Blakeslee, Sandra. "Some Biologists Ask ĎAre Genes Everything?" New York Times, 2

Blakeslee, Sandra. "Some Biologists Ask ĎAre Genes Everything?" New York Times, 2
September 1997, pp. C1, C-8.

FIFTY-THREE years ago, the physicist Erwin Schrodinger wrote a book called "What is Life?"
in which he posed some of the deepest questions then imaginable about biology: What is the
"substance" of heredity? When is a piece of matter said to be alive? What kind of process
perpetuates genes?

A generation of young scientists read the book, fell madly in love with the grand pursuit of
biology and went on to unravel the secrets of DNA, to develop methods for a commercial
biotechnology and, within the last decade, to begin spelling out the molecular sequence of every
gene in the human body.

Theirs is a triumph of reductionism - the attempt to describe all biological processes by
examining them in excruciating detail. The biologists believed that by identifying and studying
individual genes, they could learn all there was to know about the human body, including all its
diseases, personality quirks and, ultimately, death.

But, as a growing number of scientists are coming to believe, the search through the cornucopia
of chromosomes is rushing headlong into a brick wall.

"Knowing the sequence of individual genes doesn't tell you anything about the complexities of
what life is," said Dr. Brian Goodwin, a theoretical biologist at Schumacher College in Devon,
England, and a member of the Santa Fe Institute in New Mexico.

"A gene makes a protein and that's about it " Dr. Godwin said in a recent interview. "It doesn't
tell you how proteins interact, how cells and tissues communicate, how organs come into being,
how an immune system forms, or how evolution works."

Dr. Goodwin, who occasionally hangs his hat at the Santa Fe institute in New Mexico, is one of a
relatively small number of theoretical biologists who specialize in devising new biological
concepts beyond the level of individual genes. As such, he often finds himself pitted against the
vast majority of biologists who are experimentalists and who insist that any new concept, to be
worthwhile, must be testable using current laboratory methods rather than the computer
simulations or other techniques he uses to devise his theories. But most people have hardly heard
of the field, he grumbled. What people hear about on television or read about in newspapers is
that a gene has been discovered for thrill seeking, alcoholism, sociability, homosexuality -
complex behaviors that could not possibly be explained by a single gene mutation.

This "genocentric" view of biology, is both misleading and dangerous, Dr. Goodwin said,
because it engenders simplistic thinking, which prompts social acceptance of genetic
determinism and turns personal responsibility into genetic destiny "I'm not guilty, Your Honor,
my genes made me do it!"

The alternative to reductionist and genocentric thinking is called wholism, said Dr. Scott Gilbert,
a developmental biologist at Swarthmore College in Pennsylvania. Wholists believe that the
whole is greater than the sum of its parts; even if you know all the properties of each part, you
will still not understand the whole because something is missing, he said. That something
includes special properties that emerge from the interacting parts that, in turn, affect the whole.

Proponents of reductionism are unabashed by such criticism. Modern biology has produced
stunning successes using its reductionist approach, said Dr. Lewis Wolpert, a professor of
anatomy at University College London in England. The notion that so-called emergent properties
are required for understanding living organisms is "a bunch of yak, all talk and nothing more," he

Dr. Wolpert helped air the debate between reductionists and wholists last May during a
conference he organized called "The Limits of Reductionism in Biology." Last fall, leading
molecular biologists met in Santa Fe to ask the question, "After the Genome, What Next?"

At both forums, experimentalists, who make up the vast majority of biologists, argued with
theoretical biologists - a small but vocal band of wholists - about what are the "appropriate levels
of explanation" for understanding life processes.

"All the talk about the need for different levels of organization offers us absolutely nothing," Dr.
Wolpert said in an interview.

"People say there are 100,000 genes in each cell and how are we going to integrate all that
information? Well, it's going to be jolly hard, but I don't think we need a new science to do it.
Reductionism continues to be amazingly productive. We don't have all the details but the
principles are absolutely clear."

Dr. Sydney Brenner, a biologist at the Molecular Sciences Institute in San Diego, calls himself a
"practical reductionist," one who reduces information whenever possible. "Biology gets so
complicated and our brains are so linear that there are problems we probably cannot answer with
reductionism," Dr. Brenner said. "But I like to treat these problems like income taxes. While you
cannot evade them, there are legal means to avoid them."

This is possible, he went on, by using advanced research tools that include computers to find
patterns among genes and fluorescent dyes to light up those genes that are active in any given
cell, and comparing the genes of different animals to see how genetic information was swapped
in the course of evolution.

Scientists are learning, for example, that the genes of cows, dogs, rats, people and all other
mammals are extremely similar. What makes each animal different is how the genes are parceled
and lined up within chromosomes. Studying these differences and their effects may be
genocentric and reductionist, he said, but it should lead to new knowledge about gene functions
and gene interactions.

But theoretical biologists argue that these methods are not necessarily going to solve the problem
of understanding life. Reductionism has been incredibly useful - indeed indispensable - but it will
not serve the next level of inquiry, they say.

"Learning about the genome for its own sake as a means of understanding biological processes is
like learning a language by memorizing a dictionary," said Dr. Claudio Stern, a biologist at
Columbia University in New York. "You have all the pieces but you are missing the rules. This
does not mean that the dictionary is useless. But when do you come to understand a system? Is it
when you understand all the components or understand how the components interact?"

The idea that the whole is greater than the sum of its parts is as true in physics as it is in biology,
said Dr. Stuart Kauffman, a theoretical biologist at the Santa Fe Institute. Individual atoms and
molecules do not exhibit temperature, he said, but temperature emerges from the interaction of
many molecules. It is a collective phenomenon, the property of the whole and not the individual
parts. Similar kinds of collective phenomena are a hallmark of biological systems, he said.

Thus, theoretical biologists are asking a new set of post-Schrodinger questions that are less
amenable to reductionist solutions. How does the body act as an integrated whole? What is the
dynamic context in which the genes are acting? What are the emergent properties of organisms
and how do they arise in evolution?

In developing a new theory of "what is life," wholists begin with the notion that organisms must
be understood as dynamic systems in which genes play a significant but limited role, Dr. Gilbert
said. As organisms develop, both as single embryos and as players in evolutionary change, they
are influenced by internal and external forces that are only beginning to be understood.

For example, people are realizing that genes are not autonomous agents but rather they work as
assemblies, Dr. Gilbert said. "What is inherited is not so much a gene but a network of genes and
their products," he said. "What any given gene does depends on the context in which it finds

This lesson is brought home by so-called knock-out experiments. Scientists typically select a
gene that is critical for normal human development or health, find its counterpart in a mouse,
knock out that gene from mouse embryos and stand back to see what happens. More often than
not, Dr. Gilbert said, the mouse is perfectly healthy, which goes to show the complexity of gene
interactions. There is quite a bit of redundancy among genes and if one is mutated, another takes
over. "This is when you realize the extent of genetic networks," he said.

The environment exerts powerful influences on developing organisms, Dr. Goodwin said. In a set
of classic genetic experiments, researchers exposed fruit fly embryos to X-rays or toxic chemicals
and found that some flies wound up with four instead of two wings, he said. But these so-called
genetic mutations could I replicated exactly by exposing the fly embryos to an environment;
stress like heat. Thus, there is no difference between an environmental and a genetic disturbance,
D Goodwin said. Both funnel throng the same developmental pathway and it is those pathways,
which al still not well understood, that hold the secrets to physiology.

"We need to discover what bring about changes in form," Dr. Goodwi said. There are a few good
candidates. One is the cytoskeleton or scaffolding that give s internal strap to embryonic cells. As
these cell proliferate, they change shape frog spheres to sheets to folds that buckle back on
themselves to begin forming tissues and organs. The cytoskeleton is driving many of these shape
changes, he said, with the help of .a kind of glue, called cell adhesion molecules, that determines
the stickiness of each cell. When cells migrate adhesion molecules let them go of hold them
back, again using rule. that remain to be discovered, Dr. Goodwin said. While genes may hell
produce the proteins that make the skeleton or the glue, they do no determine the shape and form
of at embryo or an organism.

Another force, called a morphoge.netic field, causes cells to migrate one way, tissues to fold up
another way, and organs to develop differently in different animals, Dr. Goodwin said. "It's like
origami, the Japanese paper-folding game," he said. "There are only a few simple rules for
folding paper, but an infinite variety of forms can be made using these rules and following
different folding sequences. The same is true for building organisms. Simple rules are constraints
that early on give rise to basic body plans and then to complex additions." For example, he said
they may go on to form tentacles trunks or tails.

These rules or folding patterns for developing organisms can be modeled in computers, Dr.
Goodwin said. As "cells" interact, they fall into networks that cooperate to carry out functions,
mimicking what real organisms do. In this way, the researchers are looking for nongenetic forces
that drive development and evolution.

Similarly, adult organisms contain genetic regulatory networks, Dr. Kauffman said. Such a
network is the integrated, collective behavior of thousands of genes and the proteins they make
within cells, tissues and organs. The new paradigm is to think about these networks not one gene
at a time but as the simultaneous activity of thousands of genes, Dr. Kauffman said. "We don't
need to know all the details of the wiring diagram," he said, to find the biological equivalent of
temperature or pressure.

In terms of evolution, the coding region of a gene - the part that makes a structural element like
collagen or hemoglobin - is not as important as its regulatory or transcription regions, Dr. Gilbert
said. Regulatory regions determine when and where the gene is expressed, and when they are
rearranged, new genetic regulatory networks - and new organisms - arise. Again, an individual
gene is less important than the network in which it operates.

Dr. Goodwin said the emphasis on reductionism had not been good for society. "We need to
develop a new way of doing biology by going beyond the gene and cultivating intuitive ways of
knowing about wholes and about organisms," he said. "We live in a world of relationships that is
very different from the manipulative world of science.

"According to current biology, genes determine organisms, and organisms are simply accidental
collections of genes that are functionally useful to us human beings. Therefore, it is perfectly
legitimate to. change the genetic composition of an organism to suit our needs. We can create
chickens or turkeys with enormous amounts of breast meat, even though these animals cannot
reproduce and cannot live a normal life It's O.K. to change them this way.

"But such things are deeply wounding to our relationship with the natural world and with each
other because it means turning everything in life into a commodity. It encourages me to think of
you as just a bunch of cells or genes. These all have potential commercial value and to me, that's
suicide. Organisms are not merely survival machines. They assume intrinsic value, having worth
in and of themselves, like works of art."