GLENN ALLGOOD鈥橲 victim is heading for a battering. 鈥淚鈥檇 like to subject it to
carcinogenic materials,鈥� he muses. 鈥淚 think you should be able to give it a
suntan or a blister. I鈥檓 serious. I mean, you should be able to cut it. You
should be able to have it cough up a hairball if you want to.鈥�
Soon he might be able to do all that and more鈥攚ithout going to jail,
and without causing anyone or anything a moment鈥檚 suffering. Allgood, a
computational engineer at Oak Ridge National Laboratory in Tennessee is involved
in creating the most complex computer model ever attempted: a virtual human
being. It could take decades and billions of dollars to build it, but the dream
of a Virtual Human is now becoming reality.
This won鈥檛 be a virtual cartoon character, like cyber-newsreader Ananova. Nor
will it be a merely visual representation of a human body, like the National
Library of Medicine鈥檚 Visible Human image archive. The Virtual Human will have a
living, breathing body whose cells will replicate and die, and whose blood will
flow under Allgood鈥檚 knife. True, the Virtual Human will be alive only inside a
computer, but the simulated gash will provoke the same cascade of physiological
reactions a real person experiences. Immune cells and clotting factors will rush
to the wound, and biochemical stress reactions will reverberate throughout the
body. The Virtual Human鈥檚 accurate simulation of human biochemistry will also
mean it could test new drugs for us, and its realistic physical responses will
allow the military to test the effects of the latest weaponry. In short, it will
be given the worst job in the world: pharmaceutical guinea pig, crash test dummy
and biologists鈥� action toy, all combined in one unlucky cyber-human.
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Not only will the model work like a human, it will also be fully explorable
inside and out. Virtual-reality software being developed will allow researchers
to see inside the Virtual Human鈥檚 organs, or watch its blood vessels dilate in
response to drugs. They will even be able to set out on a journey inside the
body using interactive 鈥渢otal immersion鈥� software that will let them stand in
the airflow entering the lungs or listen to the flapping of faulty heart
valves.
Being able to sit and watch the workings of the interconnections between
different organs, map the whole body鈥檚 reaction to different chemicals or
physical stimuli, or watch how a disease affects different areas of the body
will also uncover invaluable new medical information.
The idea of building, using and abusing this virtual re-creation of humanity
was born in 1996 when Clay Easterly, a health physicist at Oak Ridge, was
approached by representatives of the US Marine Corps. They were looking for a
way to test experimental non-lethal weapons without having to shoot them at real
people. Could the weapons鈥� effects be simulated in a computer, they wondered. No
chance, said Easterly. 鈥淲e don鈥檛 have that much knowledge about the overall
human,鈥� he told them. 鈥淲e have knowledge in bits and pieces, but we don鈥檛 have
integrated knowledge鈥�.
But the enquiry got Easterly thinking about the diversity of modern
biological research. Many of the tens of thousands of journal articles published
each year must impinge on each other, he realised, but they are often considered
in isolation. There鈥檚 no sure way for the implications of one study to be
applied to another. Computer models of human cells, organs and
systems鈥攔anging from the most basic representations to relatively
sophisticated simulations of real biochemistry and function鈥攚ere also out
there, scattered among various academic and commercial laboratories.
The virtual heart developed by Denis Noble at the University of Oxford shows
vividly how useful biological modelling can be (New 杏吧原创, 20 March
1999, p 24). Noble鈥檚 heart is a carefully assembled mass of virtual cells, each
processing virtual sugar and oxygen and behaving just like the real thing. Noble
can watch his virtual heart beating on a computer screen. He can make it develop
diseases, then treat it with virtual drugs. Drugs companies have used his heart
to test for adverse reactions (see 鈥淗eart of the matter鈥�).
Noble is a co-founder of Physiome Sciences, a company that specialises in
modelling human organs and cells for the pharmaceuticals industry. Physiome has
crude but functioning models of dozens of types of human cells, and is working
on building them into complete immune, endocrine and bone systems. It鈥檚
part of a whole new industry that is springing up, offering pharmaceuticals
companies virtual versions of everything from single receptors to multi-organ
systems for testing potential drugs. Entelos, for example, a modelling company
based in the heart of Silicon Valley at Menlo Park, California, specialises in
simulating disease states. Its computer model of asthma includes elements of
every relevant structure and process, from airways to immune cell reactions. If
companies like these, along with academic researchers, could stitch their
efforts together鈥攁nd find a big enough computer to run the resulting
model鈥攁 rudimentary Virtual Human could begin to take shape tomorrow.
But it鈥檚 not going to be easy. On top of the huge technical challenge, there
is a major organisational barrier. Turning today鈥檚 models into a Virtual Human
will involve standardising the way biological information is collected, stored
and shared, since the current models are mostly incompatible. Each represents a
particular scale, from cell to tissue or organ, and is generally incapable of
receiving input from another model. Most of them were custom-designed by their
creators right down to the way they input their data and the programming
language they employ. At present, one model鈥檚 kidney would be deaf to what鈥檚
happening in another model鈥檚 liver. Anyone hoping to assemble the various
simulated organs and systems faces a digital Babel.
But this may be about to change. In March this year, Physiome Sciences
announced that it will allow non-commercial researchers to use its
cell-modelling software free of charge. The company says it wants to help
promote the idea of biological modelling, though researchers who use Physiome鈥檚
software will find there are strings attached. The company gets access to the
researchers鈥� data to improve its own models, and the researchers must agree not
to reveal the company鈥檚 algorithms. Nevertheless, Physiome has already had more
than a dozen applicants, ranging from academic researchers and biotech companies
to a group within the National Cancer Institute and another at the US Department
of Agriculture. While some may fear this raises the spectre that some of
biology鈥檚 most useful information could fall into private ownership, Easterly
welcomes Physiome鈥檚 initiative as 鈥渁 tremendous step鈥�. Anything that makes
biological modelling technology accessible to more researchers is welcome, he
says.
Easterly, Allgood and their colleagues at Oak Ridge have been hoping that
government agencies will fund the infrastructure work, such as establishing
standard data formats and programming languages. They would like to see a more
complete and realistic model than can be built with the crude commercial models.
But the scale and ultimate expense of the Oak Ridge ideal seems to alarm those
holding the public purse strings. Modelling the whole human body will mean
dealing with billions of megabytes, much more data than has come out of the
Human Genome Project. 杏吧原创s are still struggling with the glut of genome
data, so government agencies are reluctant to embark on an even more ambitious
venture.
Meanwhile, Physiome Sciences is forging ahead. 鈥淲e鈥檙e not going to wait for
them,鈥� says CEO Jeremy Levin. But he insists this doesn鈥檛 signal another
genome-style race between private enterprise and a publicly funded effort, not
least because no single company could possibly afford to build its own Virtual
Human. If a public version ever gets going, Physiome Sciences will 鈥渃ommit
heavily鈥� to it, Levin adds.
Whoever funds the Virtual Human, it won鈥檛 be much use to researchers unless
they can interact with it in a way that makes instant sense. Oak Ridge computer
engineers are already working on this. For starters, they are building a Virtual
Human portal鈥攁 website to act as a door to the model from the outside
world. The idea is that researchers will sit at their own computer terminals and
see, for example, how the Virtual Human鈥檚 blood pressure responds to being given
varying doses of a particular drug.
Eventually, things could get much more ambitious. The developers hope to pipe
the Virtual Human鈥檚 output into a total-immersion environment in which
researchers can explore inside the body. The idea is based on systems already
being developed as training and diagnostic tools for doctors. The user wears
goggles that create the impression of a 3D environment from images projected
onto four walls. Eventually, the images will respond to touch. 鈥淭his
allows you to get a real close-up feel of what鈥檚 happening with the data and
interact with it,鈥� explains Oak Ridge engineer Richard Ward.
Stepping into the immersion chamber, researchers could embark on a 鈥渇antastic
voyage鈥� into a single cell, use a haptic wand to poke a ribosome or just move
some molecules around to see what happens. Others could wade into an
artery and watch close-up how tissue properties and the fluid dynamics of blood
change in response to some simulated stimulus. A surgeon might prefer to stay
outside the body and try a new procedure to see how the Virtual Human copes.
And, of course, military researchers will be eager to shoot it with virtual
versions of their experimental weapons to see what damage they do.
But perhaps the most exciting prospect is that the Virtual Human may give us
new and unexpected insights into the way our bodies work. When biologists
program in some new observations about the pancreas, say, it might influence
parts of the Virtual Human that no one had ever guessed would be affected, such
as the lungs or the heart. The answers to mysterious medical problems could
emerge every time the model is examined or altered, Easterly believes.
The Virtual Human could also be customised to isolate the effects that drugs
have on different individuals, allowing researchers to investigate the influence
of sex, age, racial background or any other factor, without the need for
elaborate, time-consuming and expensive clinical trials. With that technology in
place, Easterly says it should eventually be possible to create a virtual
version of every one of us, tailored to our individual genome, medical history
and other specifics.
But even the most ambitious modellers are steering clear of one important
organ: the brain. 鈥淭here is every possibility of modelling a human neuron, and
perhaps a cluster of neurons,鈥� explains Levin, 鈥渂ut modelling the human brain is
outside the realm of our reality.鈥� As long as they model the brain鈥檚 basic
outputs鈥攖he autonomic nervous system and endocrine signals, for
example鈥攖he researchers believe the body will still function normally.
The Virtual Human promises to be a revolutionary tool. Once biologists get a
taste of the advantages to working 鈥渋n silico鈥�, Easterly believes demand will
escalate, continually improving the model and encouraging more researchers to
use it. Eventually, he says, many scientists will wonder how they ever lived
without the Virtual Human.
Perhaps it鈥檚 for the best that the Virtual Human will be devoid of brain
power. As it vomits up new antibiotics, takes a hail of bullets in the chest,
and develops a particularly nasty skin cancer, it can do without the added
burden of realising what a rotten day it鈥檚 having.
When pharmaceuticals giant Hoffman-LaRoche was putting its heart drug
mibefradil through clinical trials in 1997, a blip appeared in the
electrocardiograms of some subjects. It looked like a cardiac malfunction known
to be lethal. Fearing the drug might never make it to market, the company turned
to Physiome Sciences鈥� virtual heart.
Denis Noble, Physiome鈥檚 co-founder and a physiology professor at the
University of Oxford, spent decades developing the heart model, along with
collaborators Raimond Winslow of Johns Hopkins University and Peter Hunter at
the University of Auckland. When Noble 鈥渁dministered鈥� the drug to his virtual
heart, it too experienced the blip, and he was able to trace it back through the
simulation to a benign phenomenon unrelated to the deadly condition they feared
it revealed. The US Food and Drug Administration accepted Noble鈥檚 explanation of
the anomaly and went on to approve the drug.
But that鈥檚 not the end of the story. A year later, new data showed that
mibefradil was interfering with certain liver enzymes, creating a risk that
other medication might build to dangerous levels within a patient鈥檚 body. The
FDA threatened to rescind mibefradil鈥檚 approval, and although it is still
available elsewhere, Hoffman-LaRoche voluntarily withdrew it from the US market.
Had Noble been able to link his heart model with a liver model鈥攁s in a
virtual human鈥攖he problems with mibefradil would have shown up before it
reached any real-world trials.