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00:01 Okay, so this is neuroscience lecture and last lecture. We talked about

00:08 neuronal membrane potential oppressed, arresting membrane , and we discussed several very important

00:19 that air summarized on the slide here front of you. So on the

00:25 left, what we reminded ourselves is arms law, which is V equals

00:36 voltage, be I current. Our and G is equal. The inverse

00:45 resistance and G is conduct INTs. we said that across plasma membrane,

00:52 have separation off charge where there is lot off negative charge accumulated on the

00:59 of the cytoplasm and positive charge accumulated the outside of the number. So

01:05 of the charge exchange that happens fast flow across plasma membrane that happens,

01:15 across the plasma membrane. And we about the fact that the inside of

01:20 Sella's well as surrounding environment outside or away from the plasma membrane they charge

01:29 environments. There is equal amount of and positive charge, but the separation

01:35 charge across plasma number it's creates a of about minus 65 million volts,

01:42 that the inside of the cell is million volts negatively charged compared to the

01:50 of the cell. We talked about there are building blocks and the cells

01:56 all of the proteins. And these blocks are illustrated here on the

02:03 here in the middle, amino assets polit peptide bonds, forming secondary tertiary

02:11 . Ordinary structures informing what we call proteins or trans membrane proteins.

02:21 that will conduct the ions of interest us on this, conductors of ions

02:27 a very fast but a very selective . And so we talked about.

02:32 reason why we need fast things is there is quite a bit that

02:38 that needs to be done reflexively. we talked about a very simple Patel

02:46 reflects. We discuss the types of involved in the circuit after and sensory

02:54 root ganglion through the you know, AF parents that are excited Torrey onto

02:59 multipolar motor neuron south that are excited onto the muscle south. And we

03:04 that single synapse una synoptic circuit activation the quadriceps muscle spindle through the appearance

03:15 through the motor neuron e ference from spinal cord proper back into the extensive

03:22 is one synapse process. However, also discussed the fact that you would

03:29 Thio for this reflex and for the of the lower leg during the patella

03:35 reflex test for the proper movement that leg you would want the relaxation of

03:40 opposing hamstring flexor muscle. And that through the process off bifurcation of the

03:48 affair in In the spinal Cord, one contacts the motor neuron, one

03:56 of the contacts of motor neuron and motor neuron and the other part splits

04:05 contacts that inhibitory Interneuron is here, in black and the proper spinal cord

04:11 inhibitory Interneuron is that in turn, that motor neurons and inhibition of motor

04:18 allows for the relics ation of the muscle and therefore the proper reflexive movement

04:25 the leg during the patella tendon We talked about the fact that through

04:31 channels that are selective, you have flow of a lot off ions and

04:38 ions air surrounded by waters of and they get stripped of these water

04:45 as well as they interact with. mean acid residues typically and uh,

04:52 the sodium and for the potassium, would be negatively charged amino acid

04:57 Um, for the on ions would a positively charged them. You

05:02 acid residue that it will interact with ion inside the inner channel. Luminant

05:09 essentially allow for the propulsion off the , in this case of sodium from

05:14 of salted inside of itself. But channels will select for sodium. These

05:19 will select the potassium. They'll they'll their selective ions that they only passed

05:25 . But at the same time, discuss that there are channels and we'll

05:29 into them a little later, such gloom it receptor channels that ah,

05:33 of the passage of multiple clients. for the purposes of discussing the arresting

05:39 potential on the action potential generation, going to talk about sodium and potassium

05:48 channels that are actually voted voltage gated losses you will learn. So that

05:54 that these channels, the opening of channels in the flow of the ions

05:58 be influenced by several things. And of those things is a change of

06:02 . Across plasma membrane and other things a neurotransmitter, a chemical ligand binding

06:08 the channel on opening off that podium channel. Now on the right here

06:14 the bottom is a t p a showing that, uh, it acts

06:21 concentration radiant by consuming energy. And is a much slower process than the

06:26 INTs off fast conduct its of ions these channels. We further talked about

06:32 fact that we have diffusion radiance, we also have electrical attraction forces and

06:42 port forces. So we discussed for example, each ion is not

06:51 Lee flowing across plasma membrane down its radiant. But in fact, it

06:58 also once in this case, we potassium once. If you have a

07:03 channel over here and you have a of that potassium channel, there's a

07:08 of potassium on the inside of the illustrated by K plus large red

07:13 and that potassium will flow across uh, membrane across the channel.

07:19 you would think that it would flow there's equal amount of potassium on both

07:26 . On the inside of the cell well on the outside of the

07:29 But that is not the case, , as the charge flows, is

07:33 positive charge flows across plasma membrane again very close to the plasma membrane.

07:41 this positive charge accumulating close to the membrane results now into in the in

07:48 electrical force in the electrical force that a rip all repulsing that sand positive

07:56 and therefore you reach the equilibrium potential equilibrium. Potential is where you have

08:04 diffusion all or the Grady in the ingredient forces driving ion across this direction

08:13 gets counteracted by electrical forces driving the in the opposite direction and is illustrated

08:20 of the bottom right. What you is at some point these forces are

08:27 to each other and that there's no ion flow. But there's also no

08:34 Grady int that neutrality in the sense there's still a lot more potassium that

08:40 on the inside of South. so each one of these ions has

08:48 certain, uh, concentration radiant. it also has an electrical force of

08:57 , and these forces, determined based the concentration, radiant and based on

09:02 channels that are open, will determine Librium potential for individual ions and each

09:09 ion will have its own driving What? I mean by that year

09:14 number three, I only driving forces M minus e. Ion. That

09:21 for D. M stands for membrane , and e ion stands for equilibrium

09:28 for at that particular ion equals a force, meaning the greater the difference

09:36 the overall membrane potential and you'll like, What does he mean?

09:39 ? We're talking about this one eye , but you learn that the membrane

09:44 is not determined. Just attacked by . VM represents the species of ions

09:51 we already discussed primarily sodium and potassium part chloride, a small part god

09:59 . Okay, so VM actually represents number of ions where E ion represents

10:05 a single ion such as potassium. now we have to learn how to

10:11 these ionic reversal potentials. And that's we ended up talking about. Way

10:17 about potassium, who said the same stands for sodium, so there is

10:22 lot of sodium on the outside, you open the channel. Sodium will

10:25 on the inside of the cell, as soon as this positive charge accumulates

10:29 the inside of the plasma membrane that actually start pushing back on the positive

10:35 coming from the outside of the cell will reach equilibrium potential. Ah,

10:41 how do we calculate the equilibrium And we talked about the fact that

10:45 know the concentrations off ions. We the concentrations off ions inside plasma

10:53 potassium, sodium, calcium chloride. know the concentration on the outside.

11:00 know the concentration on the inside for of these four islands. We can

11:05 simplify this concentration into the ratio of outside vs inside. So, for

11:12 , in the stable for potassium, have five million Mueller on the inside

11:17 and note that the table that that graph below shows three million Mueller right

11:22 here, where we're talking about the of the plasma membrane in parenthesis that

11:27 list three mil Imola. So there a disparity. There's a disparity in

11:32 textbooks. There is a disparity in south. There is a disparity in

11:36 exact numbers and during the tasks, will not be tricked into a question

11:43 the exact number. But rather the are correct calculated calculation or correct ratio

11:52 these specific ions on the inside versus outside. So for potassium, you

11:56 a lot of potassium on the 100 million Moeller, and you have

12:01 very little potassium on the outside of South. 3 to 5 million

12:06 Let's say 3.5 to $5 million about to 20 ratio Outside, vs

12:13 and look at the sodium is just opposite. There is a lot more

12:16 times more sodium on the outside than is on the inside of the

12:22 Note that we said that for there's greatest disparity in the concentration

12:28 10,000 times more calcium on the outside the south compared to the inside of

12:33 south, giving calcium probably one of highest concentration ingredient driving forces to cross

12:44 the outside into the inside of the , we discuss how tightly regulated it

12:48 on the inside of the south, you don't have that much of the

12:52 floating side of solid calcium bouncing around nothing. Chloride again ratio is a

12:58 more chloride. 11 times more chloride the outside is compared to the inside

13:03 yourself and now in this table, also in the diagram below you have

13:08 equilibrium potentials for each ion. So on and you have e n a

13:14 56 million volts BK minus +102 chloride 76. Now notice also that the

13:22 minus 80 in the table for potassium match the numbers of potassium shown that

13:29 diagram minus 102. And that's the why I cannot ask you What is

13:34 Russell potential for potassium? Is it 85 minus 80 minus 90 minus one

13:40 two. It would be unfair of to do that because the actual text

13:45 and different South's because of different concentrations different cells are slightly different reversal,

13:52 or equilibrium ionic potential values because they slightly different concentrations of violence. Uh

14:01 . So again, you have to that they do have each,

14:06 reversal potentials. You have to remember values approximately of these reversal potentials or

14:13 equilibrium potentials. I use reversal potentials ionic equilibrium potentials interchangeably. Uh,

14:21 have to remember those values, but , minus 65 minus 70 for

14:28 let's say calcium plus 120 approximately for plus 50 plus 62 for potassium minus

14:38 minus 19 maybe even minus 100. you see, there is enough disparity

14:43 you to know that potassium ical liberal minus 80 is below chloride, which

14:49 minus 65. Okay, and that's point. And if I ask you

14:53 , is to make that particular point that is important for what we're about

14:57 talk about in this lecture nerds equation the equation that you used to calculate

15:04 reversal potential that you used to calculate Ionic equilibrium potential nerves equation is the

15:12 E For an individual, ion is 2.303 R T over ZF. Log

15:24 ion concentration on the outside of the over ion concentration on the inside of

15:31 south, where the ion is our potential or our equilibrium potential. R

15:39 for gas. Constant mhm t is temperature, and that's why in the

15:47 slide, you saw 37 Celsius because a physiological body temperature, so temperature

15:54 important in calculating biology reversal potential Z for the violence. Charge off the

16:02 or the violence f iss, or electrical constant in this case and

16:09 based on longer rhythm. I on outside the South. I am out

16:19 , and ion concentration on the inside the South. Yeah. So this

16:25 the formula that now you can plug a sodium ion where you have ion

16:31 , concentration on iron, inside concentration you have some constants that they don't

16:40 . Okay, Yeah, temperature was with your calculating in a physiological

16:50 And you have different concentrations of of course, and you have different

16:54 for these ions e plus one versus plus and so on. So what

17:02 says is the nurse equation can be from the basic principle of physical

17:08 Let's see if we can make sense it. Remember that equilibrium just that

17:15 talked about for the last few Equilibrium is the balance of two

17:22 Diffusion. That's the concentration, chemical, radiant and electricity which opposite

17:31 attract and same charges to repel each . Increasing the thermal energy of each

17:37 increases diffusion and will therefore increase the , Uh, potential difference achieved that

17:47 . That's equilibrium foran eye on is to teeth. There's there's more movement

17:56 warmer temperature. The hotter temperature on it had increasing. The electrical charge

18:01 each particle will decrease the potential difference to balance the fusion. Therefore,

18:11 equilibrium of this island is inversely proportional the charge off the ion bail and

18:20 . We need not worry about r F in the nurse equation because they're

18:26 . So we go back to the temperature 37.7 star 37 C. Everybody

18:34 checking their their temperature these days because coded. So you should know 36.6

18:43 degrees centigrade is normal physiological body temperature humans. The nurse equation for these

18:51 isles that we already know these air main, most important players for us

18:59 , sodium chloride and calcium. Now is we're gonna scroll back up and

19:09 gonna walk through the calculations for different . So if you take 2.303 our

19:24 , you simplify it to 61 54 get Mila balls. We're not gonna

19:34 through all of the details, but is a simplification of 61 54 million

19:38 . If you plug in, positive valin c f r t the

19:45 temperature. Physiological. Remember, we're at it both. Okay, So

19:55 TCF 2303 you can collapse into 61 million volts. Log of potassium outside

20:04 inside. The same goes for sodium 54 million volts. Log sodium and

20:12 vs. Inside. The sign for 54 million volts. Changes to negative

20:20 balls because you're plugging in chloride and has negative minus one violence. And

20:33 rtz f this the you remain the Constance for our for gas constant and

20:43 Faraday Electrical constant the same temperature. when you calculate for calcium, the

20:51 is two plus So that same instead being 61 54 mil of also abbreviation

21:00 30.77 It's half of that, Artie, divided by two time.

21:08 divided by two times Faraday's constant. therefore, in order to calculate the

21:15 potential for a certain type of the body temperature, we need to

21:20 the only concentration on either side of membrane. So we know that,

21:26 you should wonder how we know But it started out by people squeezing

21:32 ions from large Axiron such as, , such as a giant squid

21:41 But here I look at the, when I was just my windows so

21:44 don't look at me as much, look at the formula instead. Look

21:50 the RTZ f and look at the outside vs inside. Now you'll

21:57 like, wait a second. Where the concentration now, if you

22:01 I told you that in this formula can actually plug in either the actual

22:07 of these ions. Okay? Or can plug in the ratio off.

22:16 concentrations are side versus and says the thing if you put five over 10

22:24 100 versus 1/20. Okay, so this calculation, below in the following

22:30 is what is being used are the . So we know that there is

22:35 lot more potassium 20 times more potassium the inside of the cell versus the

22:41 of self log 1/1 20 gives us 1.3. Therefore deliberate on potential or

22:52 reversal potential for potassium equal 61 54 volts times negative 1.3 equals minus 80

23:01 volts. Notice. So now you . Now you can understand where this

23:10 comes from, where these calculations for potential comes for sodium, for

23:19 for Florida and calcium. You can this new Ernst equation and learns equation

23:25 for single ion, and you can in these ratios of ions outside vs

23:32 , and you will get similar if not the same numbers that are

23:37 in the slide above. Okay, this is how we calculate individual ion

23:44 potential. But notice that there's no in the nurse equation for permeability or

23:52 conduct INTs. So while it is into consideration the chemical and electrical

24:04 it is not taking into consideration a important point for the membrane and for

24:11 islands across the membrane. Is Is membrane permeable? Does that mean?

24:19 these channels for these specific islands thus calculating the value equilibrium potential Forgiven

24:28 does not require knowledge of the selectivity the permeability of the membrane for the

24:34 . You'll see what does that That means and implies a different aisles

24:39 different permeability across plasma membrane. The ions are favored by the membrane to

24:48 , whether it's inside or outside, on the conditions and the charge that

24:52 across plasma membrane, there is an potential for each island, the intracellular

24:58 extra salary with fluid. The equilibrium for each ion is a membrane potential

25:04 would just balance the aisles concentration radiant that no net ionic current would flow

25:10 the membrane were permissible to that So now we have to move onto

25:18 next equation, which is the Goldman . Mhm and Goldman. Equation is

25:26 from the Ernst equation because in Goldman , if you notice if the membrane

25:33 a really learn were permissible, only potassium, the resting membrane potential,

25:38 equal the equilibrium potential for potassium. agree. If you have all of

25:48 ions on two sides of the you have sodium chloride, potassium,

25:53 , But the membrane is only permissible potassium. There's only potassium channels that

25:58 open and Onley along for potassium to through. So guess what happens that

26:03 membrane potential overall numbering potential independently off other ionic species present around the

26:11 The overall number of potential is purely by potassium ion. It's dominated by

26:18 , and such is the case in . That's a great exam question.

26:25 member and potential of glial cells such Astra size is dominated by potash in

26:30 they're mostly permissible to potassium, at the rest. Okay, but

26:36 does not. The measured resting member potential okay of a typical neuron is

26:45 minus 65 million balls. So if point here is that if the cell

26:54 only permissible to potassium, then the member and potential should be minus 80

27:00 be minus 90 or whatever. The of delivering potential minus 100 is given

27:04 potassium, but the resting number and is closer to minus 65 tu minus

27:11 . Why is that? Because there other no other ionic species that these

27:18 are allowing thio flow through the plasma that they're permeable to. So this

27:25 permeability. This discrepancy is explained because neuron address or not exclusively permissible to

27:31 . There's also some sodium from the stated another way. The relative permeability

27:37 the resting neuronal membrane is quite high potassium and low to sodium, addressed

27:45 could be restated at resting. Number potential There is mawr flocks of potassium

27:53 sodium. Now what Goldman equation does below, it's essentially very similar to

28:03 Equation, but instead of taking into concentration off just a single ion,

28:12 actually calculates and combines. The concentrations potassium and sodium is the two most

28:20 ions to most important aisles and influence most off the overall number of

28:28 And it also introduces the permeability P K stands for permeability, for

28:39 from the ability for sodium. And what's interesting is how do you get

28:46 ? Overall, VM, This VM membrane potential not to confuse with E

28:54 or E ion gm. This is . In previous formula unearned situation,

29:04 were calculating equilibrium potential forgiven ion. Goldman equation calculates the membrane potential takes

29:15 consideration more than one island and also permeability. What this is showing is

29:24 rest. The cell membrane is 40 more permissible to potassium than it is

29:31 sodium, 40 times more permissible to than it is to sodium. And

29:37 you now, in this case, of the ratios off concentration of potassium

29:44 mysteries inside. Actually, it's really Mueller values that have plugged in once

29:49 calculate that taking into consideration the high for potassium over sodium through the same

29:59 54 mil of all slog is the abbreviation from nonce equation carries over

30:06 But now it's permeability of two different . The log off that,

30:12 number, which gives you in mind 65 million balls. Eso. This

30:19 how, if you take two ions I. So do you mind a

30:23 in there relative concentration on the outside inside and the permeability? And by

30:29 way, this permeability changes during the potential during the rising phase of the

30:36 potential. In the peak of the potential, the cell membrane is hugely

30:41 by sodium, and it's mostly permissible sodium miles. And that reverses again

30:46 the action potential goes back into the phase to return to the resting membrane

30:52 , where potassium once again becomes the dominant ion blowing across plasma membrane.

31:00 these are the two equations that you to know for the exam. You

31:04 not need calculators, thio calculate, , anything using either nerves to Goldman

31:12 . But you should be able to easily recognize the relative ratios of ions

31:19 relative concentrations of P ions, the ions sodium, potassium chloride, calcium

31:26 well as their who Librium potential and so understand and be able to

31:34 the formulas. Be able thio, identify that. No, this wouldn't

31:37 a correct calculation rather than actually go the calculation yourself using a calculator so

31:43 will not need to do that. you do need to know these formulas

31:47 didn't do need to know what different mean in these formulas on Do you

31:55 to be able to recognize the correct , the correct equilibrium potentials in the

32:00 calculation for the number and potential use equation for this exam for the first

32:09 . Okay, so we have E , which is nursed equation above individual

32:21 , and then we have 61.54 million log is the same abbreviation from Nervous

32:28 , and we have Goldman equation you know. So now remember,

32:38 talked about how important it is. see, if you have different if

32:44 all of a sudden have a lot potassium. That means you change this

32:49 of the potassium on the outside versus inside of the cell and the diagram

32:56 the left shows actually that if you potassium on the outside of the

33:03 you're gonna increase the drive of that . The sellers already addressed Permira ball

33:08 potassium, but now you increase its from 1 to 3 million.

33:13 five million Mueller to 10. Mila on the outside. Look what happens

33:19 the member and potential member and potential resting membrane potential of minus 80 slides

33:26 to about minus 60 minus 55 million with 10 Miller Moeller Potassium concentration

33:37 So this is this is quite If you increase the potassium concentration to

33:43 million Mahler here you are now looking about minus 40 million volts. The

33:50 for action potential generation, as you learn later in this lecture, is

33:54 minus 45 million balls. So this that if there is a local increase

34:03 extra cellular potassium concentrations, the cells of the chemical Grady, include deep

34:12 sufficiently enough to start producing action and that indeed is the case.

34:18 high potassium concentrations using potassium chloride concentrations a very common way to stimulate different

34:26 of cells. To make different types cells, especially electrically charged, sells

34:31 active, and it replicates models of activity and high potassium concentration. Also

34:39 an epileptic model off epileptic activity, when you have too much way too

34:47 of the potassium on the outside of South, the activity is not only

34:54 , not only firing action potentials, it can synchronize to produce abnormal epileptic

35:00 seizures. Uh, so this is introducing another disease very slowly. Epilepsy

35:08 way to replicate epilepsy in the model to use high potassium model for

35:16 It's one of the models for and one of the expressions of

35:22 etc. Are epileptic seizures. They've in many different shapes and forms,

35:30 loss of consciousness to retaining consciousness from jerks to almost unnoticeable changes in motor

35:41 , but very strong changes in emotional and agonizes. Uh, epileptic activity

35:50 the brain would be determined using electrons follow Graeme. We discussed that few

35:55 back where we said that to record activity from the brain. You need

36:01 to follow ground, which records activity the outside of the skull through a

36:06 like structure that has electrodes that pick activity from the surface of the cerebral

36:16 on the right. You have astro here and this Astra side. It

36:20 that if you have at the bottom increases in the potassium concentration on the

36:25 of the south, this Astra side actually slurp it up. Slurp it

36:32 . And as you can see, has a very vast dendritic tree that

36:38 these processes going off and spreading. zig Leo processes is spreading all over

36:45 they're actually spreading this potassium concentration through vast network as well as through the

36:52 of Astra sites that are interconnected with Astra sites. It would be passing

36:57 along to other Astra sites, and Astra sites will be passing it along

37:01 other distal networks, thereby preventing preventing sustained rises and extra cellular ionic concentrations

37:11 just potassium or calcium for sustained rises neurotransmitters. Because, as we discussed

37:18 , also play a significant role in transmission. A swell. So this

37:26 a very interesting story and the stories lead us to understand the science.

37:34 , a lot of it has to with a progression off technologies and science

37:39 general. And this is a story Roderick MacKinnon. Very interesting story.

37:46 you wanna look into it on a level, uh, he is one

37:54 an inspiring near scientists because he was driven by the quest to answer a

38:03 or solve the problem. And this a really good reason to think about

38:12 anything. Really. It's a good Thio even think about every day if

38:21 solving something. If you're driven by a problem, I think you will

38:31 reach your success. If you're not by getting a degree to check it

38:40 for the books, you don't really what to do with that degree.

38:47 that is okay, actually, and is quite okay for undergraduate students.

38:53 not know what they want to do their degree, especially in these very

39:00 times, so But it's important now think about what are the problems in

39:09 world. What are the problems in , what air them knows. How

39:16 I find a solution to a How, How? What is my

39:25 for this solution? And for many , is different. Callings for Roderick

39:33 was an M D medical doctor and successful career in Harvard. There's a

39:41 practitioner, but driven by the quest trying to understand there's a medical doctor

39:50 trying to understand. What do the look like? We describe that you

39:56 these Call it topped I chains of acids being folded secondary tertiary co.

40:02 structures placed essentially into sub units and forming the channels. What does it

40:08 like? How do we solve the ? Can we see a channel?

40:14 talked about that We can have electron and you can visualize synapses. There's

40:22 nanometers across 0.9 point five nanometers in . That does not show you a

40:32 structure that shows you there's a channel . It shows you the receptors there

40:39 you their nuclear transmitter vesicles, but does not show those who receptor or

40:46 channel structures. So how do you that structure when you cannot visualize

40:54 And what Roderick MacKinnon used is he genetic mutations. You would mutate As

41:01 know, you're looking at the Here is an actual, beautiful structure

41:06 he described of the potassium channel. when you're looking at all of these

41:11 rings and all of these different connections , that looks like a very complex

41:17 game. Uh, you realize Wait second. This is actually very

41:23 three dimensional model off a neuron off channel of the potassium channel. And

41:32 , you see that red dot inside , there is an ion crossing through

41:38 channel and all this complex structures amino and these amino acids are coded by

41:46 . And so, if you dio directed muted genesis, that means that

41:54 want to mutate a specific site and use genetic mutations. And he used

42:00 flies that air called shaker flies that a mutation and the mutation was in

42:05 potassium channel. And so that was of the first discoveries. Realizing that

42:11 a second. If you impair both potassium channel, it leads to shaker

42:18 . Shaker flies. Essentially, you think of it as model of convulsions

42:22 tremors. Okay, so now he of the structures with genetic mutations you

42:35 you could, you could you could because you would mutate a certain part

42:41 the channel and it will tell you that part of the channel is responsible

42:47 . But in addition, Thio uh, the mutations he was using

42:54 . So he was monitoring activity of channels. How does one mutation over

42:59 ? It causes the changes in activity this channel, and he was using

43:06 . So there are a lot of toxins in nature and some of these

43:11 actually buying two voltage gated potassium So by doing the mutations by recording

43:19 physiological activity through these channels, the and the flow of potassium through these

43:26 by using toxins which binds toxins will find a very specific binding site on

43:35 beautiful channel. And by targeting a site, it would change the function

43:40 the channel. It would change the of the potassium through this inner

43:44 the channel. So to do Roderick MacKinnon exited out of his active

43:56 medical doctor career and pursued essentially this heavy research scientific work. And it

44:08 based on gene mutation, electrophysiology, toxins and trying to solve the structure

44:18 the channel and he was successful at . But he wasn't satisfied. You

44:25 why? Because he wanted to see channel. He wanted to see the

44:32 . It wasn't enough because this structure you solved, you sold it through

44:40 knowing the genetic code through knowing the of amino acids through knowing the folding

44:48 these amino acids through doing the mutations doing the toxin analysis through recording electrical

44:55 . That does not show you the that helps you derive the structure of

45:02 channel. He was hungry. Thio the channel. So he decides to

45:11 a new career off extra crystallography and extra crystallography, which is a very

45:21 technique where you essentially trap individual trapped these individual protein channels within a

45:29 little crystal. And then you pass ray light through that crystal, and

45:38 the fraction of that light through the and bending of the light through that

45:44 by the pro dam otherwise known bending by the crystal. But now interference

45:51 the protein will actually help you visualize structure of these channels. So from

46:00 D to the lab to do the electric physiological recordings and studies on Shaker

46:08 on potassium channels. Thio predict the off the potassium channels to all the

46:20 . Now where you have visualized potassium using X ray crystallography. And believe

46:27 , if you read his personal people along the way laughed at him

46:32 said, Wait a second. Aren't satisfied as an MD here and

46:37 No. I want to be doing studies here to decide, you

46:41 to do really understand and thio to the, uh, structure of the

46:47 channel. Okay. Also, I'm do electrophysiology, and I'm going to

46:53 all of these mutations. Okay? job. Now, I'm not satisfied

46:58 I want to see the channel. really, really say I want to

47:02 the structure fully? He's looking for . His quest. His solution is

47:07 . Find out. What does this channel look like? How does it

47:12 ? What are the important parts of channel? Whether the important parts of

47:16 channel genetically what are the important parts the channel with interacting with nature in

47:21 toxins? I want to solve this . I want to understand This is

47:27 puzzle off life, and he doesn't jumping from two different locations, three

47:34 locations, three different labs, different , switching from M D, mostly

47:42 researcher. And so, um, , it's the quest. It's a

47:50 . It's a solution for nature's a for a problem. Uh, people

47:57 to see right as you know. , for example, Yuan Mosque

48:05 uh, you know, to go Mars so he can see security,

48:14 see what is happening there. so that's the quest that he is

48:25 on. A lot of people are his quest because of that,

48:32

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