various promoter regions. According to Alex Kondrashov in the accompanying News and Views piece, current estimates of the fraction of functionally important segments of mammalian non-coding DNA is less than 15%. Although, an equivalent study still needs to be done in mammals, I'm betting that a significant portion of what is thought of as junk DNA is used for regulation and in a completely novel way.

Wednesday, October 26, 2005

The Make Work Society

Recently, I've been thinking a lot about economics, the dismal science. In particular, I've been thinking about the creation and distribution of wealth. Of course this question has been analyzed countless times before, most notably by Marx, but I'll add my take anyway. Let's define the wealth of our society as the sum of everything we create. More precisely, we create wealth at a given rate and it dissipates at another rate. Some things like a restaurant meal or a pop tune, dissipate rather quickly, and others like a gold figurine can last a long time. For the most part, we only get a share of this wealth if we work.

As time goes by, we get more efficient and increase the wealth creation rate (or decrease the dissipation rate). While that seems to be a good thing it does generate some problems. One of them is quite simple. If you get more efficient at making something and you work the same amount of time, then you'll make more of that thing. However, unless someone wants to buy more of your thing, the extra stuff you've created will just sit around and not be of much use. They way around this problem is to either convince people they need more of the same stuff (i.e. marketing) or to produce other stuff. That is why thirty years ago you had a pair of dress shoes and a pair of athletic shoes but now you must have running shoes, basketball shoes, tennis shoes, squash shoes, mountain biking shoes, climbing shoes, light hiking boots, heavy hiking boots, and so forth.

However, even the best ad agency can only convince us to consume so much of one thing. So, once a market is saturated, increased efficiency means fewer people are required to make that product. These people must then find new ways to work to get a share of the wealth. Some can either make new stuff for you to buy like iPods, digital cameras, gourmet food, and storage crates to put all this stuff in or create new services like personal chefs, dog walkers, and fitness instructors. Most likely, they'll work at a low paying jobs like fast food server.

More efficiency means we will be inundated by more stuff and services we don't really need or want. Many of the new jobs will not be well compensated so the gap between the rich and poor will grow. In some sense, our solution to distributing wealth is to create a "make work" state where most of the people support themselves with artificial or menial jobs. I don't really see this as being much better than a welfare state.

One solution is that we could choose to keep wealth creation per capita fixed so as our efficiency increased we would simply work less for the same pay. So if a factory can make the same shoe in half the time then people could just work half as long. Cutting the work week even just a little bit could solve our unemployment problem. The US has twice the wealth of most western European countries. As I wrote before, we are already more than rich enough. What we now need is the time to enjoy some of this wealth.

Thursday, October 20, 2005

Your Ecological Footprint

The ecological footprint gives an estimate of how much productive land and water is necessary to support what you use and discard. This includes all the land you need for the food you eat, the fossil fuels you burn to sustain your lifestyle, the amount of forest required to absorb the green house gases you produce, and the waste you create. There are many websites estimating the ecological footprint. I recently tried You fill out a questionnaire and then it gives you the result. According to this website (and I didn't check their algorithm) the average American has a footprint of 24 acres. Worldwide there only exists 4.5 biologically productive acres per person. I answered the quiz twice. The first time I gave what I thought was the upper bound for my current lifestyle and I got a result of 24 acres - the American average. I then tried it again using the lowest bound, ignoring my now long commute and it still came up with 8 acres. It is almost impossible to live in the US and get below this value. Our whole infrastructure is based on an inexhaustible supply of natural resources. I am simply not paying for the true cost of having a New Zealand grown apple in February, working in a climate controlled office year round, and being able to jet over to Europe when I need to. If this is true then we're going run into serious trouble when the rest of the world starts to consume like we do.

Sunday, October 16, 2005

Stem Cell Loopholes

When gas mileage regulations were tightened after the energy crisis in the late seventies, the American car companies hired lawyers to challenge the regulations while the Japanese companies hired engineers to find ways to comply. Given that Toyota is on the verge of surpassing GM as the world's largest car company, it seems pretty clear which was the better strategy.

Now, a similar situation exists for stem cell research. In an earlier post, I wrote about some of the ethical questions surrounding the issue. Current US regulations only allow federal funding for human stem cell research on embryonic stem (ES) cells derived from a fixed set of cell lines established prior to August 2001. However, many of these lines have been contaminated and researches would like to create more lines. So while some people are striving for a political solution to obtaining more stem cell lines, another group is looking for a technological fix to ease the ethical and religious concerns.

Two papers appearing in today's Nature advanced online publications, demonstrate possible methods in mice to obtain stem cells without technically destroying an embryo. The first by a group from Advanced Cell Technology, extracts a single cell from a developing blastocyst when it is comprised of 8 cells. They then show that they can create an ES line from this single blastomere that remains viable even after 50 divisions. The second paper from MIT, uses a method called altered nuclear transfer (ANT). This is a means of doing therapeutic cloning without destroying an embryo. Instead of implanting adult cells directly into a donated egg that can become a viable embryo to harvest stem cells, certain developmental genes are first deactivated in the adult cell so that the ensuing blastocyst can never implant in a uterus and hence fully develop.

Both approaches have been embraced and criticized and the New York Times has a synopsis of the reactions. I find both approaches to be rather unsatisfactory and expose the hypocrisy of the whole issue. Evidently, fertility clinics already do single-cell embryo biopsy for genetic screening prior to implantation. Supposedly, it is safe and there have been many successful births from embryos that have had a cell extracted. But I wonder who were the first parents to have had this procedure done on their baby? It sounds like rolling the dice on a life to me. The child may seem normal now but we don't know if there are any long term consequences. ANT seems completely contrived. The altered blastocyst is completely identical to a normal one when the stem cell is extracted. The only difference is that if both happen to be in a uterus, then one can implant and the other can't. However, unless you actually implant it you'll never know. So, if we were to say that we fully intend to alter a nucleus prior to implantation for therapeutic cloning, would that be good enough?

If one wants to have a fully consistent position on stem cells then one can either be for them or against them. There is no middle ground. There are no semantic loopholes. Each cell contains the entire genome so it has all the information to create life. Destroying a cell is thus equivalent to destroying an embryo. If one is against stem cell research then one must be against all genetic and cellular manipulations in humans (and perhaps all animals). That means no in vitro fertilization, no gene therapy, no ultrasound imaging of the fetus and certainly no amniocentesis. One could possibly take it further and say that any biological research that destroys cells should not be performed. People must start accepting that it's the software and not the hardware that defines a human life.

Thursday, October 06, 2005

Forbes 400

Every Fall, the Nobel Prizes are awarded and Forbes Magazine publishes a list of the 400 richest Americans. The bottom line is that the rich are definitely getting richer. Bill Gates again tops the list with 51 billion dollars although the five members of the Walton family (numbers 6 through 10) if combined would exceed his fortune with close to 80 billion. Rounding out the top 11 are Warren Buffet at number 2, Paul Allen at 3, Michael Dell at 4, Larry Ellison at 5, and Steve Balmer at 11.

The combined wealth of the Forbes 400 is 1.13 trillion dollars. To put this in perspective, according the CIA world factbook, the US GDP in 2004 was 11.8 trillion dollars and the world GDP was 55.5 trillion. If we assume an income of 10% per year, the Forbes 400 makes up 1% of the US GDP and 0.2% of the world GDP.

The US per capita GDP works out to be about $40,000 a year. Thus, if income were distributed evenly, every family of four would take home $160,000 per year. You wouldn't know it after seeing the effects of Katrina but the US is wealthy enough such that every family could be upper middle class. The US is by far the richest nation on the planet. In comparison, the other group of 7 nations all have per capita incomes below $30,000.

So what is the solution to poverty? I think the argument that it can be eliminated with economic growth seems to be proven wrong. We already are more than rich enough to ensure that every person could have a comfortable life. Obviously, some form of reallocation is necessary although I'm sure there are those who would argue that any attempt to redistribute wealth would only decrease US productivity. However, this imbalance cannot be sustained forever. It took a great depression and two world wars to lessen the income disparity from the robber baron era of a century ago. Do we need to go through something catastrophic again to repair our current inequities?

Wednesday, September 28, 2005

Grass Power

A possible promising crop for biofuel may be a form of Elephant Grass (Miscanthus x giganteus). This tall grass hybrid could yield up to 60 tonnes of biomass per acre. It is currently being tested in Europe. It thrives in northern climates and requires very little fertilizer. It has a low water content so it can be easily harvested at the end of the growing season and simply burned for power. Stephen Long of University of Illinois calculates that if 8% of all the land in Illinois was dedicated to this crop, it could generate half of the electrical needs of the state. It also has little effect on the carbon balance because it simply releases the CO2 when burned that was sequestered when it was growing. The hybrid does not produce seeds so it can't spread. Further bioengineering could make it even more efficient. Who says I can't say something positive?

Thursday, September 22, 2005

Programmed for Failure

Every time I feel kind of optimistic about the future, I think back to the Roman Empire and realize that it could all end pretty quickly. It may be no accident that civilizations tend to have finite lives and our brains may be responsible. Jared Diamond(in his book Collapse) posits a framework for a society's demise but he basically believes it is some combination of bad decision making and management that leads to failure. I'm proposing that it may actually be embedded in how our brains work and how it reacts to success. What allows us to build great civilizations may ultimately be responsible for our undoing.

As has been written in countless columns and blogs, manufacturing, software development, clerical work and so forth is being or will soon be outsourced to an offshore location where labour costs are so much lower. Many have argued that the US can retain world dominance by remaining a source of innovation and ideas. However, Thomas Friedman and others have been screaming lately that the US is losing it's lead in technology and science and American students are falling behind the rest of the world in technical subjects.

The reason is not just that we've become lazy or stupid. The Flynn effect shows that average IQ's have actually been rising every generation and in the recent book Everything Bad is Good For You: How Today's Popular Culture Is Actually Making Us Smarter, Steven Johnson argues that video games and popular culture are actually making us smarter. So why is it that we are becoming less intellectual even though we are getting smarter?

I think it is related to the fact that it takes effort to concentrate on something. This effort is not because we're using more energy. Although it may seem that thinking hard burns more calories, there is in fact little evidence for this. So if there is no metabolic cost then why is it so difficult to think? The reason may be that the brain is a novelty machine that constantly seeks new stimuli. Advertising and marketing people know that they need to change a scene every 10 or 15 seconds in a commercial or people's attention will be lost. Our brains are designed to wander and seek new stimuli. This constant novelty seeking probably helps in the early stages of a civilization where things need to be built and everyone sees open opportunities for growth.

As a civilization matures, it takes longer and longer for the citizens to acquire and digest the accumulated knowledge required just to keep it running much less advance it. Years of training is necessary before anyone can make a contribution. Given our current comfortable circumstances, there is little incentive to undertake such an ordeal when there are so many other distractions to occupy us. In the past, scholastic learning might have been the most cognitively stimulating thing one could engage in. Now, our lives are filled with leisure activities that are much more interesting and entertaining than what we learn in school. For every high school kid with his nose stuck in an analysis textbook, there are hundreds or thousands of other kids who are playing video games, surfing the web, reading a Harry Potter novel or solving a Sudoku puzzle.

Is there a way out? I'm pessimistic. While it is true that those on the cutting edge are doing very interesting and stimulating things, the journey to get there is so long and arduous that fewer and fewer are likely to take it. No matter how appealing you may make calculus or organic chemistry, they just will never be able to compete with the endless variety of distractions in modern society. There will still be an educated elite but there won't be enough of them to keep the engine going.

The decline of the US could be very rapid. Even now, much of science and technology is being driven by foreigners. However, as the balance of power starts to shift overseas and the US remains xenophobic, that spigot could be shut off quickly. The incentive to come here will diminish and people may return to their native countries as things decline here accelerating the process.

It may be that the only hope for humanity is to maintain uneven economic development. If the entire world became comfortable simultaneously, it might completely collapse all at once. However, if the decline of the US is accompanied by the rise of China and India then at least some order in the world could be maintained. After a century or so, the US could rise again in a perpetual cycle of localized growth and decay.

Sunday, September 18, 2005

Peak Oil Production

We all know that the supply of oil is finite so the big question is how much do we have left. Geophysicist M. King Hubbert created a model of known oil reserves in 1956 and proposed that American oil production would peak between 1967 and 1972. US oil production peaked in 1971 and it's been downhill ever since. Hubbert died in 1989 but other geologists have applied his theory to global production and predict a peak between 2000 and 2010.

This month both American Scientist and Technology Review have book reviews of James Howard Kunstler's book 'THE LONG EMERGENCY: Surviving the Converging Catastrophes of the Twenty-First Century. Kunstler's thesis is that the 20th century defied Malthus because we have been living on cheap oil but when it does run out we will be in big trouble. He argues that all alternative sources of energy like solar, wind, nuclear, biofuels, hydrogen are a pipe dream that won't even come close to replacing oil. He believes that the depletion of oil will lead to social unrest and upheaval of the likes we've never seen before. The 14th century with the black death and all was pretty bad so this is really saying something.

The events of the past few weeks has sent me into a "The World is Going to End" kind of mood so I'm rather susceptible to this message. However, I think that we still have a chance to save ourselves. Conservation measures could prolong the supply of oil for say another century. This would buy us time to bring all alternative energy sources online. We will probably have to depend on nuclear power for much of it. If we're really lucky, we might get fusion to work in 50 years but that will also bring it's own set of problems. We will have to use bio-derived fuels for plastic and to power airplanes. However, our current unstainable American standard of living will decline. How far it drops is up to us.

Wednesday, September 14, 2005

Math and Biology

There's a nice article on the synergy between my two favourite subjects in the December 2004 issue of PLoS Biology.

Thursday, September 08, 2005

Pitch perception and beyond

American symphony orchestras tune their instruments to A 440 Hz (in Europe they tend to go a little sharper with A 444Hz). However, no instrument produces a single frequency. Instead, they tune their instruments so that it sounds like an A. Humans can do this quite easily but if you were to look at the spectrum you would see a mess of frequencies. If you removed the fundamental frequency and just listened to the harmonics of a sound you would still identify the pitch you hear as that of the fundamental. It has always been quite puzzling as to how the brain does it. In this week's issue of Nature, a group from Johns Hopkins reports that it has found neurons in the auditory cortex of the marmoset (Callithrix jacchus) that respond to pitch, the way a human responds. These neurons will fire when the animal is presented with the pure tone fundamental or a set of harmonics without the fundamental.

This is without a doubt a very nice and illuminating piece of work but I wouldn't say it was surprising. Ever since Hubel and Wiesel discovered orientation selective neurons in the visual cortex in the late fifties and early sixties, much of systems neuroscience has been driven to providing more and more exotic stimuli and looking for neurons that respond to them. Given the data from the past forty years, I would venture that for anything which we can sense, perceive or ideate, there exists some neuron who's activity is directly correlated to that thing. That is not to say there is just one neuron that responds to some given concept. The other lesson we learned from Hubel and Wiesel is that neurons are broadly tuned over some category. Thus, for any type of perception there will be a population of active neurons.

By any type of perception, I mean all aspects of a thought. So if you are viewing a Cezanne landscape for example, there will be neurons responding to primitive elements like shapes, lines, colours and so forth. Simultaneously, there will be other neurons that respond only to more specific things like a coloured square or to a pair of adjacent coloured squares. Then there will be neurons that respond just to trees or houses and if you know enough about art just to Cezanne paintings. What we don't know is what sorts of neural architectures and learning rules can give rise to such behaviour and how all this cacophony of activity gets sorted out. While there are some candidate ideas floating around, the jury is definitely still out.

Wednesday, September 07, 2005

Aquarium of the Americas

My favourite aquarium was the one in New Orleans. It had the most spectacular jelly fish display I have ever seen. I use the past tense because CNN reports that most of the sea creatures have died because of the power loss which shut down the water oxygenation systems. A few of the animals like the 250 pound sea turtle, the white alligator, birds, sea dragons and sea otters have survived. Another loss in this major tragedy.

Friday, September 02, 2005

Agriculture's downside

Brad De Long has posted an opinion piece from Jared Diamond arguing that agriculture, which displaced hunting and gathering as the means for sustenance, was actually humanity's greatest mistake. The article contends that agriculture promotes a much larger population with a lower quality of life for most people except for a dominating elite. In a recent post, I argued that welfare could be considered compensation for eliminating the right to forage. According to Diamond, that would hardly be a fair deal.

Fragility of civilization

The disaster unfolding before our eyes is even more troubling because it could have been mitigated in so many ways. I don't need to add anything more to the disbelief and anger spreading across the nation but it is hard not to. Among the many lessons to be drawn is that we are just a few days away from a complete breakdown of civil society. If ever there was an argument that government serves an essential role then this is it. It is quite clear who was able to get out and who was not. To blame the victims for their predicament is beyond reproach. If a city gives a mandatory evacuation order it must also provide a means for evacuation and resources for the evacuees. I can only hope that this tragedy will make us reevaluate what a just and fair civilization really means. Given that "values" was an issue in the last election I will quote directly from the bible:
The righteous is concerned for the rights of the poor; the wicked does not understand such concern. Proverbs 29:7

Wednesday, August 31, 2005

The flooding of New Orleans

It seems that the aftermath of Hurricane Katrina will be of much greater concern than the storm itself. Eighty percent of New Orleans is currently under water. Two levees holding back Lake Pontchartrain and the Mississippi have burst and water is pouring in (Here is a map from the NY Times). Since most of New Orleans is below sea level, this water cannot drain out. It will have to be pumped out. As of now, workers are still trying to repair the levees. Science writer Mark Frischetti wrote about such a possible disaster in the October 2001 issue of Scientific American. The only good news is that most of the inhabitants evacuated before the storm and water did not overwhelm the levees initially.

The nightmare scenario is that a severe storm surge will flow over the levee walls and flood the city quickly. The levees that were then designed to keep water out will now keep water in. In such a scenario, all of New Orleans would be under water up to 10 or more metres. Right now, the parts of the city above sea level like the French Quarter may be spared. I know I'm a doom and gloom kind of guy but it could take months just to make New Orleans habitable again. Half a million people could be displaced for a long time. I know the sentiment will be to rebuild the city but this will not be the last time a major hurricane will pummel the city. Wetlands that used to protect New Orleans to the south and east are diminishing at a pace of an acre very 24 minutes. The city sits directly in the path of where the Mississippi really wants to go and to top it all off it is slowly sinking. Should we seriously consider if it is worth maintaining New Orleans?

Tuesday, August 30, 2005

The Flying Spaghetti Monster

I've always been partial to linguini but it turns out I've been worshipping a false prophet. We must now give praise to the Flying Spaghetti Monster, who came to Bobby Henderson in a divine vision. You can learn about the Church of FSM at Henderson has written an open letter to the Kansas State Board of Education arguing that if intelligent design is to be taught in schools then all forms of it including those involving the FSM must also be taught. He is threatening legal action if they don't comply. He has started a whole movement of followers including splinter groups. There was a humourous column about it in the New York Times yesterday. In that article the author wonders if anyone has every converted parody into a religion. Does the Church of Scientology qualify? Personally, I'm all for "teaching the controversy". After all, less than 50% of the population believes or even understands evolution anyway (see a previous post). It may even stir up some interest in science.

Wednesday, August 24, 2005

Mind enhancing drugs

An article appearing yesterday in PloS Biology reports that an Ampakine known as CX717 can alleviate cognitive impairment due to sleep deprivation. The study was done in monkeys although the company that produced the drug - Cortex Pharmaceuticals, has announced in a press release that there is evidence that it works in humans as well.

The monkeys were first tested on a simple cognitive task (delayed-match-to-sample). They performed significantly better when administered CX717. After sleep deprivation of 30 to 36 hours, the same monkeys showed a markedly decrease in ability to perform the task. However, when given CX717 afterwards their performance improved dramatically, even exceeding normal levels.

The brains of the monkeys were imaged with a PET scan for glucose use during these tests. The researchers found that the medial temporal lobe (MTL) and dorsal prefrontal cortex (DPFC) showed enhanced activity during the task. With CX717, there was a slight increase in activity in these two regions and a greater increase of activity in the precuneate cortex. Sleep deprivation caused an increase in activity in MTL and precuneus but a decrease in the DPFC. With CX717, the brain activity in the sleep deprived animals approached normal vehicle levels.

Ampakines are positive modulators of the glutamate AMPA receptor. Glutamate is the main excitatory neurotransmitter in the brain. The AMPA receptor when activated produces a short (few ms) excitatory post-synaptic voltage pulse. Ampakines can make this pulse stronger and last longer. The interesting thing is that the addition of CX717 to the sleep deprived animal increased activity in some areas but decreased it in others. This goes to show you that jazzing up excitation in the brain does not necessarily lead to increased activity. Unfortunately, PET scans can only tell us about changes in glucose usage and not the actual neural activity.

It will only be a matter of time when these drugs hit the streets and college campuses. Students already take speed to stay up and Ritalin to enhance concentration. NMDA and CREB enhancers to boost memory will also soon be on the market. The CB1 blocker rimonobant will soon be approved as an obesity drug. Personally, I wouldn't go near any of this stuff. We have no idea what long term effects these drugs will have. The brain is probably pretty optimized so any enhancement will have some trade-off. I think I would like to know what that cost will be before I decide to mess with my brain.

Sunday, August 21, 2005

Tenure and Welfare

One commonly held notion is that the university tenure system is instituted mainly to protect those in the social sciences who are critical of the current establishment or hold controversial views. This is of course highly valuable for a free society. Recently there has been some suggestion that tenure should be disbanded in the sciences and be replaced with 5 or 10 year renewable contracts. The main reason for this argument is that every department has unproductive faculty and there is no way to replace them.

However, it could be argued that academic freedom is just as important for the sciences. Faculty need the ability to pursue risky ideas that may have no return. If Andrew Wiles was on a five year contract, he may never have had the peace of mind to hole away in an attic for seven years to prove Fermat's Last Theorem. Progress is not possible without failure. The tenure process should be decided carefully but once conferred, not producing another piece of research for the rest of one's career must be considered to be an acceptable outcome.

The argument could be expanded for justifying unemployment as an acceptable career choice. A just and free society should provide a minimal standard of living for all citizens. There are both practical and moral reasons for this stance. Even in our current society, people do accept that some people either through misfortune or bad judgment fall through the cracks and need temporary help to get back on their feet. One could also argue, although I bet this gets less support, that welfare could serve as a stipend for segments of the society wishing to pursue interests in areas that have no current commercial value such as writing a novel or painting. This is akin to academic freedom on the society scale.

But the most compelling argument is a moral one. A person born into a structured society does not have the freedom to live in their natural state. They must follow the conventions imposed upon them. They have no choice to opt out. They cannot choose to become a hunter-gatherer. In fact, few of us have absolute choice over what we do to support ourselves. We have some choice in the area we are trained but the market ultimately decides where we are hired. Thus, one could argue that compensation for eliminating this freedom could be a welfare system. Now, obviously, if everyone chose to take welfare the system would collapse. So to make it viable, any form of work should have a higher compensation than welfare. Did I hear someone say minimum wage?

Tuesday, August 16, 2005


I've always found so-called innate behaviour to be much more puzzling than learned behaviour. I can somewhat fathom how a neural network might learn a complex task through training but how does a gene do it? My research program over the past ten years has basically been to show that just knowing the connections of a neural network is not enough to specify what it does. Details like time scales and synaptic strengths matter crucially. Although the neural circuit of the worm C. elegans has been mapped out for quite some time, we still don't know how the creature functions. Since most of the animal world functions just fine on genetically programmed traits, we must be missing something.

An advanced online paper in Nature (Manoli et al., June 15, 2005) has found that the fruitless (fru) gene in Drosophila is responsible for male courtship behaviour. This gene encodes a set of male-specific transcription factors that are expressed in about 2% of neurons in the central nervous system. Inactivating this gene completely wipes out all male courtship behaviour but seemingly preserves all other functions. Expressing the gene in females induces courtship behaviour. Yes, females with fru will attempt to mate with other females even though they lack the apparatus to do so.

Most interestingly is when the gene is selectively inhibited in specific systems like olfaction. Naive males will typically court all drosophila they encounter, male or female, but they quickly learn to not try to mate with other males. However, when fruitless is inhibited in the olfactory receptor neurons, the flies will persist in courting males. This fact has been played up in the press as evidence of a gay gene but it actually indicates an inability to distinguish between males and females. What is amazing to me is that a single gene (although it does encode for a number of proteins) has a nonmonotonic action. Knock it out everywhere and the fly won't mate; knock it out in a specific location and the fly won't stop mating.

We still have no idea what the gene does but this result seems to imply that male courtship behaviour is pre-programmed into the neural circuitry and is activated by priming a subset of neurons or neural connections. Now we need to do the electrophysiology on the neurons expressing fru and try to untangle this mystery.

Sunday, August 14, 2005


I've been occupying my time during my two hour train rides to work by listening to podcasts on my Apple iPod. My listening selections include The Science Show and All in the Mind, both produced by the Australian Broadcasting Corporation and Quirks and Quarks produced by the Canadian Broadcasting Corporation. I used to listen to Quarks on CBC radio when I was a kid in Toronto. It was hosted by David Suzuki in those days.

I'm amazed at how good the Australian shows are. They focus on a topic each week and interview several experts from all over the world. The hosts of the shows are highly knowledgeable. These shows are so much better than NPR's Talk of the Nation Science Fridays. It is rather sad that the United States does not have a decent science show on the radio. It is no coincidence that Canada and Australia are both Commonwealth countries that followed the tradition of a national network in the vein of the BBC.

Saturday, August 06, 2005

Stem cells, cloning and beginning of life

The stem cell debate and cloning was again in the news this past week. A South Korean team announced that they had successfully cloned a dog (a very cute Afghan named Snuppy). Dogs had been notoriously difficult to clone and the team only obtained one success in one thousand tries. This work shows that it is just a matter of time before primates including humans will be cloned.

In terms of therapeutic promise, this research implies that someday we will be able to extract genetic material from a person and create a blastocyst from which embryonic stem cells could be harvested. These cells would be pluripotent and potentially be able to replace or repair any tissue in the body. Additionally, they would be a complete genetic match to the donor eliminating the chance of rejection and the need for immunosuppressive drugs which have many side effects.

In order to make this work we first need to understand how to manipulate stem cells to create desired cell types. Right now we have very little understanding of what causes differentiation in cells. Implanted stem cells could possible replace damaged neurons but they could also become tumor cells. Currently, federal funding is restricted to research only on established embryonic stem cell lines. Unfortunately, many of these lines may be contaminated with other genetic material or damaged from repeated replication. While the rest of the world is pushing forward the US is beginning to lag behind.

However, the tide may be turning. In May, the US House voted overwhelmingly to repeal the ban on creating new stem cell lines. This past week, US Senate majority leader Bill Frist, shifted his position and is now supporting a bill to expand federal funding of stem cell research although the president is threatening to veto the measure.

The argument against the use of embryonic stem cells and cloning is the same as that against abortion and that is the destruction of an embryo is tantamount to taking a human life - the premise being that life begins at conception. The curious thing is that those that support this position don't seem to have a problem with in vitro fertilization where many eggs are extracted and fertilized to create an embryo but only a few ever make it to term. The rest are either frozen, donated or discarded.

That aside, the notion of a well defined moment where life begins is not so clear cut. Is it the moment that the sperm fuses with the egg or the moment that the formed zygote implants in the uterus? If it's the former, then why not make it the moment the sperm collides with the egg or even the moment the sperm will inevitably collide with the egg. Given that we now know any cell in the body can become a new life form, should we prohibit the destruction of any cell? Should we go further and prohibit the destruction of human genetic material of any form including the sequence itself?

Someday, the only thing we'll have left of monarch butterflies, giant pandas or blue whales will be the sequence. Currently, we can build a virus starting from just the genetic map but eventually we will be able to reconstruct any life form. What protection should the genetic code have when it's erasure implies the extinction of an entire species? Perhaps in the distant (or not so distant) future, we will reproduce entirely algorithmically. A computer could combine the sequences of two people and generate the genetic material for their child. Suppose there were only one copy of that sequence and it were destroyed. Would that be murder? When biology fully merges with computer science, how do we define life then?

Monday, August 01, 2005

Bursting of the low carb bubble

The backlash against the Atkins diet is definitely on. Atkins Nutritionals, the company founded by the namesake of the diet, filed for bankruptcy today. It is in debt for 300 million dollars. The company greatly expanded over the past few years when the hype over low carb diets was at it's frenzied highest. Earlier this year I predicted that this diet fad was in its waning moments. I also wrote about some of the theory behind the diet. Basically, all diets will fail within a couple of years. It is much more difficult to keep off weight than to lose it. Maybe Krispy Kreme donuts will now make a comeback.

Thursday, July 28, 2005


The herbal supplement industry is a multi-billion dollar juggernaut. It's nice to see some of their outlandish claims finally get put to the test. The New England Journal of Medicine today reports that echinacea ( E. angustifolia root) has no effect for curing the common cold. There is a nice story in the New York Times. I'm sure adherents that swear by it (like my parents) will continue to take it but perhaps this study will put a little dent into sales.

The study took 437 volunteers, challenged them with the cold virus and randomly assigned them with pretreatment, treatment or placebo. The result was that there was no evidence that any form of treatment with echinacea had any significant effect in combating the cold or alleviating its symptoms.

Sunday, July 24, 2005

Phosphorus and nitrogen

The six most important elements for life are carbon, oxygen, hydrogen, nitrogen, sulfur and phosphorus. The abundances of these elements in biomass approximately mirror what is found in the earth's crust except for phosphorus which is about 6 times more abundant in biomass. However, the abundance of phosphorus in the ocean is the same as that found in biomass. This is no accident. Oceanographer Alfred Redfield found 70 years ago that the nitrogen to phosphorus ratio was 16:1 in both sea plankton and the ocean. He noted that this was not a coincidence but that the plankton was setting the ratio of the ocean. There is no intrinsic need for this ratio as plankton grown in laboratory conditions can exhibit a wide range.

The phosphorus in the ocean comes from the weathering of rocks on land. It is sequestered by oceanic life forms like plankton and then precipitates to the ocean floor when these organisms die. The availability of phosphorus sets the limit to how much life can be sustained by the ocean. This then sets the balance between oxygen and carbon dioxide in the oceans which in turn affects the balance of carbon dioxide in the atmosphere.

Now, some have argued that the increase of carbon dioxide in the atmosphere will lead to more vegetation which will counter the growth in CO2. However, more vegetation can grow only if it can acquire enough phosphorus and nitrogen. Although the atmosphere is 78% nitrogen, plants, other than legumes, cannot utilize it. They must obtain their nitrogen from the soil which mostly comes from animal waste or decaying biomass. Land animals that eat fish will transfer some nitrogen from the ocean back to the earth. The bottom line is that life on earth is precariously balanced and we really have no idea what will happen when we begin to perturb the system.

Tuesday, July 19, 2005

Modern Living

The June issue of Smithsonian Magazine has some interesting numbers:

The List: 1970 Price Index

Gasoline $.36/gallon
Median Income $8,734/year
Median Rent $108/month
Median Home $17,000
Bacon $.97/pound
Eggs $.51/dozen
Bread $.24/loaf
Vitamin D Milk $1.14/gallon
First-Class Postage Stamp $.06
Harvard College Tuition $2,600/year

Compared to 2005, the cost of food has changed surprisingly little. The price for eggs and milk have only doubled over the last 35 years while Harvard's tuition and the cost of housing has gone up by more than a factor of ten. You only have to walk down the streets of any large American city to realize that getting enough food is no longer a major problem. The problem these days is finding affordable housing and putting your kids through college.

According to a February article in Amber Waves (a USDA publication):
Between 1952 and 2003, the ratio of food prices to the price of all other goods has fallen by 12 percent. The drop is even more dramatic if you factor in `quality improvements'—the reduced time cost of acquiring and preparing food (convenience), greater variety, and omnipresent restaurants and vending machines.Foods that once were available only seasonally are now available year-round. Advances in food processing and packaging have introduced a multitude of ready-to-eat foods, available virtually anywhere and at any time.
Harvard University's David Cutler, Edward Glaser, and Jesse Shapiro have suggested that the increase in food consumption prompted by the falling time cost of food is the major cause behind the surge in obesity since 1980. They note: "Technological innovations—including vacuum packing, improved preservatives, deep freezing, artificial flavors, and microwaves—have enabled food manufacturers to cook food centrally and ship it to consumers for rapid consumption. In 1965, a married woman who didn't work spent over two hours per day cooking and cleaning up from meals. In 1995, the same tasks took less than half the time."

Sunday, July 17, 2005

Face Cells

The June 23, 2005 issue of Nature reports work by Christof Koch and colleagues on the existence of "face recognition" cells in the hippocampus of the brain. This paper got a lot of play in the popular press because some of the cells only responded to famous people such as Halle Berry. The group found that the cells were highly selective to various views of a given person but not to another person. I think this work confirms some current theories of memory (see for example McClelland et al. Psychological Review, 102:419 (1995)). It's also more proof that there isn't much difference between humans and other mammals.

It is known that cells in the hippocampus in the rat code for spatial location in the same way. A given cell will only fire when a rat runs through a given spatial location in a given environment. When the environment changes, that same cell will then code for a completely different location. Location is important to a rat, just as the recognition of people is important to humans.

When the hippocampus is removed, humans can no longer form long term memories. They can remember things as long as they pay attention to it but once they lose their train of thought, the memory is completely gone. It is thus thought that the hippocampus is a form of mid-term memory that stores lots of information that is then slowly uploaded to the cortex for longer term storage.

It's useful to have different memory systems for different time scales because every time you remember something new you run the risk of erasing something old. One way out of this conundrum is to separate long term memory from short term memory. Simplistically, your hippocampus would store whatever information comes in and indiscriminately overwrite old information. Then slowly over time, the hippocampus would upload information to the temporal cortex (perhaps during dreams) which would update its synapses in a controlled fashion making sure not to erase important old memories.

What this paper shows is completely consistent with this idea. From theoretical work on associative memory, we know that the capacity of any neural network is limited by how correlated the stored patterns are with each other. The more correlated the patterns, the more likely they are to interfere. Thus, one way to make sure you don't overwrite old memories is to make sure the input patterns are orthogonal. The hippocampus may serve this purpose. A very sparse code, where only a few neurons encode a given concept (like Halle Berry), automatically orthogonalizes the patterns representing given memories presented to the higher cortical areas.

A sparse code is not robust because if you knock out that particular neuron you lose the memory it coded. A more robust code would be a population code where a large group of neurons encodes a given concept. The problem with this type of memory is that it's hard to train a network. So the way to overcome the trade-off between robustness and speed is to have a fast but fragile system (hippocampus) feed inputs to a slow but robust system (temporal cortex).

It is known that inferotemporal (IT) cortex of monkeys also respond to faces among many other percepts and that a given cell in IT will respond to a wide variety of images. So, if they ever get a chance to implant electrodes in the temporal cortex of humans, I'm sure they'll find similarly behaving cells.

Wednesday, May 25, 2005


I am finally starting to recover enough from my recent wedding and honeymoon to start posting again. The June 2005 issue of Technology Review covers the topic of Intellectual Property. There is a debate between Lawrence Lessig who believes that new laws governing copyright known as "digital rights management" (DRM), will undermine creativity and culture and Richard Epstein who thinks we need strong copyright laws to protect creators who add value to society.

I think this issue revolves on how we should value things in our society. The music and film industry is very worried about digital piracy. CD sales have gone down since illegal downloading of music became prevalent. I think that it will be impossible to fully stop it. Will this be the end of music? No, but I think it will be the end of powerful record companies who restrict the supply of recording artists so the prices can remain high. The argument is that making a record is expensive and they prescreen for quality. However, with inexpensive recording software like Apple's GarageBand and the internet, anyone can make a record now. The old model will become obsolete.

I can see two models for how artists might support themselves in the future. One is that they distribute their music for free or for a low fee and make money on concerts. The Grateful Dead has used this model for years. Classical and jazz musicians basically make their money from performances. The second is that we could re-establish a system of patronage for the arts. Artists would be paid a salary and their music would be given away for free. This last model is essentially the model for science. Scientists have jobs in research labs or universities and their work is given away for free.

In either model, the millionaire recording artist will become extinct. However, this won't change the lives of that many people. In the current system, only a handful of lucky people "make it" and become incredibly rich while everyone else waits on tables. What separates the people often has little to do with talent. It always seemed rather unfair to me that the world's greatest harmonica player is probably just getting by while a well marketed, lip synching pop star with little talent makes millions.

The motion picture industry does have an argument that films cost a lot to make and thus they need to be compensated. However, I think people will always want to see movies on the big screen. VCR's and DVD's have not reduced ticket sales. What will likely happen here is that more and more pictures will become digital and movie stars may become obsolete. Actors may only be necessary for live theatre.

Even in this world, I'm sure there will still be those that rise to be top and become stars. They may not be as well compensated as they are today but they will be as popular and probably a lot happier.

Wednesday, April 27, 2005

Suspended animation

In the April 22 issue of Science, a group from the Fred Hutchinson Cancer Center reports that a state of suspended animation can be achieved in (nonhibernating) mice when administered hydrogen sulfide (H2S). H2S is a reversible inhibitor of oxidative phosporylation. It is known that this induces hibernation in some animals.

When the mice were exposed to 80 ppm of H2S, their oxygen consumption dropped by 50% in the first 5 minutes. After 6 hours, their metabolic rate dropped by 90% and the core body temperature reached 15 degrees Celsius where the ambient temperature was 13 degrees. When the mice were returned to room air and temperature, their metabolic rate and body temperature returned to normal.

If this works in humans, we may now have a means of reducing metabolic demand after traumatic injury or surgery. H2S may become a standard part of the repertoire of paramedics. I won't bother to dwell on the space travel implications.

Hydrogen sulfide is the gas emitted by volcanos and geysers responsible for the rotten egg smell. It is usually considered toxic but now you know that if you see someone looking lifeless at the edge of a volcano, make sure to pull them out because they may note be dead but just be in a state of suspended animation.

Tuesday, April 12, 2005

Mathematical Biology

I am the first to admit that I'm not sure how much mathematics and theory has contributed to biology. Certainly the buzz is there. With the reams of data generated by the human genome project, biologists are begining to realize that they could use some help to understand all of this new data. The result has been a surge of available grant money and a flood of physicists, computer scientists and mathematicians into the field. (For the record, I made the jump over ten years ago when it was less fashionable.) I think it's safe to say that the jury is still out on whether or not the hype has been justified.

However, there has been one instance where mathematics has made a major difference and that is in the development of the triple cocktail treatment for HIV-AIDS. HIV is a particularly insidious virus because it attacks CD4 T cells of the immune system. However, it is rather slow acting. So often, when a person is infected with HIV, their virus load will remain low and CD4 counts will remain relatively high for a long period of time. Then, suddenly, the CD4 count will plummet and they will lapse into fully developed AIDS. It was first assumed that the virus replicated slowly and then accelerated at some point.

In the early 90's, David Ho and his group were testing treatments for HIV infection and decided that mathematically modeling the virus dynamics may give clues as to what was really happening. So they called in Los Alamos biological physicists Alan Perelson and Avidan Neumann (who is currently visiting our lab at NIH) to see if anything could be inferred about the virus. They used simple models of just a few ordinary differential equations to fit to the virus load during perturbation experiments where a potent protease inhibitor was administered.

Their simple model showed that the virus was far more active than previously believed. During the quiet phase where virus loads were low, the virus was actually replicating very rapidly but the immune system was running at high speed to compensate. Full blown AIDS developed when the immune system wore out and could no longer keep up with the virus. The implication was that any anti-viral treatment that targeted a single specific mechanism would fail because the virus would quickly evolve a defense. Thus the triple cocktail was invented. The virus would then need to evolve three separate defenses and this was difficult enough to keep it at bay. The results were published in two deservedly celebrated papers - the first in Nature in 1995 and the second in Science in 1996. I think their achievement represents the best example of how theoretical ideas can be useful in biology.

Wednesday, April 06, 2005

A new new world order

An excerpt from Thomas Friedman's book "The World Is Flat: A Brief History of the Twenty-First Century" appeared in last Sunday's New York Times magazine. The premise is that the information age has truly arrived and now people all over the world can compete on equal terms. Steve Hsu summarizes the idea in his blog. The tone of Friedman's excerpt and Hsu's posts is that the Chinese, the Indians, and the Russians are coming and we better get ready for the new competition. America's dominance over the world is beginning to decline and if we don't recognize it now our standard of living will fall with it as our wealth starts to diffuse across the globe.

I certainly believe this is happening and it is unavoidable. Improving our educational system or motivating our citizens won't solve the real problem and that is the US only constitutes five percent of the world's population and if life were fair, it should have only five percent of the wealth. Even given that life is not fair, having only five percent of the world's population means that we only have five percent of the brightest, most innovative, and most energetic people to create the wealth for the future. Eventually, things will equalize. It's a battle we just can't win.

So what should we do? One solution is to bring the rest of the world up to our economic level. Unfortunately, I don't think a world where everyone lives like an American is sustainable. See my estimate of energy use from a previous post. A possible scenario is that as the world catches up and begins to compete for scarcer and scarcer resources, the pecking order will be sorted out through military means. I truly hope we are sane enough to avoid that fate. My deluded, quasi-utopian vision, is that we all scale back and share. The pessimistic nihilist in me says that won't happen in my lifetime.

Tuesday, April 05, 2005

The North Pole

The earth's magnetic field is generated by the motion of molten iron in the earth's core. The combination of convection and coriolis forces generates the right set of currents to establish a dipole field with the north and south poles approximately in line with the rotational north and south poles. We partially owe our existence to this magnetic field because it provides a shield against charged particles from the solar wind. Without it, we would be subject to ionizing radiation and may also lose our atmosphere.

Neither Mars nor Venus has a significant magnetic field and we're not fully sure why. Mars once had a thick atmosphere of CO2 that may have been blown away by the solar wind. It could be that the molten iron has solidified or that the pattern of flow no longer supports a magnetic field. In any case, I think the lack of a field on Mars should make us less secure that we'll always have ours.

The earth's dipole flips every 250,000 years on average. We're not exactly sure why but some recent magnetohydrodynamic simulations of the geodynamo have shown examples of field reversals due to instabilities in the turbulent flow. It's been 780,000 years since the last reversal so we may be due for another one soon. It will take approximately 4,000 to 10,000 years for a reversal to take place. During the transition, the magnetic field may lose its intensity as well as its dipole structure which may have implications for life on the earth.

Another consequence of the turbulent geodynamic flow is that the north pole is in constant motion. It usually moves about ten kilometres a year but recently it has been moving forty! If it keeps moving at this rate, in about fifty years it will leave Canada and reach Siberia. This increased speed of drift of the north pole may be nothing more than natural random variations but it definitely makes me worry just a little.

Friday, April 01, 2005

Engineers in Government

Ever wonder why science and engineering policy doesn't make much sense. Here's an article from this month's Technology Review that may give a reason why.
Engineers and Political Power
by Ed Tenner, April 2005

In the united states, engineers don’t rule. According to a Congressional Quarterly survey of the 109th Congress, there are just four engineers in the House and one in the Senate. When the engineering specialties in the 2004–2005 Statistical Abstract of the United States are combined, there are 2.12 million engineers in the U.S. versus 952,000 lawyers and 819,000 doctors; yet 10 physicians now sit in the House and two in the Senate, and CQ lists 160 representatives and 58 senators with legal backgrounds.

One explanation for those discrepancies is that rapid technological change makes it hard for engineers to return from political office to professional life. In a 1992 interview with Technology Review, John H. Sununu, President George H. W. Bush’s chief of staff, acknowledged that as a consulting mechanical engineer, he was lagging ten years behind the field. Physicians, however, face equally great problems keeping up with the latest research, and by entering public service, they often forgo even greater potential income.

Another theory is that engineers are self-selected for social distance. Sylvia Kraemer is an intellectual historian who became a senior NASA official and interviewed 51 colleagues for her insightful study NASA Engineers and the Age of Apollo. She found that lab engineers and those promoted into management endorsed the reputation of awkwardness. A manager declared that most engineers "wouldn’t recognize an emotion if it hit them in the face." One rocket engineer flatly acknowledged, "I related to things."

This is an old American stereotype. In The Engineers and the Price System, the maverick economist Thorstein Veblen, championing what was later called technocracy, wrote that the public considered engineers a "somewhat fantastic brotherhood of overspecialized cranks, not to be trusted out of sight except under the restraining hand of safe and sane businessmen." He added, "Nor are the technicians themselves in the habit of taking a greatly different view of their own case."

But in many other cultures, especially in Eastern Europe, Asia, and the Middle East, engineers have been in the thick of power. The’ve been prominent in Marxist movements, such as the brief Hungarian Communist revolution of 1919. They became influential enough in the early Soviet Union that Stalin directed one of his first purges against them. Later, scientists and engineers were put to work in the gulags’ special research prisons, the sharashkas. After Stalin’s death, engineering degrees became desirable credentials for the politically ambitious. As the historian Kendall Bailes wrote in 1974, "What lawyers and businessmen are in the American political system—the major professional groups from which most politicians and policymakers are recruited—men with engineering backgrounds have become to a large extent in the Soviet Union."

In 2004, almost all two dozen members of China’s ruling Politburo had engineering degrees, including all nine members of the Politburo’s Standing Committee. In the Middle East, prominent engineers fill the political spectrum, from former president S├╝leyman Demirel of Turkey to the members of the Society of Muslim Engineers, pillars of the ayatollahs’ Iran, to the late secular nationalist Yasser Arafat. In many countries, engineering appeals -to the civic minded. On the other hand, disaffected young men recruited in European engineering schools were prominent among the September 11 hijackers. As R. Scott Appleby and Martin E. Marty observe in Foreign Affairs, "fundamentalists tend to read scriptures [as] engineers read blueprints—as a prosaic set of instructions and specifications." Civil engineer Osama bin Laden surely did.

Globally, then, the unpolitical Anglo-American nerd is the exception. The argument that gained credence in 19th-century France and was echoed in other regimes is that a state must be guided by a scientific and technological elite. Two forces kept that notion from taking hold in the United States. The first was American suspicion of central government. The second was industry’s appetite for engineers; at the turn of the 20th century, U.S. companies fearing manpower shortages resisted attempts to make elite postgraduate degrees the norm for engineers, as they were becoming for lawyers, doctors, and executives. So engineers in this country continue to design and implement everything but our laws.

Wednesday, March 30, 2005

Krakatoa and the Tsunami of 2004

The southern coast of Indonesia is one of the most active tectonic zones in the world because the Indian plate is subducting beneath the Burma microplate. This was borne out tragically in the Aceh-Andaman earthquake and Tsunami of 2004. In this week's Nature, Stein and Okal argue that the magnitude of that earthquake was 2.5 times greater than previously thought and should have been a 9.3 instead of a 9.0. Just this past Monday, another earthquake of 8.7 magnitude struck southern Sumatra. Fortunately, this one was in shallower water so much less water was displaced and thus no Tsunami was generated.

It was over a century ago, on August 27, 1883, that the volcano Krakatoa exploded nearby. The volcano was part of an island consisting of three main cones in the straight between Sumatra and Java. It stood nearly 800 metres high and had a diameter of 15 kilometres. Two of the cones were completely blown apart in the eruption. The Tsunami generated was estimated to be 40 metres high although it was of short wavelength so it didn't travel very far. It did kill 36,000 people in southern Sumatra and western Java. It carried a steamship 2 miles inland. The explosion was so loud it was heard as far away as Perth Australia and the atmospheric shock wave travelled around the world seven times. There were brilliant red sunsets for five years afterwards due to the 21 cubic kilometres of material thrown up.

The eruption was extremely well documented by the scientists of the day. The field of volcanology was invented to understand why the eruption was so violent. The current theory is that Krakatoa had been dormant for 200 years before the 1883 eruption and this allowed the magma to cool inside the volcano. About four months before the August eruption, Krakatoa became active and this cool magma escaped in a series of minor eruptions. It was then replaced by hot magma from below. The entering hot new magma heated up the remaining cool old magma releasing gases and built up tremendous pressure which was released in a massive explosion equivalent to 21,000 megatons of TNT. The amazing thing is that a new volcano has almost entirely replaced the old one. In just a hundred years, Anak Krakatau (child of Krakatoa) has risen to a height of 300 metres and is still growing. It is not expected to explode like it's parent in the near future but given recent events one never knows.

Monday, March 28, 2005


Scott Sandage, an associate professor in history at Carnegie Mellon University, has recently penned a book entitled - Born Losers - A History of Failure in America. An interesting fact that Sandage points out is that the concept of being a failure as a human being did not exist until the late nineteenth century. Prior to that, failure was only used to imply bankruptcy, a circumstance that did not necessarily imply any personal deficiency. Unlike today where a lack of ambition and vision is synonymous with being a loser, it was perfectly fine to be satisfied with one's lot. Social climbers, like Becky Sharp in Vanity Fair, were considered crass.

Sandage finds that the Civil War may have been a turning point. Prior to the war, America divided itself into citizens and slaves. However, after the war, the division changed to winners and losers. It was also a time where the robber baron class arose. These were usually self-made men such as Carnegie, Mellon and Rockefeller who rose to prominence in a burgeoning industries such as steel, banking and oil. They also defined success in American as earned (plundered?) wealth. This attitude is probably even more apparent today. It is only in America (until recently perhaps) that being called aggressive was a compliment. I'm not suggesting that we all return to a society without ambition but perhaps defining ourselves exclusively in terms of our achievements and finances may not be the most satisfying way to live.

Friday, March 25, 2005

Jurassic Park

The possibility of resurrecting extinct animals some day in the future may not be as far fetched as previously thought. A paper in this week's Science reports that soft tissue from a 70 million year old Tyrannosaurus Rex was found in Montana. The specimen contained blood vessels and possibly cells. Finding pieces of DNA is a long shot but remains a remote possibility.

In fact, extracting DNA from extinct animals is becomng more common A recent article in PLOS Biology reviews the many ways that ancient DNA has been used to ask questions about population genetics in the past. It is probably not surprising that there are signs that our current descriptions of the evolutionary process based on the fossil record and modern DNA is far too simple. Since DNA is a fragile molecule, most studies are limited to DNA less than 60,000 years old. However, that's still old enough to get some interesting information. The hardest thing to prove is that the sample is not contaminated with modern DNA.

Thursday, March 17, 2005

The X chromosome

This week's Nature has a picture of the X chromosome on the cover. The issue has two articles on the topic. The first contains an analysis of the recently completed sequence. As I wrote before on the Y chromosome, women have two copies of the X. Previously, it had been thought that one was suppressed and the other is expressed. In the second paper, it is shown that about 15% of genes are still expressed on the inactive chromosome. The same genes on the active chromosome are also expressed so this could mean that more of the protein is produced. This could provide a basis for the differences between individual women and for this month's hot button topic - the differences between women and men.

Ironically, the X chromosome may actually be more important for men than for women. Since men only have one X, any advantageous mutation for men will we be selected for strongly even if it is somewhat deleterious for women. Conversely, a deleterious mutation will be strongly selected against. It has been proposed by Horst Hameisterat of the University of Ulm in Germany that females may be responsible for intelligence in humans. His group proposes that early females had a preference for intelligence and if the genes for superior intelligence and the preference for intelligence are found near each other then they would be selected together and this could lead to an instability because both lead to enhanced survival. It had been known for some time that many of the genes related to mental retardation are found on the X and now it is confirmed that there are many crucial genes on the X for neural development. Hence, the X could be what makes humans human.

Tuesday, March 15, 2005


Congress has subpoenaed seven baseball players to testify about steroid use in major league baseball. This is a result of the recent BALCO scandal that implicated sprinter Marion Jones, Barry Bonds, Jason Giambi among others and the recent publication of Jose Canseco's book alleging steroid use by several stars including Mark McGwire. Given the current debates on our fiscal crisis, the Iraqi war, social security, the Arctic National Wildlife Refuge, North Korea, outsourcing and so on, aren't there more important things for Congress to do? I love sports and baseball as much as the other guy but come on it's just a game.

I believe that international sporting bodies must accept that medical enhancement will only increase in the future and there is virtually no chance to completely stop it. If they ever get gene therapy to work we'll be in real trouble. I think testing for cheating is the wrong strategy. What we will eventually need to do is to set physiological standards that athletes cannot exceed. So everyone is allowed up to some level of testosterone, human growth hormone, myostatin, red blood cells and so forth. You can do whatever you want to get to these standards but you can't go beyond. I suppose those that exceed the standards "naturally" would be able to petition the governing body to obtain an exemption. I agree that this would take away something from sport but in some sense it also levels the playing field. After all, isn't being born with better genes an advantage?

Sunday, March 13, 2005

Dyson's take on evolution

Freeman Dyson always has something interesting to say on most topics. In the March issue of Technology Review he summarizes Carl Woese's idea about the end of Darwinian evolution due to bioengineering. I don't think we've stopped evolving since we're still battling microbes but the thought is intriguing and terrifying.
Carl Woese published a provocative and illuminating article, A New Biology for a New Century, in the June 2004 issue of Microbiology and Molecular Biology Reviews. His main theme is the obsolescence of reductionist biology as it has been practiced for the last hundred years, and the need for a new biology based on communities and ecosystems rather than on genes and molecules. He also raises another profoundly important question: when did Darwinian evolution begin? By Darwinian evolution he means evolution as Darwin himself understood it, based on the intense competition for survival among noninterbreeding species. He presents evidence that Darwinian evolution did not go back to the beginning of life. In early times, the process that he calls horizontal gene transfer, the sharing of genes between unrelated species, was prevalent. It becomes more prevalent the further back you go in time. Carl Woese is the worlds greatest expert in the field of microbial taxonomy. Whatever he writes, even in a speculative vein, is to be taken seriously.

Woese is postulating a golden age of pre-Darwinian life, during which horizontal gene transfer was universal and separate species did not exist. Life was then a community of cells of various kinds, sharing their genetic information so that clever chemical tricks and catalytic processes invented by one creature could be inherited by all of them. Evolution was a communal affair, the whole community advancing in metabolic and reproductive efficiency as the genes of the most efficient cells were shared. But then, one evil day, a cell resembling a primitive bacterium happened to find itself one jump ahead of its neighbors in efficiency. That cell separated itself from the community and refused to share. Its offspring became the first species. With its superior efficiency, it continued to prosper and to evolve separately. Some millions of years later, another cell separated itself from the community and became another species. And so it went on, until all life was divided into species.

The basic biochemical machinery of life evolved rapidly during the few hundred million years that preceded the Darwinian era and changed very little in the following two billion years of microbial evolution. Darwinian evolution is slow because individual species, once established, evolve very little. Darwinian evolution requires species to become extinct so that new species can replace them. Three innovations helped to speed up the pace of evolution in the later stages of the Darwinian era. The first was sex, which is a form of horizontal gene transfer within species. The second innovation was multicellular organization, which opened up a whole new world of form and function. The third was brains, which opened a new world of cordinated sensation and action, culminating in the evolution of eyes and hands. All through the Darwinian era, occasional mass extinctions helped to open opportunities for new evolutionary ventures.

Now, after some three billion years, the Darwinian era is over. The epoch of species competition came to an end about 10 thousand years ago when a single species, Homo sapiens, began to dominate and reorganize the biosphere. Since that time, cultural evolution has replaced biological evolution as the driving force of change. Cultural evolution is not Darwinian. Cultures spread by horizontal transfer of ideas more than by genetic inheritance. Cultural evolution is running a thousand times faster than Darwinian evolution, taking us into a new era of cultural interdependence that we call globalization. And now, in the last 30 years, Homo sapiens has revived the ancient pre-Darwinian practice of horizontal gene transfer, moving genes easily from microbes to plants and animals, blurring the boundaries between species. We are moving rapidly into the post-Darwinian era, when species will no longer exist, and the evolution of life will again be communal.

In the post-Darwinian era, biotechnology will be domesticated. There will be do-it-yourself kits for gardeners, who will use gene transfer to breed new varieties of roses and orchids. Also, biotech games for children, played with real eggs and seeds rather than with images on a screen. Genetic engineering, once it gets into the hands of the general public, will give us an explosion of biodiversity. Designing genomes will be a new art form, as creative as painting or sculpture. Few of the new creations will be masterpieces, but all will bring joy to their creators and diversity to our fauna and flora

Thursday, March 10, 2005

Cold Spring

The weather has not been kind for us on the east coast these past few weeks. After a reasonably mild winter, late winter/early spring has been filled with snow, cold, and more snow. There may be a silver lining to this though. Here is my completely unsubstantiated account of North American weather patterns.

Anyone who watches the weather channel knows that when it is cold on the east it's because a cold front has moved in from Canada. I heard it being called an Alberta Clipper this morning. The atmosphere gets warmed or cooled primarily through contact with the ground since solar radiation mostly passes through the air and is absorbed by the ground. In the winter and spring, the air over north western Canada is cold while the air over the Gulf of Mexico and the southern US is mostly warm. Thus a pressure gradient can arise with high pressure in Canada and low pressure in the southern US. This causes air to flow from north to south.

Now all that air coming down must go somewhere so it makes it's way up the Atlantic coast and returns to the arctic. Along the way, it picks up warmth and moisture which often ends up as snow in New England. Hence, the more cold air there is coming from the north, the more warm air there will be returning to the arctic. This should then lessen the temperature and pressure gradient between the north and the south. So, perhaps a cold late winter may actually lead to a milder late spring.

Monday, March 07, 2005

Hans Bethe

Yesterday marked the passing of Hans Bethe, the last of the great physicists from the Manhattan Project. I had the privilege of seeing Bethe speak twice when I was a graduate student at MIT in the late 1980's. Bethe was in his early eighties at the time and was still sharp as a tack. One talk was on neutrino oscillations and the other was on disarmament policy. Both talks were well thought out and exhibited the clear thinking that marked Bethe's career.

The amazing thing about Bethe was that he remained relevant for much of the twentieth century. Bethe was held in the highest regard by both his peers and the political establishment throughout his life. He was Sommerfeld's graduate student. His Nobel Prize work on energy production in stars was done in 1938. He played an important role in the development of QED and was Richard Feynman's mentor. He was instrumental in pushing for arms limitation treaties and derailing the Star Wars space-based anti-missile defense during the Reagan administration. He and John Bahcall wrote a landmark paper outlining how the solar neutrino problem was finally solved in 1990. He was a true giant among giants.

Friday, March 04, 2005

The Y chromosome

DNA is packaged into discrete units called chromosomes. The chromosomes come in pairs with one from the mother and one from the father. There does not seem to be any rhyme or reason to the number of chromosomes a species may have. For example, humans have 23 pairs, the other three great apes have 24 pairs, mice have 21 and horses have 32. It appears that during the course of evolution chromosomes can undergo fission and fusion or be lost altogether.

It is not necessary for two species to have the same number of chromosomes to produce fertile offspring. For example, Przewalski's wild horse has 33 pairs yet when crossed with a domesticated horse with 32, the offspring are fertile and can mate with other domesticated horses (Chandley AC, Short RV, Allen WR, J Reprod Fertil Suppl 23:356-70, 1975). What happens is that two of the chromosomal pairs from the wild horse fuse in a process called Robertsonian translocation. This can happen in humans as well and some people are walking around with 45 chromosomes.

The X and Y chromosomes determine sex. Females have two X chromosomes and males have an X and a Y. While female offspring will obtain an X chromosome from each of their parents, male offspring will always inherit their father's Y chromosome. So mutations in the Y chromosome will always get passed on and thus can accumulate. Jennifer Graves of the Australian National University, believes that the Y chromosome is rapidly shrinking and may disappear altogether. The basis of her claim is from comparing the genomes of various mammals. For example, she has found that kangaroos diverged from humans 180 million years ago and the platypus 210 million years ago. These mammals also have analogues to human sex chromosomes. In the last 300 million years the Y has lost most of its original genes. She estimates that the remaining genes have about 10 million more years to go. Hence to avoid extinction, humans may need to evolve into a new hominid species.

There is some dissent though. David Page of the Whitehead Institute has discovered 78 genes on the Y (about twice as much as previously believed) and there could be more. He also found palindromic sequences so there could be some redundency. The Y might be able to repair errors by taking hairpin configurations. So are we men on our last legs? I guess we'll have to wait to see.

Wednesday, March 02, 2005

Out on the tail

As the world's population gets larger, should we expect more Newtons, Mozarts and Tiger Woods or should we expect fewer? By this, I mean should the gap between the best in a field and the second best, be larger than the gap between the second best and the rest? If you presume that the aptitude level of people for some enterprise is normally distributed then the answer is no. The probability to be between n standard deviations and n+1 standard deviations above the mean decreases exponentially. As you go out onto the tail, the probability of someone being a standard deviation better than you is decreasing very quickly. Thus we should see a lot of people bunched near the top.

So why is it that we have Tiger Woods? Tiger is dominating golf like no one since perhaps Bobby Jones in the twenties and Ben Hogan in the early fifties. He was more dominant over a stretch of five years than Jack Nicklaus ever was although his dominance declined slightly last year. There are many more golfers now then there were fifty years ago so if anything we should see a much more competitive environment. Except for Woods and perhaps Vijay Singh, this is true as there is very little separating the rest. Dominance is not just limited to golf. Ten years ago we had Michael Jordan in basketball and Wayne Gretzky in hockey. Right now we have Barry Bonds in baseball and Lance Armstrong in cycling. These people are dominating or have dominated their sports as much or more than anyone else before.

Part of the reason is surely that a normal distribution is a bad approximation for the tail. Anyone in finance certainly knows this. The central limit theorem does not converge uniformly over the entire range, so even though the bulk is well described by a normal distribution, the tail can still experience low number statistics. Thus as the population increases, more of the tail gets sampled and that could actually increase the probability of rare events not decrease it as would be expected. So my prediction is that we will see more dominant athletes in the future.

Now what about physics and music? By this argument we should see more anomalies in these areas as well. However, it is not clear who is the Newton of our day. Ed Witten maybe? I think the reason is that there are fewer objective measures of mastery in these areas as compared to sports. A lot of what leads to great impact in physics is the choice of problem. In this case, there is a greater element of luck. One could be way out on the tail in terms of sheer brilliance (if that can even be measured) but not have a great impact if they worked in a dead end field. In this case, physics may suffer from low number statistics in the bulk and the tail so there will be no correlation of dominance with population size.

Music has a similar problem. Who in the 20th century compared to Mozart? Diatonic Western classical music reached its acme with Mahler. After that, composers either became atonal or "popular". The 20th century was the century of performers. Perhaps if Rubenstein, Heifetz, or Yo Yo Ma was born in the 18th century they would have been great composers. The playing field changed in the 20th century so the question of dominance became more difficult to answer. In 200 years, we may look back at the 20th century and consider a Jazz or Rock musician to be the Mozart of the day.

Sunday, February 27, 2005

Low Carb Diets II

The new Dietary Guidelines for Americans 2005 is specifically targeted towards preventing obesity. The previous food guide pyramid from 1992 emphasized a reduction in saturated fats to prevent heart disease. With an estimated 300 million worldwide expected to be afflicted with Type 2 diabetes in the near future, mostly due to obesity, we have a new priority. The guidelines recommend a diet that is high in fruits and vegetables, low in fat, and low in sugar. The latter recommendation was especially contentious with the food industry.

As expected, low carbohydrate diets like the Atkins diet were not held in high regard. However, there really isn't overly strong evidence that they are unhealthy and in some cases they have been found to actually lower blood lipid levels! As a weight loss measure, low carb diets do seem to work although keeping that weight off is another matter as I discussed previously.

The Atkins idea is that carbohydrates make you fat. When you eat carbohydrates they get broken down to glucose (except fructose) which then triggers an insulin response. Insulin allows muscles to uptake and burn glucose (instead of fat). At the same time it suppresses the release of free fatty acids from adipocytes (fat cells). Thus when insulin levels are low, the muscles mostly burn fat (except during exercise). Glucose is thus spared for the brain which cannot burn fat. This much is true. However, Atkins also claims that when insulin levels drop after a meal, you get a strong hunger response. The data is not so clear on this point.

To make up for the lack of carbohydrates, you must eat more protein and a lot more fat. Thus low carb diets are high fat diets. The traditional Inuit diet is an Atkins diet. When you begin a low carb diet, the first thing that happens is that you get depleted of your glycogen (which is the body's only store of carbohydrates). This is accompanied by a loss of water so you lose a lot of weight quickly. Your body then goes into a state of ketosis where the liver makes ketones. The brain only burns glucose or ketones. No one knows if maintaining ketosis for prolonged periods of time is detrimental. The fact that the Inuit did it for generations probably means it's okay.

There may be other reasons for why the Atkins diet works. For one, the diet does limit calories. Secondly, there is some data that shows that restricting food choices can result in eating less. Thirdly, until recently, there were very few snacks that are low in carbs. Finally, the quick weight loss in glycogen and water may motivate people to stay on the diet.
However, people do eventually give up and the weight inevitably returns after two years.

I personally think, from a health point of view, that controlling the total amount of calories consumed is more important than the composition of the diet. If you are in energy balance, you will basically burn everything you eat so it doesn't really matter if it is mostly fat or carbs. When you overeat, you are going to store that extra energy as fat. The data shows that losing just a little bit of weight can greatly reduce insulin resistance which is a precursor to Type 2 diabetes. Exercise also seems to confer benefits that go beyond the extra calories burned. So although eating lots of fruits and vegetables is probably good for you, if eating pork rinds helps you lose weight, then stick with that.